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Son J, Accili D. Dedifferentiation as a Stealthy Disruptor of β-Cell Function in Diabetes. J Clin Endocrinol Metab 2025; 110:e2096-e2097. [PMID: 39257186 DOI: 10.1210/clinem/dgae624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/12/2024]
Affiliation(s)
- Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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Wang LK, Kong CC, Yu TY, Sun HS, Yang L, Sun Y, Li MY, Wang W. Endoplasmic reticulum stress and forkhead box protein O1 inhibition mediate palmitic acid and high glucose-induced β-cell dedifferentiation. World J Diabetes 2025; 16:95431. [DOI: 10.4239/wjd.v16.i5.95431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 01/13/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Type 2 diabetes mellitus is characterized by pancreatic β-cell dysfunction and insulin resistance. Studies have suggested that β-cell dedifferentiation is one of the pathogeneses of β-cell dysfunction, but the detailed mechanism is still unclear. Most studies of β-cell dedifferentiation rely on rodent models and human pathological specimens. The development of in vitro systems can facilitate the exploration of β-cell dedifferentiation.
AIM To investigate the molecular mechanism of β-cell dedifferentiation. Hence, an in vitro model of β-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1 832/13 cell line.
METHODS The study was further analyzed using RNA-sequencing, transmission electron microscopy, quantitative real-time polymerase chain reaction and Western blot.
RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulated β-cell forbidden genes and endocrine precursor cell marker genes, and down-regulated the expression of β-cell specific markers. Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum (ER) stress-related genes. Moreover, the results also showed that forkhead box O1 (Foxo1) inhibition potentiated genetic changes in β-cell dedifferentiation induced by palmitic acid and high glucose.
CONCLUSION ER stress is sufficient to trigger β-cell dedifferentiation and is necessary for palmitic acid and high glucose-induced β-cell dedifferentiation. Foxo1 inhibition can further enhance these phenomena.
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Affiliation(s)
- Li-Kun Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Chu-Chu Kong
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Hui-Song Sun
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Lu Yang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ying Sun
- Department of Equipment and Materials, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ming-Yu Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
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Kang F, Zhang Z, Fu H, Sun J, Zhang J, Wang Q. β-Cell Dedifferentiation in HOMA-βlow and HOMA-βhigh Subjects. J Clin Endocrinol Metab 2025; 110:e1430-e1438. [PMID: 39133811 PMCID: PMC12012814 DOI: 10.1210/clinem/dgae538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 09/12/2024]
Abstract
CONTEXT β-Cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo β-cell function in human remains unclear. OBJECTIVE The present study was designed to investigate whether β-cell dedifferentiation in situ was closely associated with β-cell function in vivo and to identify targets crucial for β-cell dedifferentiation/function in human. METHODS We acquired homeostasis model assessment of β-cell function (HOMA-β) values, calculated the number of hormone-negative endocrine cells, and evaluated important markers and novel candidates for β-cell dedifferentiation/function on paraneoplastic pancreatic tissues from 13 patients with benign pancreatic cystic neoplasm or intrapancreatic accessory spleen. RESULTS Both the β-cell dedifferentiation ratio and the dedifferentiation marker (Aldh1a3) were inversely related to in vivo β-cell function (HOMA-β) and in situ β-cell functional markers Glut2 and Ucn3 in humans. Moreover, the islets from HOMA-βlow subjects were manifested as (1) increased β-cell dedifferentiation ratio, (2) enriched dedifferentiation maker Aldh1a3, and (3) lower expression of Glut2 and Ucn3 compared with those from HOMA-βhigh subjects. We found that basic leucine zipper transcription factor 2 (Bach2) expression was significantly induced in islets from HOMA-βlow patients and was positively correlated with the ratio of β-cell dedifferentiation in humans. CONCLUSION Our findings emphasize the contribution of β-cell dedifferentiation to β-cell dysfunction in humans. Bach2 induction in β-cells with higher frequency of dedifferentiation observed in HOMA-βlow subjects reinforces its distinctive role as a pharmaceutical target of β-cell dedifferentiation for the treatment of people with diabetes.
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Affiliation(s)
- Fuyun Kang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhuo Zhang
- Department of Surgery, Shanghai United Family Hospital, Shanghai 200021, China
| | - Hui Fu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiajun Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qidi Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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Wang YN, Liu S. The role of ALDHs in lipid peroxidation-related diseases. Int J Biol Macromol 2025; 288:138760. [PMID: 39674477 DOI: 10.1016/j.ijbiomac.2024.138760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 12/16/2024]
Abstract
Lipid peroxidation presents the oxidative degradation of polyunsaturated fatty acids lincited by reactive species. Excessive accumulation of lipid peroxidation byproducts, including 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), causes protein dysfunction and various illnesses. Aldehyde dehydrogenases (ALDHs) catalyze the metabolism of both endogenous and exogenous aldehydes. These enzymes participate in detoxification and intermediary metabolism. Contemporary research has affirmed the involvement of both enzymatic and non-enzymatic pathways of ALDHs in modulating the evolution of diseases associated with lipid peroxidation. This review provides an overview of the biological functions and clinical implications concerning the enzymatic and non-enzymatic pathways of ALDHs in diseases related to lipid peroxidation, such as, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2DM). Furthermore, the activators or inhibitors of ALDHs represent a promising therapeutic strategy for lipid peroxidation-related diseases.
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Affiliation(s)
- Ya-Nan Wang
- Department of Implantology & Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong 250012, China; Suzhou Research Institute, Shandong University, Suzhou, Jiangsu 215123, China
| | - Shiyue Liu
- Department of Implantology & Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong 250012, China.
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Ducote MP, Cothern CR, Batdorf HM, Fontenot MS, Martin TM, Iftesum M, Gartia MR, Noland RC, Burk DH, Ghosh S, Burke SJ. Pancreatic expression of CPT1A is essential for whole body glucose homeostasis by supporting glucose-stimulated insulin secretion. J Biol Chem 2025; 301:108187. [PMID: 39814231 PMCID: PMC11849070 DOI: 10.1016/j.jbc.2025.108187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/27/2024] [Accepted: 01/09/2025] [Indexed: 01/18/2025] Open
Abstract
Pancreatic islet β-cells express the Cpt1a gene, which encodes the enzyme carnitine palmitoyltransferase 1A (CPT1A), an enzyme that facilitates entry of long-chain fatty acids into the mitochondria. Because fatty acids are required for glucose-stimulated insulin secretion, we tested the hypothesis that CPT1A is essential to support islet β-cell function and mass. In this study, we describe genetic deletion of Cpt1a in pancreatic tissue (Cpt1aPdx1-/-) using C57BL/6J mice. Islet morphology, β-cell transcription factor abundance, islet ATP levels, glucose transporter 2 abundance, and expression of the dedifferentiation marker ALDH1A3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance were assessed to investigate the metabolic status of genetic reductions in Cpt1a. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. Pancreatic deletion of Cpt1a reduced glucose tolerance but did not alter insulin sensitivity. Glucose-stimulated insulin secretion was reduced both in vivo and in islets isolated from Cpt1aPdx1-/- mice relative to control islets. Pancreatic islets from Cpt1aPdx1-/- mice displayed elevations in ALDH1A3, a marker of dedifferentiation, but no reduction in nuclear abundance of the β-cell transcription factors MafA and Nkx6.1 or the GLUT2 glucose transporter. However, intracellular ATP abundance was markedly decreased in islets isolated from Cpt1aPdx1-/- relative to littermate control mice. We conclude that there is an important physiological role for pancreatic CPT1A to maintain whole body glucose homeostasis by supporting glucose-stimulated insulin secretion and maintaining intracellular ATP levels in male mice.
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Affiliation(s)
- Maggie P Ducote
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Caroline R Cothern
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Heidi M Batdorf
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Molly S Fontenot
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Thomas M Martin
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Maria Iftesum
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Manas R Gartia
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Robert C Noland
- Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - David H Burk
- Cell Biology and Bioimaging Core, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Sujoy Ghosh
- Laboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Susan J Burke
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA.
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Wu WB, Gao F, Tang YH, Wang HZ, Dong H, Lu FE, Yuan F. Huanglian-Renshen-Decoction Maintains Islet β-Cell Identity in T2DM Mice through Regulating GLP-1 and GLP-1R in Both Islet and Intestine. Chin J Integr Med 2025; 31:39-48. [PMID: 39551849 DOI: 10.1007/s11655-024-3915-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 11/19/2024]
Abstract
OBJECTIVE To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. METHODS The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. RESULTS HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). CONCLUSION HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.
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Affiliation(s)
- Wen-Bin Wu
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fan Gao
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yue-Heng Tang
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hong-Zhan Wang
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hui Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fu-Er Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fen Yuan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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8
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Nicolas JC, Lee TH, Quarta C. Can brain neurons change identity? Lessons from obesity. Trends Endocrinol Metab 2024:S1043-2760(24)00297-2. [PMID: 39643545 DOI: 10.1016/j.tem.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 12/09/2024]
Abstract
It has long been thought that the functional identity of mammalian brain neurons is programmed during development and remains stable throughout adult life; however, certain populations of neurons continue to express active regulators of neuronal identity into adulthood. Prolonged exposure to diet-induced metabolic stress induces features of neuronal identity modification in adult mice, and maladaptive changes in neuronal identity maintenance have been linked to cognitive impairment in humans suffering from neurodegenerative diseases often associated with obesity. Here we discuss how, by unraveling the neurological roots of obesity, we may solve the puzzle of whether mammalian brain neurons retain identity plasticity into adulthood, while advancing knowledge of the pathogenic mechanisms at the interface of metabolic and neurodegenerative disorders.
