|
1
|
Gao Y, Chen Q, Wu Z, Yuan L. Regulation of pancreatic β cells by exosomes from different sources. Diabetes Res Clin Pract 2025; 224:112222. [PMID: 40324722 DOI: 10.1016/j.diabres.2025.112222] [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: 02/26/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Diabetes is a chronic metabolic disorder with rising global prevalence, particularly in developed and high-income regions. Central to its pathogenesis is the dysfunction of pancreatic β-cells, alongside impaired glucose and lipid metabolism in peripheral insulin-responsive tissues. Exosomes are nano-sized extracellular vesicles essential for intercellular communication and have emerged as pivotal regulators of metabolic homeostasis. Secreted by virtually all cell types, exosomes encapsulate bioactive cargo that reflects their cellular origin and physiological state, thereby exerting diverse functional effects. Recent evidence highlights the role of exosomes derived from the liver, gut, adipose tissue, skeletal muscle, and mesenchymal stem cells in modulating β-cell proliferation, insulin secretion, and survival. In peripheral tissues exosomes also influence insulin sensitivity by regulating glucose and lipid metabolism, ultimately shaping β-cell responses under hyperglycemic conditions. A more comprehensive understanding of exosome-mediated crosstalk between metabolic organs and pancreatic β-cells could pave the way for the development of exosome-based diagnostic tools and therapeutic strategies aimed at improving early detection, prevention, and treatment of the diabetes.
Collapse
Affiliation(s)
- Yuanyuan Gao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qi Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhuoying Wu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| |
Collapse
|
|
2
|
Song J, Wang C, Zhao T, Zhang Y, Xing J, Zhao X, Zhang Y, Zhang Z. Multi-omics approaches for biomarker discovery and precision diagnosis of prediabetes. Front Endocrinol (Lausanne) 2025; 16:1520436. [PMID: 40162315 PMCID: PMC11949806 DOI: 10.3389/fendo.2025.1520436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025] Open
Abstract
Recent advancements in multi-omics technologies have provided unprecedented opportunities to identify biomarkers associated with prediabetes, offering novel insights into its diagnosis and management. This review synthesizes the latest findings on prediabetes from multiple omics domains, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and radiomics. We explore how these technologies elucidate the molecular and cellular mechanisms underlying prediabetes and analyze potential biomarkers with predictive value in disease progression. Integrating multi-omics data helps address the limitations of traditional diagnostic methods, enabling early detection, personalized interventions, and improved patient outcomes. However, challenges such as data integration, standardization, and clinical validation and translation remain to be resolved. Future research leveraging artificial intelligence and machine learning is expected to further enhance the predictive power of multi-omics technologies, contributing to the precision diagnosis and tailored management of prediabetes.
Collapse
Affiliation(s)
- Jielin Song
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
| | - Chuanfu Wang
- Department of Encephalopathy, Liangping District Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Tong Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
| | - Yu Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
| | - Jixiang Xing
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
| | - Xuelian Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
| | - Yunsha Zhang
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhaohui Zhang
- TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Institute of Traditional Chinese Medicine Surgery, Tianjin, China
- Department of Traditional Chinese Medicine Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| |
Collapse
|
|
3
|
Wang H, Qi L, Han H, Li X, Han M, Xing L, Li L, Jiang H. Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies. Acta Pharm Sin B 2024; 14:4756-4775. [PMID: 39664424 PMCID: PMC11628839 DOI: 10.1016/j.apsb.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
Collapse
Affiliation(s)
- Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Han Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xuena Li
- College of Pharmacy, Yanbian University, Yanji 133000, China
| | - Mengmeng Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing 210009, China
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- College of Pharmacy, Yanbian University, Yanji 133000, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| |
Collapse
|
|
4
|
Zhou Z, Zhang L, Wei X, Wang A, Hu Y, Xiao M, Zheng Y. 1,25(OH) 2D 3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM. Endocrine 2024; 85:1193-1205. [PMID: 38656750 DOI: 10.1007/s12020-024-03833-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 04/11/2024] [Indexed: 04/26/2024]
Abstract
PURPOSE To evaluate the effect and mechanism of 1,25(OH)2D3 on pancreatic stellate cells (PSCs) in type 2 diabetes mellitus (T2DM). METHODS A mouse model of T2DM was successfully established by high-fat diet (HFD) /streptozotocin (STZ) and administered 1,25(OH)2D3 for 3 weeks. Fasting blood glucose (FBG), glycated hemoglobin A1c (GHbA1c), insulin (INS) and glucose tolerance were measured. Histopathology changes and fibrosis of pancreas were examined by hematoxylin and eosin staining and Masson staining. Mouse PSCs were extracted, co-cultured with mouse insulinoma β cells (MIN6 cells) and treated with 1,25(OH)2D3. ELISA detection of inflammatory factor expression. Tissue reactive oxygen species (ROS) levels were also measured. Immunofluorescence or Western blotting were used to measure fibrosis and inflammation-related protein expression. RESULTS PSCs activation and islets fibrosis in T2DM mice. Elevated blood glucose was accompanied by significant increases in serum inflammatory cytokines and tissue ROS levels. 1,25(OH)2D3 attenuated islet fibrosis by reducing hyperglycemia, ROS levels, and inflammatory factors expression. Additionally, the co-culture system confirmed that 1,25(OH)2D3 inhibited PSCs activation, reduced the secretion of pro-inflammatory cytokines, down-regulated the expression of fibrosis and inflammation-related proteins, and promoted insulin secretion. CONCLUSION Our findings identify that PSCs activation contributes to islet fibrosis and β-cell dysfunction. 1,25(OH)2D3 exerts beneficial effects on T2DM potentially by inhibiting PSCs activation and inflammatory response, highlighting promising control strategies of T2DM by vitamin D.