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Affiliation(s)
- Jean Charles Nicolas
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Thomas H Lee
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Carmelo Quarta
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France.
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Bourgeois S, Coenen S, Degroote L, Willems L, Van Mulders A, Pierreux J, Heremans Y, De Leu N, Staels W. Harnessing beta cell regeneration biology for diabetes therapy. Trends Endocrinol Metab 2024; 35:951-966. [PMID: 38644094 DOI: 10.1016/j.tem.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2024]
Abstract
The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.
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Affiliation(s)
- Stephanie Bourgeois
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Sophie Coenen
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Laure Degroote
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Lien Willems
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Annelore Van Mulders
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Julie Pierreux
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Yves Heremans
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Nico De Leu
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; Endocrinology, Universiteit Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium; Endocrinology, ASZ Aalst, 9300 Aalst, Belgium.
| | - Willem Staels
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, Universiteit Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium.
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Liu L, Ke W, Li H, Li F, Fan G, Kuang J, Ma J, Zhang X, Ji B, Li S, Du Y, Xue Y, Lyu Z, Gao L, Qu S, Shi Y, Yan L, Deng W, Xu C, Dai P, Xu L, Liu J, Wan X, Wei G, Yu S, Hong S, Zhang P, Huang Z, Cao X, Liao Z, Xiao H, Mu Y, Handelsman Y, Li Y. Intense simplified strategy for newly diagnosed type 2 diabetes in patients with severe hyperglycaemia: multicentre, open label, randomised trial. BMJ 2024; 387:e080122. [PMID: 39406449 PMCID: PMC11474422 DOI: 10.1136/bmj-2024-080122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2024] [Indexed: 10/20/2024]
Abstract
OBJECTIVE To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. DESIGN Multicentre, open label, randomised trial. SETTING 15 hospitals in China between December 2017 and December 2020. PARTICIPANTS 412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA1c ≥8.5%). INTERVENTIONS All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks. MAIN OUTCOME MEASURES The primary outcome was the percentage of participants achieving HbA1c <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, β cell function, and variations in insulin sensitivity. RESULTS 412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA1c was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA1c <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA1c <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA1c <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and β cell function indices. All treatments were well tolerated. CONCLUSIONS The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and β cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus. TRIAL REGISTRATION ClinicalTrials.gov NCT03194945.
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Affiliation(s)
- Liehua Liu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Weijian Ke
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Hai Li
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Fangping Li
- The Seventh Affiliated Hospital of Sun Yat-sen University, Yantian District, Shenzen, Guangdong Province, China
| | - Guanjie Fan
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong Province, China
| | - Jian Kuang
- Department of Endocrinology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jianhua Ma
- Nanjing First Hospital, Nanjing, Jiangsu Province, China
| | - Xiuwei Zhang
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Wanjiang District, Dongguan City, Guangdong Province, China
| | - Bing Ji
- Clifford Hospital, Panyu District, Guangzhou, Guangdong Province, China
| | - Shu Li
- Huizhou Municipal Central Hospital, Huizhou, Guangdong Province, China
| | - Yinghong Du
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Panyu district, Guangzhou, Guangdong Province, China
| | - Yaoming Xue
- Southern Medical University Nanfang Hospital, Guangzhou, Guangdong Province, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center, Chinese People's Liberation Army General Hospital, Haidian District, Beijing, China
| | - Leili Gao
- Peking University People's Hospital, Xicheng District, Beijing, China
| | - Shen Qu
- Shanghai Tenth People's Hospital of TongJi University, Shanghai, China
| | | | - Li Yan
- Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Wanping Deng
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Chaoyan Xu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Peiji Dai
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Lijuan Xu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Juan Liu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xuesi Wan
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Guohong Wei
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shuang Yu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shubin Hong
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Pengyuan Zhang
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhimin Huang
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiaopei Cao
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhihong Liao
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Haipeng Xiao
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center, Chinese People's Liberation Army General Hospital, Haidian District, Beijing, China
| | | | - Yanbing Li
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
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11
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Belousova AV, Sokolova KV, Danilova IG, Chereshnev VA, Abidov MT. Effect of Sodium Aminophthalhydrazide on Structural and Functional Characteristics of Pancreatic Islands in Experimental Type 2 Diabetes Mellitus. Bull Exp Biol Med 2024; 177:721-724. [PMID: 39441438 DOI: 10.1007/s10517-024-06257-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Indexed: 10/25/2024]
Abstract
Under the influence of inflammation, pancreatic β cells can transdifferentiate into cells with a different phenotype. When inflammation decreases, the opposite process is possible. We studied the effect of intramuscular injection of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt (APH) on the structural and functional characteristics of the pancreatic islets in rats with experimental type 2 diabetes mellitus. Insulin-producing, glucagon-producing, and proliferating cells were identified by immunohistochemistry. After APH administration, an increase in the number of β cells, a decrease in the number of α cells and cells synthesizing both insulin and glucagon (insulin-glucagon-positive) were observed; mitotic activity of β cells did not change. It is likely that APH promotes transdifferentiation of α cells into β cells by changing the microenvironment of endocrine cells and reducing inflammation in pancreatic islets.
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Affiliation(s)
- A V Belousova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia.
| | - K V Sokolova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
| | - I G Danilova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
| | - V A Chereshnev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
| | - M T Abidov
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
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12
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Niu F, Liu W, Ren Y, Tian Y, Shi W, Li M, Li Y, Xiong Y, Qian L. β-cell neogenesis: A rising star to rescue diabetes mellitus. J Adv Res 2024; 62:71-89. [PMID: 37839502 PMCID: PMC11331176 DOI: 10.1016/j.jare.2023.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/08/2023] [Accepted: 10/08/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Diabetes Mellitus (DM), a chronic metabolic disease characterized by elevated blood glucose, is caused by various degrees of insulin resistance and dysfunctional insulin secretion, resulting in hyperglycemia. The loss and failure of functional β-cells are key mechanisms resulting in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). AIM OF REVIEW Elucidating the underlying mechanisms of β-cell failure, and exploring approaches for β-cell neogenesis to reverse β-cell dysfunction may provide novel strategies for DM therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW Emerging studies reveal that genetic susceptibility, endoplasmic reticulum (ER) stress, oxidative stress, islet inflammation, and protein modification linked to multiple signaling pathways contribute to DM pathogenesis. Over the past few years, replenishing functional β-cell by β-cell neogenesis to restore the number and function of pancreatic β-cells has remarkably exhibited a promising therapeutic approach for DM therapy. In this review, we provide a comprehensive overview of the underlying mechanisms of β-cell failure in DM, highlight the effective approaches for β-cell neogenesis, as well as discuss the current clinical and preclinical agents research advances of β-cell neogenesis. Insights into the challenges of translating β-cell neogenesis into clinical application for DM treatment are also offered.
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Affiliation(s)
- Fanglin Niu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wenxuan Liu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yuanyuan Ren
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Ye Tian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Department of Neurology, Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Wenzhen Shi
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Medical Research Center, the affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Man Li
- Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Yujia Li
- Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Yuyan Xiong
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Lu Qian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
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13
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Zhang Y, Parajuli KR, Fonseca VA, Wu H. PAX4 gene delivery improves β-cell function in human islets of Type II diabetes. Regen Med 2024; 19:239-246. [PMID: 39118533 PMCID: PMC11321267 DOI: 10.1080/17460751.2024.2343538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/09/2024] [Indexed: 08/10/2024] Open
Abstract
Aim: Type II diabetes (T2D) stems from insulin resistance, with β-cell dysfunction as a hallmark in its progression. Studies reveal that β cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for β differentiation and survival, thus may be a potential enhancer of β-cell function in T2D islets. Materials & methods: Human PAX4 cDNA was delivered into T2D human islets with an adenoviral vector, and its effects on β cells were examined. Results: PAX4 gene delivery significantly improved β-cell survival, and increased β-cell composition in the T2D human islets. Basal insulin and glucose-stimulated insulin secretion in PAX4-expressing islets were substantially higher than untreated or control-treated T2D human islets. Conclusion: Introduced PAX4 expression in T2D human islets improves β-cell function, thus could provide therapeutic benefits for T2D treatment.
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Affiliation(s)
- Yanqing Zhang
- Section of Endocrinology, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave, #8553,New Orleans, LA 70112, USA
| | - Keshab R Parajuli
- Section of Endocrinology, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave, #8553,New Orleans, LA 70112, USA
| | - Vivian A Fonseca
- Section of Endocrinology, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave, #8553,New Orleans, LA 70112, USA
| | - Hongju Wu
- Section of Endocrinology, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave, #8553,New Orleans, LA 70112, USA
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14
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Leenders F, de Koning EJP, Carlotti F. Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research. Int J Mol Sci 2024; 25:4720. [PMID: 38731945 PMCID: PMC11083883 DOI: 10.3390/ijms25094720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.
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Affiliation(s)
| | | | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.L.); (E.J.P.d.K.)
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15
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Cui D, Feng X, Lei S, Zhang H, Hu W, Yang S, Yu X, Su Z. Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes. Chin Med J (Engl) 2024; 137:791-805. [PMID: 38479993 PMCID: PMC10997226 DOI: 10.1097/cm9.0000000000003034] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Indexed: 04/06/2024] Open
Abstract
ABSTRACT Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.
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Affiliation(s)
- Daxin Cui
- Molecular Medicine Research Center and Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xingrong Feng
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Siman Lei
- Clinical Translational Innovation Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hongmei Zhang
- Molecular Medicine Research Center and Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wanxin Hu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shanshan Yang
- Molecular Medicine Research Center and Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaoqian Yu
- Molecular Medicine Research Center and Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhiguang Su
- Molecular Medicine Research Center and Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Clinical Translational Innovation Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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16
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Fu Q, Qian Y, Jiang H, He Y, Dai H, Chen Y, Xia Z, Liang Y, Zhou Y, Gao R, Zheng S, Lv H, Sun M, Xu K, Yang T. Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation. SCIENCE CHINA. LIFE SCIENCES 2024; 67:504-517. [PMID: 37930473 DOI: 10.1007/s11427-022-2372-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 05/17/2023] [Indexed: 11/07/2023]
Abstract
During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet β cells. Cre-LoxP systems were used to generate islet cell type-specific (α, β, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.
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Affiliation(s)
- Qi Fu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yu Qian
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hemin Jiang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yunqiang He
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hao Dai
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yang Chen
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhiqing Xia
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yucheng Liang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yuncai Zhou
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Rui Gao
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shuai Zheng
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hui Lv
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Min Sun
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Kuanfeng Xu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Tao Yang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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Chapple B, Woodfin S, Moore W. The Perfect Cup? Coffee-Derived Polyphenols and Their Roles in Mitigating Factors Affecting Type 2 Diabetes Pathogenesis. Molecules 2024; 29:751. [PMID: 38398503 PMCID: PMC10891742 DOI: 10.3390/molecules29040751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/29/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Type 2 diabetes (T2D) is a growing health concern with an estimated 462 million people having been diagnosed worldwide. T2D is characterized by chronically elevated blood glucose and insulin resistance, which culminate in a diminished function of the β-cell mass in its later stages. This can be perpetuated by and result in inflammation, excess reactive oxygen species production, obesity, and the dysregulation of multiple cellular pathways. Many naturally occurring small molecules have been investigated in terms of their roles in modulating glucose homeostasis and β-cell function. Many of these compounds can be found in commonly used sources of food and drink. Interestingly, a correlation has been observed between coffee consumption and T2D incidence. However, the specific compounds responsible for this correlation and their mechanisms are still somewhat undetermined. This paper reviews recent research findings on the effects of several polyphenols that are either found in coffee or are metabolites of compounds found in coffee (enterodiol, enterolactone, matairesinol, secoisolariciresinol, kaempferol, quercetin, and chlorogenic acid) on glucose homeostasis and health complications associated with glucose dysregulation, with a special emphasis on their potential anti-diabetic effects. The factors that affect polyphenol content in coffee are also addressed.
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Affiliation(s)
| | | | - William Moore
- Department of Biology and Chemistry, School of Health Sciences, Liberty University, Lynchburg, VA 24515, USA; (B.C.); (S.W.)
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Tanday N, Tarasov AI, Moffett RC, Flatt PR, Irwin N. Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable? Diabetes Obes Metab 2024; 26:16-31. [PMID: 37845573 DOI: 10.1111/dom.15300] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/18/2023]
Abstract
The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin-secreting β-cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β-cell identity through de- or transdifferentiation. Importantly, the glucose-lowering effects of approved and experimental antidiabetic agents, including glucagon-like peptide-1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β-cell dedifferentiation or promoting the transdifferentiation of non-β-cells towards an insulin-positive β-cell-like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β-cell loss or generating new β-cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β-cell decline in diabetes.
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Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Andrei I Tarasov
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - R Charlotte Moffett
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Nigel Irwin
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
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19
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Son J, Accili D. Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med 2023; 55:1652-1658. [PMID: 37524865 PMCID: PMC10474037 DOI: 10.1038/s12276-023-01043-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/29/2023] [Accepted: 04/24/2023] [Indexed: 08/02/2023] Open
Abstract
The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell failure. The failure of β-cells to compensate for insulin resistance results in hyperglycemia, which in turn drives altered lipid metabolism and β-cell failure. Thus, insulin secretion by pancreatic β-cells is a primary component of glucose homeostasis. Impaired β-cell function and reduced β-cell mass are found in diabetes. Both features stem from a failure to maintain β-cell identity, which causes β-cells to dedifferentiate into nonfunctional endocrine progenitor-like cells or to trans-differentiate into other endocrine cell types. In this regard, one of the key issues in achieving disease modification is how to reestablish β-cell identity. In this review, we focus on the causes and implications of β-cell failure, as well as its potential reversibility as a T2D treatment.
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Affiliation(s)
- Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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20
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Kattner N. Immune cell infiltration in the pancreas of type 1, type 2 and type 3c diabetes. Ther Adv Endocrinol Metab 2023; 14:20420188231185958. [PMID: 37529508 PMCID: PMC10387691 DOI: 10.1177/20420188231185958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 06/16/2023] [Indexed: 08/03/2023] Open
Abstract
The different types of diabetes differ in disease pathogenesis but share the impairment or loss of β-cell function leading to chronic hyperglycaemia. While immune cells are present throughout the whole pancreas in normality, their number and activation is increased in diabetes. Different patterns and composition of inflammation could be observed in type 1, type 2 and type 3c diabetes. Immune cells, pancreatic stellate cells and fibrosis were present in the islet microenvironment and could add to β-cell dysfunction and therefore development and progression of diabetes. First studies investigating the use of anti-inflammatory drugs demonstrate their ability to rescue remaining β-cell function and their potential benefit in diabetes treatment. This article provides an overview of immune cell infiltrates in different types of diabetes, highlights the knowledge of their impact on β-cell function and introduces the potential of immunomodulatory strategies.
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Affiliation(s)
- Nicole Kattner
- Translational and Clinical Research Institute, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne, UK
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21
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Wu W, Xia Q, Guo Y, Wang H, Dong H, Lu F, Yuan F. Berberine enhances the function of db/db mice islet β cell through GLP-1/GLP-1R/PKA signaling pathway in intestinal L cell and islet α cell. Front Pharmacol 2023; 14:1228722. [PMID: 37469873 PMCID: PMC10352779 DOI: 10.3389/fphar.2023.1228722] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 06/26/2023] [Indexed: 07/21/2023] Open
Abstract
Background: The evidence on berberine stimulating the secretion of GLP-1 in intestinal L cell has been studied. However, few research has explored its role on generating GLP-1 of islet α cell. Our experiment aims to clarify the mechanism of berberine promoting the secretion of GLP-1 in intestinal L cell and islet α cell, activating GLP-1R and its downstream molecules through endocrine and paracrine ways, thus improving the function of islet β cell and treating T2DM. Methods: After confirming that berberine can lower blood glucose and improve insulin resistance in db/db mice, the identity maintenance, proliferation and apoptosis of islet cells were detected by immunohistochemistry and immunofluorescence. Then, the activation of berberine on GLP-1/GLP-1R/PKA signaling pathway was evaluated by Elisa, Western blot and PCR. Finally, this mechanism was verified by in vitro experiments on Min6 cells, STC-1 cells and aTC1/6 cells. Results: Berberine ameliorates glucose metabolism in db/db mice. Additionally, it also increases the number and enhances the function of islet β cell. This process is closely related to improve the secretion of intestinal L cell and islet α cell, activate GLP-1R/PKA signaling pathway through autocrine and paracrine, and increase the expression of its related molecule such as GLP-1, GLP-1R, PC1/3, PC2, PKA, Pdx1. In vitro, the phenomenon that berberine enhanced the GLP-1/GLP-1R/PKA signal pathway had also been observed, which confirmed the results of animal experiments. Conclusion: Berberine can maintain the identity and normal function of islet β cell, and its mechanism is related to the activation of GLP-1/GLP-1R/PKA signal pathway in intestinal L cell and islet α cell.
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Affiliation(s)
- Wenbin Wu
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qingsong Xia
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yujin Guo
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongzhan Wang
- Institution of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hui Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fuer Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fen Yuan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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22
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Huerta-Chagoya A, Schroeder P, Mandla R, Deutsch AJ, Zhu W, Petty L, Yi X, Cole JB, Udler MS, Dornbos P, Porneala B, DiCorpo D, Liu CT, Li JH, Szczerbiński L, Kaur V, Kim J, Lu Y, Martin A, Eizirik DL, Marchetti P, Marselli L, Chen L, Srinivasan S, Todd J, Flannick J, Gubitosi-Klug R, Levitsky L, Shah R, Kelsey M, Burke B, Dabelea DM, Divers J, Marcovina S, Stalbow L, Loos RJF, Darst BF, Kooperberg C, Raffield LM, Haiman C, Sun Q, McCormick JB, Fisher-Hoch SP, Ordoñez ML, Meigs J, Baier LJ, González-Villalpando C, González-Villalpando ME, Orozco L, García-García L, Moreno-Estrada A, Aguilar-Salinas CA, Tusié T, Dupuis J, Ng MCY, Manning A, Highland HM, Cnop M, Hanson R, Below J, Florez JC, Leong A, Mercader JM. The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes. Diabetologia 2023; 66:1273-1288. [PMID: 37148359 PMCID: PMC10244266 DOI: 10.1007/s00125-023-05912-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 02/03/2023] [Indexed: 05/08/2023]
Abstract
AIMS/HYPOTHESIS The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. METHODS We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. RESULTS Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10-9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. CONCLUSIONS/INTERPRETATION Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. DATA AVAILABILITY Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).