Collapse
Affiliation(s)
- Zhengyu Zhou
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China.
| | - Lewen Zhang
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Xun Wei
- Center of Laboratory Animal, Shanghai Jiao Tong University, Shanghai, China
| | - Aiqing Wang
- Suzhou Medical college of Soochow University, Suzhou, China
| | - Yudie Hu
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Min Xiao
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Yuxuan Zheng
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| |
Collapse
|
|
5
|
Fukui H, Onishi H, Nakamoto A, Tsuboyama T, Ota T, Honda T, Kiso K, Yoshidome E, Enchi Y, Tatsumi M, Tomiyama N. Hepatic and pancreatic extracellular volume fraction analysis using contrast-enhanced CT in patients with diabetes mellitus and pre-diabetes. Jpn J Radiol 2024; 42:599-611. [PMID: 38351253 PMCID: PMC11139686 DOI: 10.1007/s11604-024-01531-5] [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: 10/21/2023] [Accepted: 01/05/2024] [Indexed: 05/31/2024]
Abstract
PURPOSE Liver and pancreatic fibrosis is associated with diabetes mellitus (DM), and liver fibrosis is associated with pancreatic fibrosis. This study aimed to investigate the relationship between the hepatic and pancreatic extracellular volume fractions (fECVs), which correlate with tissue fibrosis, and their relationships with DM and pre-DM (pDM). MATERIAL AND METHODS We included 100 consecutive patients with known or suspected liver and/or pancreatic diseases who underwent contrast-enhanced CT. Patients were classified as nondiabetes, pDM, and DM with hemoglobin A1c (HbA1c) levels of < 5.7%, 5.7%-6.5%, and ≥ 6.5% or fasting plasma glucose (FPG) levels of < 100, 100-125 mg/dL, and ≥ 126 mg/dL, respectively. Subtraction images between unenhanced and equilibrium-phase images were prepared. The liver and the pancreas were automatically extracted using a high-speed, three-dimensional image analysis system, and their respective mean CT values were calculated. The enhancement degree of the aorta (Δaorta) was measured. fECV was calculated using the following equation: fECV = (100 - hematocrit) * Δliver or pancreas/Δaorta. Differences were investigated in hepatic and pancreatic fECVs among the three groups, and the correlation between each two in hepatic fECV, pancreatic fECV, and HbA1c was determined. RESULTS The pancreatic fECV, which was positively correlated with the hepatic fECV and HbA1c (r = 0.51, P < 0.001, and r = 0.51, P < 0.001, respectively), significantly differed among the three groups (P < 0.001) and was significantly greater in DM than in pDM or nondiabetes and in pDM with nondiabetes (P < 0.001). Hepatic fECV was significantly greater in DM than in nondiabetes (P < 0.05). CONCLUSION The pancreatic fECV and pDM/DM are closely related.