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Affiliation(s)
- Alicia Huerta-Chagoya
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico.
| | - Philip Schroeder
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Mandla
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Aaron J Deutsch
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Wanying Zhu
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lauren Petty
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xiaoyan Yi
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Joanne B Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Miriam S Udler
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Peter Dornbos
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Bianca Porneala
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Daniel DiCorpo
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Ching-Ti Liu
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Josephine H Li
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Lukasz Szczerbiński
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | | | - Joohyun Kim
- Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yingchang Lu
- Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alicia Martin
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
- WELBIO, Université Libre de Bruxelles, Brussels, Belgium
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy
| | - Ling Chen
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Shylaja Srinivasan
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Jennifer Todd
- Department of Pediatrics, University of Vermont, Burlington, VT, USA
| | - Jason Flannick
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA
| | - Rose Gubitosi-Klug
- Pediatric Endocrinology, Diabetes, and Metabolism, Case Western Reserve University and Rainbow Babies and Children's Hospital, Cleveland, OH, USA
| | - Lynne Levitsky
- Department of Pediatrics, Division of Pediatric Endocrinology and Pediatric Diabetes Center, Massachusetts General Hospital, Boston, MA, USA
| | - Rachana Shah
- Pediatric Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Megan Kelsey
- Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Brian Burke
- Biostatistics Center, The George Washington University, Rockville, MD, USA
| | - Dana M Dabelea
- Department of Epidemiology, University of Colorado School of Medicine, Aurora, CO, USA
| | | | | | - Lauren Stalbow
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Burcu F Darst
- Division of Public Health Science, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Charles Kooperberg
- Division of Public Health Science, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Laura M Raffield
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christopher Haiman
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Quan Sun
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Joseph B McCormick
- School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, USA
| | - Susan P Fisher-Hoch
- School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, USA
| | - Maria L Ordoñez
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
| | - James Meigs
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Leslie J Baier
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA
| | - Clicerio González-Villalpando
- Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico
| | - Maria Elena González-Villalpando
- Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico
| | - Lorena Orozco
- Laboratorio Inmunogénomica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Andrés Moreno-Estrada
- Laboratorio Nacional de Genómica para la Biodiversidad (LANGEBIO), Unidad de Genómica Avanzada (UGA), CINVESTAV, Irapuato, Mexico
| | - Carlos A Aguilar-Salinas
- Unidad de Investigación de Enfermedades Metabólicas y Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Teresa Tusié
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
| | - Josée Dupuis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Maggie C Y Ng
- Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alisa Manning
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Heather M Highland
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Robert Hanson
- Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Jennifer Below
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jose C Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
| | - Aaron Leong
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
| | - Josep M Mercader
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Son J, Du W, Esposito M, Shariati K, Ding H, Kang Y, Accili D. Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure. Nat Commun 2023; 14:558. [PMID: 36732513 PMCID: PMC9895451 DOI: 10.1038/s41467-023-36315-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic animals is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of β-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against β-cell dysfunction in diabetes.
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Affiliation(s)
- Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
| | - Wen Du
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Mark Esposito
- Kayothera Inc, Seattle, WA, USA
- Department of Molecular Biology, Princeton University, 08544, Princeton, NJ, USA
| | - Kaavian Shariati
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Hongxu Ding
- Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, 08544, Princeton, NJ, USA
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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24
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Liu L, Ke W, Xu L, Li H, Liu J, Wan X, Liu J, Deng W, Cao X, Xiao H, Li Y. Evaluating the role of time in range as a glycemic target during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes. J Diabetes 2023; 15:133-144. [PMID: 36650669 PMCID: PMC9934958 DOI: 10.1111/1753-0407.13355] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/02/2022] [Accepted: 12/29/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Tight glycemic control during short-term intensive insulin therapy (SIIT) is critical for inducing diabetes remission in patients with newly diagnosed type 2 diabetes (T2D). This work aimed to investigate the role of time in range (TIR) during SIIT as a novel glycemic target by predicting clinical outcomes. METHODS SIIT was given to 116 patients with newly diagnosed T2D, with daily eight-point capillary glucose monitored. Glycemic targets (fasting/premeal glucose, 3.9-6.0 mmol/L; 2 h postprandial blood glucose, 3.9-7.8 mmol/L) were achieved and maintained for 2 weeks. TIRPIR was calculated as the percentage of glucose points within these glycemic targets during the maintenance period and was compared to TIR3.9-7.8mmol/L and TIR3.9-10.0mmol/L . Acute insulin response (AIR), HOMA-IR, HOMA-B, and disposition index (DI) were measured. Patients were followed up for 1 year to observe clinical outcomes. RESULTS TIRPIR , TIR3.9-7.8mmol/L , and TIR3.9-10.0mmol/L were 67.2 ± 11.2%, 80.8 ± 9.2%, and 90.1 ± 6.2%, respectively. After SIIT, β-cell function and insulin sensitivity improved remarkably, and the 1-year remission rate was 55.2%. △AIR and △DI were positively correlated with all the TIR values, whereas only TIRPIR was correlated with △HOMA-IR (r = -0.22, p = 0.03). Higher TIRPIR but not TIR3.9-7.8mmol/L or TIR3.9-10.0mmol/L was robustly associated with diabetes remission; patients in the lower TIRPIR tertile had an elevated risk of hyperglycemia relapse (hazard ratio 3.4, 95% confidence interval 1.6-7.2， p = .001). Only those with TIRPIR ≥ 65% had a one-year remission rate of over 60%. CONCLUSIONS These findings advocate TIRPIR ≥ 65% as a novel glycemic target during SIIT for clinical decision-making.
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Affiliation(s)
- Liehua Liu
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Weijian Ke
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Lijuan Xu
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Hai Li
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Juan Liu
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Xuesi Wan
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jianbin Liu
- Endocrinology DepartmentEastern HealthMelbourneVictoriaAustralia
| | - Wanping Deng
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Xiaopei Cao
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Haipeng Xiao
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Yanbing Li
- Department of Endocrinologythe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
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25
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Jin Z, Korol SV. GABA signalling in human pancreatic islets. Front Endocrinol (Lausanne) 2023; 14:1059110. [PMID: 36891061 PMCID: PMC9986413 DOI: 10.3389/fendo.2023.1059110] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 02/09/2023] [Indexed: 02/22/2023] Open
Abstract
The pancreatic islets are essential microorgans controlling the glucose level in the blood. The islets consist of different cell types which communicate with each other by means of auto- and paracrine interactions. One of the communication molecules produced by and released within the islets is γ-aminobutyric acid (GABA), a well-known inhibitor of neuronal excitability in the mammalian nervous system. Interestingly, GABA is also present in the blood in the nanomolar concentration range. Thus, GABA can affect not only islet function per se (e.g. hormone secretion) but also interactions between immune cells and the pancreatic islet cells in physiological conditions and in pathological states (particularly in type 1 diabetes). In the last decade the interest in GABA signalling in islets has increased. The broad research scope ranges from fundamental physiological studies at the molecular and cellular level to pathological implications and clinical trials. The aim of this mini-review is to outline the current status of the islet GABA field mostly in relation to human islets, to identify the gaps in the current knowledge and what clinical implications GABA signalling may have in islets.
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Accili D, Du W, Kitamoto T, Kuo T, McKimpson W, Miyachi Y, Mukhanova M, Son J, Wang L, Watanabe H. Reflections on the state of diabetes research and prospects for treatment. Diabetol Int 2023; 14:21-31. [PMID: 36636157 PMCID: PMC9829952 DOI: 10.1007/s13340-022-00600-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/02/2022] [Indexed: 01/16/2023]
Abstract
Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.
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Affiliation(s)
- Domenico Accili
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Wen Du
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Takumi Kitamoto
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Chiba 260-8670 Japan
| | - Taiyi Kuo
- Department of Neurobiology, Physiology, and Behavior, University of California at Davis, Davis, CA 95616 USA
| | - Wendy McKimpson
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Yasutaka Miyachi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka Japan
| | - Maria Mukhanova
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Jinsook Son
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Liheng Wang
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Hitoshi Watanabe
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
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Song J, Ni Q, Sun J, Xie J, Liu J, Ning G, Wang W, Wang Q. Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans. J Clin Endocrinol Metab 2022; 107:3231-3241. [PMID: 36125175 PMCID: PMC9693768 DOI: 10.1210/clinem/dgac535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Diabetes is an age-related disease; however, the mechanism underlying senescent beta cell failure is still unknown. OBJECTIVE The present study was designed to investigate whether and how the differentiated state was altered in senescent human beta cells by excluding the effects of impaired glucose tolerance. METHODS We calculated the percentage of hormone-negative/chromogranin A-positive endocrine cells and evaluated the expressions of forkhead box O1 (FoxO1) and Urocortin 3 (UCN3) in islets from 31 nondiabetic individuals, divided into young (<40 years), middle-aged (40-60 years) and elderly (>60 years) groups. We also assessed adaptive unfolded protein response markers glucose-regulated protein 94 (GRP94), and spliced X-box binding protein 1 (XBP1s) in senescent beta cells and their possible contributions to maintaining beta cell identity and differentiation state. RESULTS We found an almost 2-fold increase in the proportion of dedifferentiated cells in elderly and middle-aged groups compared with the young group (3.1 ± 1.0% and 3.0 ± 0.9% vs 1.7 ± 0.5%, P < .001). This was accompanied by inactivation of FoxO1 and loss of UCN3 expression in senescent human beta cells. In addition, we demonstrated that the expression levels of adaptive unfolded protein response (UPR) components GRP94 and XBP1s declined with age. In vitro data showed knockdown GRP94 in Min6-triggered cells to dedifferentiate and acquire progenitor features, while restored GRP94 levels in H2O2-induced senescent Min6 cells rescued beta cell identity. CONCLUSION Our finding highlights that the failure to establish proper adaptive UPR in senescent human beta cells shifts their differentiated states, possibly representing a crucial step in the pathogenesis of age-related beta cell failure.
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Affiliation(s)
| | | | - Jiajun Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xie
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianmin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Correspondence: Qidi Wang, MD, PhD, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ; or Weiqing Wang, MD, PhD, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qidi Wang
- Correspondence: Qidi Wang, MD, PhD, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ; or Weiqing Wang, MD, PhD, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Chen G, Tan C, Liu X, Chen Y. Association Between the Neutrophil-To-Lymphocyte Ratio and Diabetes Secondary to Exocrine Pancreatic Disorders. Front Endocrinol (Lausanne) 2022; 13:957129. [PMID: 35937787 PMCID: PMC9352859 DOI: 10.3389/fendo.2022.957129] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/22/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Diabetes mellitus among patients with exocrine pancreatic disorders is commonly known to be associated with chronic inflammation, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). The neutrophil-to-lymphocyte ratio (NLR) is a novel marker that indicates the presence of various chronic inflammatory diseases, including type 2 diabetes (T2DM). However, no studies have examined the relationship between the NLR value and diabetes secondary to exocrine pancreatic disorders. AIM To determine whether the NLR value is associated with diabetes secondary to exocrine pancreatic disorders. METHODS The medical data of subjects with confirmed pancreatic disease who were admitted to the Department of Pancreatic Surgery of our institution from August 2017 to October 2021 were obtained from the database and retrospectively analyzed. Anthropometric measures, laboratory data, including HbA1c, fasting insulin, and fasting C-peptide levels and the inflammatory index (white blood cell count, NLR, platelet-to-lymphocyte ration, monocyte-to-lymphocyte ratio) were recorded. The NLR is the ratio of neutrophils to lymphocytes. A homeostasis model (HOMA-B and HOMA-IR) was used to measure beta-cell dysfunction and insulin resistance. RESULTS The NLR values of the diabetes secondary to exocrine pancreatic disorders group were significantly higher than those of the nondiabetic group (P=0.001). In multivariate logistic regression, after adjusting for covariates, high NLR values were found to be an independent risk factor for diabetes secondary to exocrine pancreatic disorders (OR: 1.37, 95% CI: 1.138-1.649, P=0.001). According to Spearman correlation analysis, the NLR was significantly correlated with fasting plasma glucose levels (P<0.0001) and HOMA2-IR values (P=0.02). CONCLUSION The NLR inflammation marker was significantly higher in subjects with diabetes secondary to exocrine pancreatic disorders and was associated with insulin resistance. NLR values may be reliable predictive markers for diabetes among patients with exocrine pancreatic disorders.
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Affiliation(s)
| | | | | | - Yonghua Chen
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, China
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Zhu X, Liu D, Li G, Zhi M, Sun J, Qi L, Li J, Pandol SJ, Li L. Exosomal miR-140-3p and miR-143-3p from TGF-β1-treated pancreatic stellate cells target BCL2 mRNA to increase β-cell apoptosis. Mol Cell Endocrinol 2022; 551:111653. [PMID: 35513284 DOI: 10.1016/j.mce.2022.111653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/30/2022] [Accepted: 04/19/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND People with chronic pancreatitis (CP) normally develop a fibrotic pancreas with reduced β-cell mass. Limited studies have focused on the development and pathogenesis of CP-related diabetes. MiRNAs packaged as exosomes are the key regulators of β-cell dysfunction. This study aimed to define the effect of exosomal miRNA from activated pancreatic stellate cells (PSCs) on β-cells. METHODS Exosomes in the supernatants of mouse PSCs lines were extracted via ultracentrifugation and then identified. The role of exosomes secreted by transforming growth factor-β1 (TGF-β1)-treated PSCs in β-cell function was assessed. MiRNAs were prepared from exosomes extracted from TGF-β1-treated and untreated PSCs (T-Exo or C-Exo), and the miRNA expression profiles were compared by microarray. Then, miR-140-3p and miR-143-3p were overexpressed or inhibited in MIN6 cells and islets to determine their molecular and functional effects. RESULTS Exosomes were the predominant extracellular vesicles secreted by PSCs into the culture medium. The MIN6 cells incubated with T-Exo had less insulin secretion and lower viability than the MIN6 cells incubated with PBS or C-Exo. MiR-140-3p and miR-143-3p were notably upregulated in T-Exo. Enhancing the expression of miR-140-3p and miR-143-3p in β-cells decreased the cell count and viability and increased the cleaved caspase-3 levels. Mechanistically, T-Exo mediated the intercellular transfer of miR-140-3p and miR-143-3p by targeting the B-cell lymphoma 2 gene in recipient β-cells to induce cell death. CONCLUSIONS Exosomal miRNA transfer as a communication mode between PSCs and β-cells, which may be explored for its therapeutic utility.
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Affiliation(s)
- Xiangyun Zhu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Dechen Liu
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Guoqing Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Mengmeng Zhi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Ji Sun
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Jingbo Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China
| | - Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA.
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, China.
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Lee K, Chan JY, Liang C, Ip CK, Shi YC, Herzog H, Hughes WE, Bensellam M, Delghingaro-Augusto V, Koina ME, Nolan CJ, Laybutt DR. XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice. Diabetologia 2022; 65:984-996. [PMID: 35316840 PMCID: PMC9076738 DOI: 10.1007/s00125-022-05669-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/13/2021] [Indexed: 01/01/2023]
Abstract
AIMS/HYPOTHESIS Pancreatic beta cell dedifferentiation, transdifferentiation into other islet cells and apoptosis have been implicated in beta cell failure in type 2 diabetes, although the mechanisms are poorly defined. The endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) is a major regulator of the unfolded protein response. XBP1 expression is reduced in islets of people with type 2 diabetes, but its role in adult differentiated beta cells is unclear. Here, we assessed the effects of Xbp1 deletion in adult beta cells and tested whether XBP1-mediated unfolded protein response makes a necessary contribution to beta cell compensation in insulin resistance states. METHODS Mice with inducible beta cell-specific Xbp1 deletion were studied under normal (chow diet) or metabolic stress (high-fat diet or obesity) conditions. Glucose tolerance, insulin secretion, islet gene expression, alpha cell mass, beta cell mass and apoptosis were assessed. Lineage tracing was used to determine beta cell fate. RESULTS Deletion of Xbp1 in adult mouse beta cells led to beta cell dedifferentiation, beta-to-alpha cell transdifferentiation and increased alpha cell mass. Cell lineage-specific analyses revealed that Xbp1 deletion deactivated beta cell identity genes (insulin, Pdx1, Nkx6.1, Beta2, Foxo1) and derepressed beta cell dedifferentiation (Aldh1a3) and alpha cell (glucagon, Arx, Irx2) genes. Xbp1 deletion in beta cells of obese ob/ob or high-fat diet-fed mice triggered diabetes and worsened glucose intolerance by disrupting insulin secretory capacity. Furthermore, Xbp1 deletion increased beta cell apoptosis under metabolic stress conditions by attenuating the antioxidant response. CONCLUSIONS/INTERPRETATION These findings indicate that XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and is required for beta cell compensation and prevention of diabetes in insulin resistance states.
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Affiliation(s)
- Kailun Lee
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Jeng Yie Chan
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Cassandra Liang
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Chi Kin Ip
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Yan-Chuan Shi
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Herbert Herzog
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - William E Hughes
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Mohammed Bensellam
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
- Secteur des sciences de la santé, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Université catholique de Louvain, Brussels, Belgium
| | - Viviane Delghingaro-Augusto
- Medical School and John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Mark E Koina
- ACT Pathology, Canberra Health Services, Garran, ACT, Australia
| | - Christopher J Nolan
- Medical School and John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
- Department of Endocrinology, The Canberra Hospital, Garran, ACT, Australia
| | - D Ross Laybutt
- Garvan Institute of Medical Research, St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia.