Collapse
Affiliation(s)
- Hideyuki Fukui
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Hiromitsu Onishi
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Japan
| | - Atsushi Nakamoto
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Tsuboyama
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takashi Ota
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Toru Honda
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kengo Kiso
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Eriko Yoshidome
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yukihiro Enchi
- Division of Radiology, Department of Medical Technology, Osaka University Hospital, Suita, Japan
| | - Mitsuaki Tatsumi
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Noriyuki Tomiyama
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| |
Collapse
|
|
6
|
Malik SS, Padmanabhan D, Hull-Meichle RL. Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes. Front Endocrinol (Lausanne) 2023; 14:1269139. [PMID: 38075070 PMCID: PMC10704027 DOI: 10.3389/fendo.2023.1269139] [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: 07/29/2023] [Accepted: 10/03/2023] [Indexed: 12/18/2023] Open
Abstract
Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in CFTR (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from β cells in the pancreatic islet, but the mechanisms underlying the loss of β cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in β cells and an increase in α, δ and γ cell abundance. The small amount of available data suggest that substantial loss of pancreatic/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the β cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD.
Collapse
Affiliation(s)
- Sarah S. Malik
- Department of Pharmacology, University of Washington, Seattle, WA, United States
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Diksha Padmanabhan
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Seattle Institute for Biomedical and Clinical Research, Seattle, WA, United States
| | - Rebecca L. Hull-Meichle
- Department of Pharmacology, University of Washington, Seattle, WA, United States
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Seattle Institute for Biomedical and Clinical Research, Seattle, WA, United States
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| |
Collapse
|
|
7
|
Park MN. Therapeutic Strategies for Pancreatic-Cancer-Related Type 2 Diabetes Centered around Natural Products. Int J Mol Sci 2023; 24:15906. [PMID: 37958889 PMCID: PMC10648679 DOI: 10.3390/ijms242115906] [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: 08/25/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a highly malignant neoplasm, is classified as one of the most severe and devastating types of cancer. PDAC is a notable malignancy that exhibits a discouraging prognosis and a rising occurrence. The interplay between diabetes and pancreatic cancer exhibits a reciprocal causation. The identified metabolic disorder has been observed to possess noteworthy consequences on health outcomes, resulting in elevated rates of morbidity. The principal mechanisms involve the suppression of the immune system, the activation of pancreatic stellate cells (PSCs), and the onset of systemic metabolic disease caused by dysfunction of the islets. From this point forward, it is important to recognize that pancreatic-cancer-related diabetes (PCRD) has the ability to increase the likelihood of developing pancreatic cancer. This highlights the complex relationship that exists between these two physiological states. Therefore, we investigated into the complex domain of PSCs, elucidating their intricate signaling pathways and the profound influence of chemokines on their behavior and final outcome. In order to surmount the obstacle of drug resistance and eliminate PDAC, researchers have undertaken extensive efforts to explore and cultivate novel natural compounds of the next generation. Additional investigation is necessary in order to comprehensively comprehend the effect of PCRD-mediated apoptosis on the progression and onset of PDAC through the utilization of natural compounds. This study aims to examine the potential anticancer properties of natural compounds in individuals with diabetes who are undergoing chemotherapy, targeted therapy, or immunotherapy. It is anticipated that these compounds will exhibit increased potency and possess enhanced pharmacological benefits. According to our research findings, it is indicated that naturally derived chemical compounds hold potential in the development of PDAC therapies that are both safe and efficacious.
Collapse
Affiliation(s)
- Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Republic of Korea
| |
Collapse
|
|
8
|
Oliveira AG, Carvalho BM, Zweig Rocha G. Editorial: Pharmacological and non-pharmacological therapy for obesity and diabetes - volume II. Front Endocrinol (Lausanne) 2023; 14:1252536. [PMID: 37929042 PMCID: PMC10623447 DOI: 10.3389/fendo.2023.1252536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/05/2023] [Indexed: 11/07/2023] Open
Affiliation(s)
- Alexandre Gabarra Oliveira