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Ciochina M, Balaban DV, Manucu G, Jinga M, Gheorghe C. The Impact of Pancreatic Exocrine Diseases on the β-Cell and Glucose Metabolism-A Review with Currently Available Evidence. Biomolecules 2022; 12:618. [PMID: 35625546 PMCID: PMC9139037 DOI: 10.3390/biom12050618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic exocrine and endocrine dysfunctions often come together in the course of pancreatic diseases as interdependent manifestations of the same organ. However, the mechanisms underlying the bidirectional connection of the exocrine and endocrine pancreas are not fully understood. In this review, we aimed to synthetize the current knowledge regarding the effects of several exocrine pancreatic pathologies on the homeostasis of β-cells, with a special interest in the predisposition toward diabetes mellitus (DM). We focused on the following pancreatic exocrine diseases: chronic pancreatitis, acute pancreatitis, cystic fibrosis, pancreatic cancer, pancreatic resections, and autoimmune pancreatitis. We discuss the pathophysiologic mechanisms behind the impact on β-cell function and evolution into DM, as well as the associated risk factors in progression to DM, and we describe the most relevant and statistically significant findings in the literature. An early and correct diagnosis of DM in the setting of pancreatic exocrine disorders is of paramount importance for anticipating the disease's course and its therapeutical needs.
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Affiliation(s)
- Marina Ciochina
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
| | - Daniel Vasile Balaban
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - George Manucu
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Mariana Jinga
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Cristian Gheorghe
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania
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Yuan HQ, Miao JX, Xu JP, Zhu SX, Xu F, Wang XH, Wang CH, Yu C, Wang XQ, Su JB, Zhang DM. Increased serum cystatin C levels and responses of pancreatic α- and β-cells in type 2 diabetes. Endocr Connect 2022; 11:e210597. [PMID: 35179515 PMCID: PMC8942323 DOI: 10.1530/ec-21-0597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/18/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND Increased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and β-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and β-cell functions in T2D. METHODS In this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic β-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda's index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln). RESULTS With quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= -0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (β= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (β= -0.137, t= -7.118, P < 0.001), lnF-GLA (β= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (β= 0.121, t= 5.730, P < 0.001). CONCLUSIONS Increased serum CysC levels may be partly responsible for increased insulin secretion from β-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.
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Affiliation(s)
- Hui-qing Yuan
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Jia-xi Miao
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Jia-ping Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Su-xiang Zhu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Xiao-hua Wang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Chun-hua Wang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Chao Yu
- Department of Clinical Laboratory, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Xue-qin Wang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
| | - Jian-bin Su
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
- Correspondence should be addressed to J Su or D Zhang: or
| | - Dong-mei Zhang
- Medical Research Center, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China
- Correspondence should be addressed to J Su or D Zhang: or
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Fatty Pancreas-Centered Metabolic Basis of Pancreatic Adenocarcinoma: From Obesity, Diabetes and Pancreatitis to Oncogenesis. Biomedicines 2022; 10:biomedicines10030692. [PMID: 35327494 PMCID: PMC8945032 DOI: 10.3390/biomedicines10030692] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/15/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, and it is currently the third most common cause of cancer death in the U.S.A. Progress in the fight against PDAC has been hampered by an inability to detect it early in the overwhelming majority of patients, and also by the reduced oxygen levels and nutrient perfusion caused by new matrix formation through the activation of stromal cells in the context of desmoplasia. One harbinger of PDAC is excess intrapancreatic fat deposition, namely, fatty pancreas, which specifically affects the tumor macro- and microenvironment in the organ. Over half of PDAC patients have diabetes mellitus (DM) at the time of diagnosis, and fatty pancreas is associated with subsequent DM development. Moreover, there is a strong association between fatty pancreas and fatty liver through obesity, and a higher intrapancreatic fat percentage has been noted in acute pancreatitis patients with DM than in those without DM. All these findings suggest that the link between fatty pancreas and PDAC might occur through metabolic alterations, either DM-related or non-DM-related. Based on clinical, in vivo and in vitro evidence, the current review highlights the etiologies of fatty pancreas (including fatty infiltration and replacement) and the fatty pancreas-associated metabolic alterations involved in oncogenesis to provide crucial targets to prevent, detect, and/or effectively treat PDAC.
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Lei L, Huan Y, Liu Q, Li C, Cao H, Ji W, Gao X, Fu Y, Li P, Zhang R, Abliz Z, Liu Y, Liu S, Shen Z. Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic β-Cell Function by Preventing Dedifferentiation and Apoptosis. Front Pharmacol 2022; 13:841981. [PMID: 35308210 PMCID: PMC8927674 DOI: 10.3389/fphar.2022.841981] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background:Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood. Purpose: This study explored the protective effects of SZ-A on islet β cells and the underlying mechanism. Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and β-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet β-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells. Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the β-cell dedifferentiation marker ALDH1A3 and upregulated β-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects. Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet β cells and ameliorates β-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.
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Affiliation(s)
- Lei Lei
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Huan
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yi Huan, ; Shuainan Liu,
| | - Quan Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Caina Li
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Cao
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenming Ji
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuefeng Gao
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yaxin Fu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pingping Li
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruiping Zhang
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeper Abliz
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuling Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuainan Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yi Huan, ; Shuainan Liu,
| | - Zhufang Shen
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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35
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Wei T, Wei R, Hong T. Regeneration of β cells from cell phenotype conversion among the pancreatic endocrine cells. Chronic Dis Transl Med 2022; 8:1-4. [PMID: 35620156 PMCID: PMC9128562 DOI: 10.1002/cdt3.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/12/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
- Tianjiao Wei
- Department of Endocrinology and Metabolism Peking University Third Hospital Beijing 100191 China
| | - Rui Wei
- Department of Endocrinology and Metabolism Peking University Third Hospital Beijing 100191 China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism Peking University Third Hospital Beijing 100191 China
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36
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Petrov MS, Taylor R. Intra-pancreatic fat deposition: bringing hidden fat to the fore. Nat Rev Gastroenterol Hepatol 2022; 19:153-168. [PMID: 34880411 DOI: 10.1038/s41575-021-00551-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/04/2021] [Indexed: 02/07/2023]
Abstract
Development of advanced modalities for detection of fat within the pancreas has transformed understanding of the role of intra-pancreatic fat deposition (IPFD) in health and disease. There is now strong evidence for the presence of minimal (but not negligible) IPFD in healthy human pancreas. Diffuse excess IPFD, or fatty pancreas disease (FPD), is more frequent than type 2 diabetes mellitus (T2DM) (the most common disease of the endocrine pancreas) and acute pancreatitis (the most common disease of the exocrine pancreas) combined. FPD is not strictly a function of high BMI; it can result from the excess deposition of fat in the islets of Langerhans, acinar cells, inter-lobular stroma, acinar-to-adipocyte trans-differentiation or replacement of apoptotic acinar cells. This process leads to a wide array of diseases characterized by excess IPFD, including but not limited to acute pancreatitis, chronic pancreatitis, pancreatic cancer, T2DM, diabetes of the exocrine pancreas. There is ample evidence for FPD being potentially reversible. Weight loss-induced decrease of intra-pancreatic fat is tightly associated with remission of T2DM and its re-deposition with recurrence of the disease. Reversing FPD will open up opportunities for preventing or intercepting progression of major diseases of the exocrine pancreas in the future.
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Affiliation(s)
- Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
| | - Roy Taylor
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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37
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Desentis-Desentis MF. Regenerative approaches to preserve pancreatic β-cell mass and function in diabetes pathogenesis. Endocrine 2022; 75:338-350. [PMID: 34825343 DOI: 10.1007/s12020-021-02941-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 11/07/2021] [Indexed: 01/21/2023]
Abstract
In both type 1 diabetes (T1D) and type 2 diabetes (T2D), there is a substantial β-cell mass loss. Residual β-cell mass is susceptible to cellular damage because of specific pancreatic β-cell characteristics. β cells have a low proliferation rate, being in human adults almost zero and a low antioxidant system that makes β cells susceptible to oxidative stress and increases their vulnerability to cell destruction. Different strategies have been addressed to preserve pancreatic β-cell residual mass and function in patients with diabetes. However, the effect of many compounds proposed in rodent models to trigger β-cell replication has different results in human β cells. In this review, scientific evidence of β-cell of two major regenerative approaches has been gathered. Regeneration proceedings for pancreatic β cells are promising and could improve β-cell proliferation capacity and contribute to the conservation of mature β-cell phenotypic characteristics. This evidence supports the notion that regenerative medicine could be a helpful strategy to yield amelioration of T1D and T2D pathogenesis.
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Affiliation(s)
- Maria Fernanda Desentis-Desentis
- Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Jalisco, Mexico.
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38
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Evans RM, Wei Z. Interorgan crosstalk in pancreatic islet function and pathology. FEBS Lett 2022; 596:607-619. [PMID: 35014695 DOI: 10.1002/1873-3468.14282] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/16/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance β-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.