- Department of Physical Education, Bioscience Institute, São Paulo State University (UNESP), Rio Claro, São Paulo, Brazil
| | - Bruno Melo Carvalho
- Institute of Biological Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil
| | - Guilherme Zweig Rocha
- Department of Internal Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| |
Collapse
|
|
9
|
Lee E, Ryu GR, Ko SH, Ahn YB, Song KH. Pancreatic stellate cells promote pancreatic β-cell death through exosomal microRNA transfer in hypoxia. Mol Cell Endocrinol 2023; 572:111947. [PMID: 37150285 DOI: 10.1016/j.mce.2023.111947] [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: 03/30/2023] [Revised: 04/26/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023]
Abstract
Hypoxia in pancreatic islets (islet hypoxia) can occur in type 2 diabetes mellitus. Previously, our in vitro experiments demonstrated that pancreatic stellate cells (PSCs) within the islet are activated in hypoxia, promoting pancreatic β-cell death. Here, we aimed to demonstrate the in vivo activation of intra-islet PSCs and investigate the mechanism of PSC-induced β-cell death in hypoxia. A novel in vivo model of islet hypoxia was established by injecting fluorescent microspheres into a carotid artery of Balb/c mice (Microsphere mice). The intraperitoneal glucose tolerance (IPGTT) was performed, and pancreatic tissues were stained for insulin expression after tissue clearing. Pimonidazole staining was also performed in the pancreas to detect the presence of hypoxia in islets. Next, primary PSCs were isolated and cultured from Balb/c mice. Exosomes were isolated from culture media from PSCs cultured in hypoxia (1% oxygen). MicroRNAs (miRNAs) were prepared from exosomes from PSCs, and miRNA expression profiles were analyzed by miRNA sequencing. Several miRNAs were overexpressed in islets using miRNA mimics. Two weeks after injection of microspheres, the Microsphere mice showed worsening of glucose tolerance in IPGTT. Later, cataracts were developed in the eyes of the mice. The pancreas showed that the areas, perimeters, and diameters of insulin-positive cells decreased in Microsphere mice. Pimonidazole adducts were detected in the islets of these mice, indicating the presence of islet hypoxia. In addition, α-smooth muscle actin-positive areas per islet were higher in Microsphere mice, confirming the in vivo activation of intra-islet PSCs in hypoxia. Mouse islets cultured with exosomes isolated from PSCs cultured in hypoxia showed a decrease in cell viability. The exosomes contained a variety of miRNAs, of which miR-23a-3p was found to notably increase β-cell death through apoptosis. Together, our in vivo and in vitro data provide evidence to support that PSCs within the islets are activated in hypoxia and promote β-cell death through exosomal miRNA transfer, which may contribute to the progression of type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Esder Lee
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Gyeong Ryul Ryu
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Hyun Ko
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yu-Bae Ahn
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ki-Ho Song
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
| |
Collapse
|
|
10
|
Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
Collapse
Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | | | | | | | | | | |
Collapse
|
|
11
|
Kokabi F, Ebrahimi S, Mirzavi F, Ghiasi Nooghabi N, Hashemi SF, Hashemy SI. The neuropeptide substance P/neurokinin-1 receptor system and diabetes: From mechanism to therapy. Biofactors 2023. [PMID: 36651605 DOI: 10.1002/biof.1935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023]
Abstract
Diabetes is a significant public health issue known as the world's fastest-growing disease condition. It is characterized by persistent hyperglycemia and subsequent chronic complications leading to organ dysfunction and, ultimately, the failure of target organs. Substance P (SP) is an undecapeptide that belongs to the family of tachykinin (TK) peptides. The SP-mediated activation of the neurokinin 1 receptor (NK1R) regulates many pathophysiological processes in the body. There is also a relation between the SP/NK1R system and diabetic processes. Importantly, deregulated expression of SP has been reported in diabetes and diabetes-associated chronic complications. SP can induce both diabetogenic and antidiabetogenic effects and thus affect the pathology of diabetes destructively or protectively. Here, we review the current knowledge of the functional relevance of the SP/NK1R system in diabetes pathogenesis and its exploitation for diabetes therapy. A comprehensive understanding of the role of the SP/NK1R system in diabetes is expected to shed further light on developing new therapeutic possibilities for diabetes and its associated chronic conditions.
Collapse
Affiliation(s)
- Fariba Kokabi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | | | | | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
12
|
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.
Collapse
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.
| |
Collapse
|
|
13
|
Zhang J, Bai J, Zhou Q, Hu Y, Wang Q, Yang L, Chen H, An H, Zhou C, Wang Y, Chen X, Li M. Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway. Cell Death Dis 2022; 13:440. [PMID: 35523788 PMCID: PMC9076672 DOI: 10.1038/s41419-022-04894-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022]
Abstract
The activation of pancreatic stellate cells (PSCs) is the key mechanism of pancreatic fibrosis, which can lead to β-cell failure. Oxidative stress is an important risk factor for PSC activation. There is no direct evidence proving if administration of glutathione can inhibit fibrosis and β-cell failure. To explore the role of glutathione in pancreatic fibrosis and β-cell failure induced by hyperglycaemia, we established a rat model of pancreatic fibrosis and β-cell failure. The model was founded through long-term oscillating glucose (LOsG) intake and the setup of a sham group and a glutathione intervention group. In vitro, rat PSCs were treated with low glucose, high glucose, or high glucose plus glutathione to explore the mechanism of high glucose-induced PSC activation and the downstream effects of glutathione. Compared with sham rats, LOsG-treated rats had higher reactive oxygen species (ROS) levels in peripheral leukocytes and pancreatic tissue while TGFβ signalling was upregulated. In addition, as the number of PSCs and pancreatic fibrosis increased, β-cell function was significantly impaired. Glutathione evidently inhibited the upregulation of TGFβ signalling and several unfavourable outcomes caused by LOsG. In vitro treatment of high glucose for 72 h resulted in higher ROS accumulation and potentiated TGFβ pathway activation in PSCs. PSCs showed myofibroblast phenotype transformation with upregulation of α-SMA expression and increased cell proliferation and migration. Treatment with either glutathione or TGFβ pathway inhibitors alleviated these changes. Together, our findings suggest that glutathione can inhibit PSC activation-induced pancreatic fibrosis via blocking ROS/TGFβ/SMAD signalling in vivo and in vitro.
Collapse
Affiliation(s)
- Jitai Zhang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Juan Bai
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Zhou
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuxin Hu
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lanting Yang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huamin Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hui An
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632Department of Anesthesia and Critical Care, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chuanzan Zhou
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yongyu Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiufang Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ming Li
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
14
|
Qin R, Zhao Q, Han B, Zhu HP, Peng C, Zhan G, Huang W. Indole-Based Small Molecules as Potential Therapeutic Agents for the Treatment of Fibrosis. Front Pharmacol 2022; 13:845892. [PMID: 35250597 PMCID: PMC8888875 DOI: 10.3389/fphar.2022.845892] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 01/19/2022] [Indexed: 12/17/2022] Open
Abstract
Indole alkaloids are widely distributed in nature and have been particularly studied because of their diverse biological activities, such as anti-inflammatory, anti-tumor, anti-bacterial, and anti-oxidant activities. Many kinds of indole alkaloids have been applied to clinical practice, proving that indole alkaloids are beneficial scaffolds and occupy a crucial position in the development of novel agents. Fibrosis is an end-stage pathological condition of most chronic inflammatory diseases and is characterized by excessive deposition of fibrous connective tissue components, ultimately resulting in organ dysfunction and even failure with significant morbidity and mortality. Indole alkaloids and indole derivatives can alleviate pulmonary, myocardial, renal, liver, and islet fibrosis through the suppression of inflammatory response, oxidative stress, TGF-β/Smad pathway, and other signaling pathways. Natural indole alkaloids, such as isorhynchophylline, evodiamine, conophylline, indirubin, rutaecarpine, yohimbine, and vincristine, are reportedly effective in organ fibrosis treatment. In brief, indole alkaloids with a wide range of pharmacological bioactivities are important candidate drugs for organ fibrosis treatment. The present review discusses the potential of natural indole alkaloids, semi-synthetic indole alkaloids, synthetic indole derivatives, and indole-contained metabolites in organ fibrosis treatment.
Collapse
Affiliation(s)
- Rui Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hong-Ping Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Gu Zhan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Wei Huang, ; Gu Zhan,
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Wei Huang, ; Gu Zhan,
| |
Collapse
|
|
15
|
Schuurman M, Wallace M, Sahi G, Barillaro M, Zhang S, Rahman M, Sawyez C, Borradaile N, Wang R. N-acetyl-L-cysteine treatment reduces beta-cell oxidative stress and pancreatic stellate cell activity in a high fat diet-induced diabetic mouse model. Front Endocrinol (Lausanne) 2022; 13:938680. [PMID: 36093092 PMCID: PMC9452715 DOI: 10.3389/fendo.2022.938680] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity plays a major role in type II diabetes (T2DM) progression because it applies metabolic and oxidative stress resulting in dysfunctional beta-cells and activation of intra-islet pancreatic stellate cells (PaSCs) which cause islet fibrosis. Administration of antioxidant N-acetyl-L-cysteine (NAC) in vivo improves metabolic outcomes in diet-induced obese diabetic mice, and in vitro inhibits PaSCs activation. However, the effects of NAC on diabetic islets in vivo are unknown. This study examined if dosage and length of NAC treatment in HFD-induced diabetic mice effect metabolic outcomes associated with maintaining healthy beta-cells and quiescent PaSCs, in vivo. Male C57BL/6N mice were fed normal chow (ND) or high-fat (HFD) diet up to 30 weeks. NAC was administered in drinking water to HFD mice in preventative treatment (HFDpNAC) for 23 weeks or intervention treatment for 10 (HFDiNAC) or 18 (HFDiNAC+) weeks, respectively. HFDpNAC and HFDiNAC+, but not HFDiNAC, mice showed significantly improved glucose tolerance and insulin sensitivity. Hyperinsulinemia led by beta-cell overcompensation in HFD mice was significantly rescued in NAC treated mice. A reduction of beta-cell nuclear Pdx-1 localization in HFD mice was significantly improved in NAC treated islets along with significantly reduced beta-cell oxidative stress. HFD-induced intra-islet PaSCs activation, labeled by αSMA, was significantly diminished in NAC treated mice along with lesser intra-islet collagen deposition. This study determined that efficiency of NAC treatment is beneficial at maintaining healthy beta-cells and quiescent intra-islet PaSCs in HFD-induced obese T2DM mouse model. These findings highlight an adjuvant therapeutic potential in NAC for controlling T2DM progression in humans.