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Affiliation(s)
- Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Zong Wei
- Department of Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale, AZ, USA
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39
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Murao N, Yokoi N, Takahashi H, Hayami T, Minami Y, Seino S. Increased glycolysis affects β-cell function and identity in aging and diabetes. Mol Metab 2022; 55:101414. [PMID: 34871777 PMCID: PMC8732780 DOI: 10.1016/j.molmet.2021.101414] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/25/2021] [Accepted: 12/01/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D. METHODS We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob/ob mice as aging models. As a diabetes model, we used db/db mice. The glucose responsiveness of insulin secretion and the [U-13C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of β-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of β-cell identity. β cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1, a component of the shuttle. We analyzed Got1 KO β cells as a model of increased glycolysis. RESULTS We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse β cells. We also observed a metabolic commonality between aged and diabetic β cells: hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 (Nmnat2), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO β cells showed increased glycolysis, β-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO β cells, we show that attenuation of glycolysis or Nmnat2 activity can restore β-cell function and identity. CONCLUSIONS Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic β cells, which may underlie age-related β-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.
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Affiliation(s)
- Naoya Murao
- Division of Molecular and Metabolic Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan
| | - Norihide Yokoi
- Division of Molecular and Metabolic Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan; Laboratory of Animal Breeding and Genetics, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Kyoto 606-8502, Japan
| | - Harumi Takahashi
- Division of Molecular and Metabolic Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
| | - Tomohide Hayami
- Division of Molecular and Metabolic Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan; Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan
| | - Yasuhiro Minami
- Division of Cell Physiology, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan
| | - Susumu Seino
- Division of Molecular and Metabolic Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan
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40
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Son J, Ding H, Farb TB, Efanov AM, Sun J, Gore JL, Syed SK, Lei Z, Wang Q, Accili D, Califano A. BACH2 inhibition reverses β cell failure in type 2 diabetes models. J Clin Invest 2021; 131:153876. [PMID: 34907913 DOI: 10.1172/jci153876] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/28/2021] [Indexed: 12/31/2022] Open
Abstract
Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
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Affiliation(s)
- Jinsook Son
- Department of Medicine and.,Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Hongxu Ding
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Thomas B Farb
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Alexander M Efanov
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Jiajun Sun
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Julie L Gore
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Samreen K Syed
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Zhigang Lei
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Qidi Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Domenico Accili
- Department of Medicine and.,Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Andrea Califano
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA
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41
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Miyachi Y, Kuo T, Son J, Accili D. Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets. PLoS One 2021; 16:e0260526. [PMID: 34843575 PMCID: PMC8629236 DOI: 10.1371/journal.pone.0260526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 11/12/2021] [Indexed: 12/11/2022] Open
Abstract
Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results from increased Foxo1 protein degradation, due to hyperacetylation of Foxo1 from increased nutrient turnover. To understand the mechanisms of Foxo1-related beta cell failure, we performed genome-wide analyses of its target genes, and identified putative mediators of sub-phenotypes of cellular dysfunction. Chromatin immunoprecipitation analyses demonstrated a striking pattern of Foxo1 binding to the promoters of a cluster of aldo-ketoreductases on chromosome 13: Akr1c12, Akr1c13, Akr1c19. Of these, Akr1c19 has been reported as a marker of Pdx1-positive endodermal progenitor cells. Here we show that Akr1c19 expression is dramatically decreased in db/db islets. Thus, we investigated whether Akr1c19 is involved in beta cell function. We performed gain- and loss-of-function experiments in cultured beta cells and generated Akr1c19 knockout mice. We show that Foxo1 and HNF1a cooperatively regulate Akr1c19 expression. Nonetheless, functional characterization of Akr1c19 both using islets and knockout mice did not reveal abnormalities on glucose homeostasis. We conclude that reduced expression of Akr1c19 is not sufficient to affect islet function.
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Affiliation(s)
- Yasutaka Miyachi
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians & Surgeons of Columbia University, New York, New York, United States of America
| | - Taiyi Kuo
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians & Surgeons of Columbia University, New York, New York, United States of America
| | - Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians & Surgeons of Columbia University, New York, New York, United States of America
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians & Surgeons of Columbia University, New York, New York, United States of America
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42
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Kuo T, Du W, Miyachi Y, Dadi PK, Jacobson DA, Segrè D, Accili D. Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function. Mol Metab 2021; 53:101256. [PMID: 34048961 PMCID: PMC8225970 DOI: 10.1016/j.molmet.2021.101256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear. METHODS In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α enhancers according to a HOMER analysis. RESULTS To model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell "disallowed" genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. CONCLUSIONS The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.
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Affiliation(s)
- Taiyi Kuo
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
| | - Wen Du
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Yasutaka Miyachi
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Prasanna K Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - David A Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Daniel Segrè
- Department of Biology, Department of Biomedical Engineering, Department of Physics, Boston University, Boston, MA, USA
| | - Domenico Accili
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
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Nimkulrat SD, Bernstein MN, Ni Z, Brown J, Kendziorski C, Blum B. The Anna Karenina Model of β-Cell Maturation in Development and Their Dedifferentiation in Type 1 and Type 2 Diabetes. Diabetes 2021; 70:2058-2066. [PMID: 34417264 PMCID: PMC8576426 DOI: 10.2337/db21-0211] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/10/2021] [Indexed: 11/13/2022]
Abstract
Loss of mature β-cell function and identity, or β-cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β-cell dedifferentiation in diabetes. In the first model, β-cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β-cells resemble β-cell progenitors. In the second model, β-cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the "Anna Karenina" model, predicts that in each type of diabetes, β-cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β-cell-specific lineage-tracing system coupled with RNA sequencing in mice. We constructed a multidimensional map of β-cell transcriptional trajectories during the normal course of β-cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob ). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β-cells, β-cell dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.
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Affiliation(s)
- Sutichot D Nimkulrat
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | | | - Zijian Ni
- Department of Statistics, University of Wisconsin-Madison, Madison, WI
| | - Jared Brown
- Department of Statistics, University of Wisconsin-Madison, Madison, WI
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Barak Blum
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
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An inhibitor-mediated beta-cell dedifferentiation model reveals distinct roles for FoxO1 in glucagon repression and insulin maturation. Mol Metab 2021; 54:101329. [PMID: 34454092 PMCID: PMC8476777 DOI: 10.1016/j.molmet.2021.101329] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/20/2021] [Accepted: 08/20/2021] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE The loss of forkhead box protein O1 (FoxO1) signaling in response to metabolic stress contributes to the etiology of type II diabetes, causing the dedifferentiation of pancreatic beta cells to a cell type reminiscent of endocrine progenitors. Lack of methods to easily model this process in vitro, however, have hindered progress into the identification of key downstream targets and potential inhibitors. We therefore aimed to establish such an in vitro cellular dedifferentiation model and apply it to identify novel agents involved in the maintenance of beta-cell identity. METHODS The murine beta-cell line, Min6, was used for primary experiments and high-content screening. Screens encompassed a library of small-molecule drugs representing the chemical and target space of all FDA-approved small molecules with an automated immunofluorescence readout. Validation experiments were performed in a murine alpha-cell line as well as in primary murine and human diabetic islets. Developmental effects were studied in zebrafish and C. elegans models, while diabetic db/db mouse models were used to elucidate global glucose metabolism outcomes. RESULTS We show that short-term pharmacological FoxO1 inhibition can model beta-cell dedifferentiation by downregulating beta-cell-specific transcription factors, resulting in the aberrant expression of progenitor genes and the alpha-cell marker glucagon. From a high-content screen, we identified loperamide as a small molecule that can prevent FoxO inhibitor-induced glucagon expression and further stimulate insulin protein processing and secretion by altering calcium levels, intracellular pH, and FoxO1 localization. CONCLUSIONS Our study provides novel models, molecular targets, and drug candidates for studying and preventing beta-cell dedifferentiation.
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Lau H, Li S, Corrales N, Rodriguez S, Mohammadi M, Alexander M, de Vos P, Lakey JRT. Necrostatin-1 Supplementation to Islet Tissue Culture Enhances the In-Vitro Development and Graft Function of Young Porcine Islets. Int J Mol Sci 2021; 22:8367. [PMID: 34445075 PMCID: PMC8394857 DOI: 10.3390/ijms22168367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 11/20/2022] Open
Abstract
Pre-weaned porcine islets (PPIs) represent an unlimited source for islet transplantation but are functionally immature. We previously showed that necrostatin-1 (Nec-1) immediately after islet isolation enhanced the in vitro development of PPIs. Here, we examined the impact of Nec-1 on the in vivo function of PPIs after transplantation in diabetic mice. PPIs were isolated from pancreata of 8-15-day-old, pre-weaned pigs and cultured in media alone, or supplemented with Nec-1 (100 µM) on day 0 or on day 3 of culture (n = 5 for each group). On day 7, islet recovery, viability, oxygen consumption rate, insulin content, cellular composition, insulin secretion capacity, and transplant outcomes were evaluated. While islet viability and oxygen consumption rate remained high throughout 7-day tissue culture, Nec-1 supplementation on day 3 significantly improved islet recovery, insulin content, endocrine composition, GLUT2 expression, differentiation potential, proliferation capacity of endocrine cells, and insulin secretion. Adding Nec-1 on day 3 of tissue culture enhanced the islet recovery, proportion of delta cells, beta-cell differentiation and proliferation, and stimulation index. In vivo, this leads to shorter times to normoglycemia, better glycemic control, and higher circulating insulin. Our findings identify the novel time-dependent effects of Nec-1 supplementation on porcine islet quantity and quality prior to transplantation.
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Affiliation(s)
- Hien Lau
- Department of Surgery, University of California Irvine, Irvine, CA 92868, USA; (H.L.); (N.C.); (S.R.); (M.A.)
| | - Shiri Li
- Weill Cornell Medical College, Cornell University, Ithaca, NY 14850, USA;
| | - Nicole Corrales
- Department of Surgery, University of California Irvine, Irvine, CA 92868, USA; (H.L.); (N.C.); (S.R.); (M.A.)
| | - Samuel Rodriguez
- Department of Surgery, University of California Irvine, Irvine, CA 92868, USA; (H.L.); (N.C.); (S.R.); (M.A.)
| | - Mohammadreza Mohammadi
- Sue and Bill Gross Stem Cell Research Center, Department of Materials Science and Engineering, University of California Irvine, Irvine, CA 92697, USA;
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Irvine, CA 92868, USA; (H.L.); (N.C.); (S.R.); (M.A.)
| | - Paul de Vos
- University Medical Center Groningen, Department of Pathology and Medical Biology, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Jonathan RT Lakey
- Department of Surgery, University of California Irvine, Irvine, CA 92868, USA; (H.L.); (N.C.); (S.R.); (M.A.)
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA
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Zhang L, Sheng C, Zhou F, Zhu K, Wang S, Liu Q, Yuan M, Xu Z, Liu Y, Lu J, Liu J, Zhou L, Wang X. CBP/p300 HAT maintains the gene network critical for β cell identity and functional maturity. Cell Death Dis 2021; 12:476. [PMID: 33980820 PMCID: PMC8116341 DOI: 10.1038/s41419-021-03761-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022]
Abstract
Loss of β cell identity and functional immaturity are thought to be involved in β cell failure in type 2 diabetes. CREB-binding protein (CBP) and its paralogue p300 act as multifunctional transcriptional co-activators and histone acetyltransferases (HAT) with extensive biological functions. However, whether the regulatory role of CBP/p300 in islet β cell function depends on the HAT activity remains uncertain. In this current study, A-485, a selective inhibitor of CBP/p300 HAT activity, greatly impaired glucose-stimulated insulin secretion from rat islets in vitro and in vivo. RNA-sequencing analysis showed a comprehensive downregulation of β cell and α cell identity genes in A-485-treated islets, without upregulation of dedifferentiation markers and derepression of disallowed genes. A-485 treatment decreased the expressions of genes involved in glucose sensing, not in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. In the islets of prediabetic db/db mice, CBP/p300 displayed a significant decrease with key genes for β cell function. The deacetylation of histone H3K27 as well as the transcription factors Hnf1α and Foxo1 was involved in CBP/p300 HAT inactivation-repressed expressions of β cell identity and functional genes. These findings highlight the dominant role of CBP/p300 HAT in the maintenance of β cell identity by governing transcription network.
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Affiliation(s)
- Linlin Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxiang Sheng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feiye Zhou
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kecheng Zhu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shushu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianqian Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Miaomiao Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaoqian Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jieli Lu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianmin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Libin Zhou
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xiao Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes. Nutrients 2021; 13:nu13051593. [PMID: 34068827 PMCID: PMC8151793 DOI: 10.3390/nu13051593] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 01/09/2023] Open
Abstract
Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.
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Fukuda T, Bouchi R, Takeuchi T, Amo-Shiinoki K, Kudo A, Tanaka S, Tanabe M, Akashi T, Hirayama K, Odamaki T, Igarashi M, Kimura I, Tanabe K, Tanizawa Y, Yamada T, Ogawa Y. Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes. Diabetes Care 2021; 44:1002-1011. [PMID: 33627367 DOI: 10.2337/dc20-0864] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 01/18/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To elucidate the pathogenesis of postpancreatectomy diabetes mellitus (PPDM). RESEARCH DESIGN AND METHODS Forty-eight patients without diabetes undergoing either pancreatoduodenectomy (PD) (n = 20) or distal pancreatectomy (DP) (n = 28) were included. A 75-g oral glucose tolerance test was performed every 6 months. Microbiome composition and short-chain fatty acids (SCFAs) in feces were examined before and 6 months after surgery. The association of histological characteristics of the resected pancreas with PPDM was examined. RESULTS During follow-up (median 3.19 years), 2 of 20 PD patients and 16 of 28 DP patients developed PPDM. Proteobacteria relative abundance, plasma glucagon-like peptide 1 (GLP-1), and fecal butyrate levels increased only after PD. Postsurgical butyrate levels were correlated with postsurgical GLP-1 levels. With no significant difference in the volume of the resected pancreas between the surgical procedures, both β-cell and α-cell areas in the resected pancreas were significantly higher in DP patients than in PD patients. In DP patients, the progressors to diabetes showed preexisting insulin resistance compared with nonprogressors, and both increased α- and β-cell areas were predictors of PPDM. Furthermore, in DP patients, α-cell and β-cell areas were associated with ALDH1A3 expression in islets. CONCLUSIONS We postulate that a greater removal of β-cells contributes to the development of PPDM after DP. Islet expansion along with preexisting insulin resistance is associated with high cellular plasticity, which may predict the development of PPDM after DP. In contrast, PD is associated with alterations of gut microbiome and increases in SCFA production and GLP-1 secretion, possibly protecting against PPDM development.
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Affiliation(s)
- Tatsuya Fukuda
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryotaro Bouchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
- Diabetes and Metabolism Information Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takato Takeuchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kikuko Amo-Shiinoki
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takumi Akashi
- Department of Human Pathology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuhiro Hirayama
- Laboratory of Veterinary Public Health, Department of Veterinary Medical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Toshitaka Odamaki
- R&D Division, Next Generation Science Institute, Morinaga Milk Industry Co., Ltd., Kanagawa, Japan
| | - Miki Igarashi
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Ikuo Kimura
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Katsuya Tanabe
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihiro Ogawa
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- AMED-CREST, Tokyo, Japan
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Campbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol 2021; 22:142-158. [PMID: 33398164 PMCID: PMC8115730 DOI: 10.1038/s41580-020-00317-7] [Citation(s) in RCA: 343] [Impact Index Per Article: 85.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2020] [Indexed: 02/07/2023]
Abstract
Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic β-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory mechanisms and is essential for the control of blood levels of glucose. The deregulation of these mechanisms leads to various pathologies, most notably type 2 diabetes, which is driven by the combined lesions of impaired insulin action and a loss of the normal insulin secretion response to glucose. Glucose stimulates insulin secretion from β-cells in a bi-modal fashion, and new insights about the underlying mechanisms, particularly relating to the second or amplifying phase of this secretory response, have been recently gained. Other recent work highlights the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of the β-cell glucose response. These advances provide a new perspective for the understanding of the β-cell failure that triggers type 2 diabetes.
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Affiliation(s)
- Jonathan E Campbell
- Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA
- Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
- Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC, USA.
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
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50
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Sun S, Zhou N, Feng Y, Lv Y, He J, Liu S, Chen W, Kong W, Zhou Z. Evaluation of Chronic Pancreatitis With T 1 ρ MRI: A Preliminary Study. J Magn Reson Imaging 2021; 53:577-584. [PMID: 32770605 DOI: 10.1002/jmri.27302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Chronic pancreatitis (CP) can result in persistent damage to the endocrine and exocrine tissues of the pancreas. There is an unmet need for quantitative methods to evaluate CP noninvasively. PURPOSE To investigate the utility of T1 ρ magnetic resonance imaging (MRI) for the assessment of CP. STUDY TYPE Prospective. POPULATION Twenty patients with CP and 24 healthy volunteers. FIELD STRENGTH/SEQUENCE 3T MRI including T1 ρ sequence (spin lock time = 0, 1, 10, 20, 40, 60 msec). ASSESSMENT Pancreatic T1 ρ values and anterior-posterior (AP) diameters in the head, body, and tail were measured in all participants. Regions of interest with circle (ROIcircle ) and free-hand (ROIFH ) were drawn for T1 ρ value measurements. STATISTICAL TESTS Mann-Whitney U-test; Wilcoxon Signed Ranks test; receiver operating characteristic (ROC) curve; and Bland-Altman analysis. RESULTS The T1 ρ values of pancreatic tail and the mean T1 ρ values for ROIcircle and the T1 ρ values of pancreatic tail for ROIFH in patients with CP were significantly higher than those in healthy volunteers (all P < 0.05). Pancreatic head AP diameter significantly increased, while pancreatic tail AP diameter significantly decreased in patients with CP compared with healthy volunteers (both P < 0.05). The areas under the ROC curves (AUCs) of pancreatic tail T1 ρ values with ROIcircle and tail AP diameter in diagnosing CP were 0.744 and 0.798, respectively. A combination of pancreatic tail T1 ρ values with ROIcircle and tail AP diameter achieved good performance for diagnosing CP (AUC = 0.838). DATA CONCLUSION T1 ρ MRI might be a potential technique for the noninvasive evaluation of CP. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:577-584.
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Affiliation(s)
- Shuangshuang Sun
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Nan Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yongjing Feng
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jian He
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Song Liu
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | | | - Wentao Kong
- Department of Ultrasound, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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