Collapse
Affiliation(s)
- Meg Schuurman
- Children’s Health Research Institute, London, ON, Canada
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Madison Wallace
- Children’s Health Research Institute, London, ON, Canada
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON, Canada
| | - Gurleen Sahi
- Children’s Health Research Institute, London, ON, Canada
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Malina Barillaro
- Children’s Health Research Institute, London, ON, Canada
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Siyi Zhang
- Children’s Health Research Institute, London, ON, Canada
| | - Mushfiqur Rahman
- Children’s Health Research Institute, London, ON, Canada
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Cynthia Sawyez
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Nica Borradaile
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Rennian Wang
- Children’s Health Research Institute, London, ON, Canada
- Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
- *Correspondence: Rennian Wang,
| |
Collapse
|
|
16
|
Lee JM, Kim HS, Lee M, Park HS, Kang S, Nahm JH, Park JS. Association between pancreatic fibrosis and development of pancreoprivic diabetes after pancreaticoduodenectomy. Sci Rep 2021; 11:23538. [PMID: 34876608 PMCID: PMC8651673 DOI: 10.1038/s41598-021-02858-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/23/2021] [Indexed: 11/29/2022] Open
Abstract
This study investigated the correlation between pancreatic fibrosis (PF) and development of pancreoprivic diabetes after pancreaticoduodenectomy (PD). Ninety-five patients who underwent PD at Gangnam Severance Hospital between 2014 and 2017 were enrolled. PF grade was evaluated with alpha-smooth muscle actin (SMA) and Masson’s trichrome (TRC) staining. New-onset pancreoprivic diabetes and recurrence of disease were evaluated using fasting blood glucose measurement and radiography taken at 3-month intervals. Sixty-one patients did not have preoperative diabetes, however, 40 (65.6%) patients developed pancreoprivic diabetes after PD. High-grade PF was more common in the diabetes group than in the normal group (SMA, 42.5% vs. 28.6%, P = 0.747; TRC, 47.5% vs. 28.6%, P = 0.361). The 1-year cumulative incidence of hyperglycemia/pancreoprivic diabetes was higher with high-grade PF than low-grade PF (SMA, 94.4% vs. 73.0%, P = 0.027; TRC, 89.3% vs. 75.0%, P = 0.074). The SMA-TRC combined high-grade group had a higher proportion of primary pancreatic disease than the combined low-grade group (90.0% vs. 37.5%, P = 0.001). The 5-year disease-free survival of patients with pancreatic cancer was worse with high-grade PF than low-grade PF (SMA, 24.5% vs. 66.3%, P = 0.026; TRC, 23.6% vs. 58.4%, P = 0.047). In conclusion, patients with severe PF are more likely to develop pancreoprivic diabetes after PD and have worse disease-free survival.
Collapse
Affiliation(s)
- Jung Min Lee
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Republic of Korea
| | - Hyung Sun Kim
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ho Seon Park
- Department of Internal Medicine, Severance Institute for Vascular and Metabolic Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Shinae Kang
- Department of Internal Medicine, Severance Institute for Vascular and Metabolic Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hae Nahm
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Republic of Korea.
| | - Joon Seong Park
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Republic of Korea.
| |
Collapse
|
|
17
|
Perera CJ, Falasca M, Chari ST, Greenfield JR, Xu Z, Pirola RC, Wilson JS, Apte MV. Role of Pancreatic Stellate Cell-Derived Exosomes in Pancreatic Cancer-Related Diabetes: A Novel Hypothesis. Cancers (Basel) 2021; 13:5224. [PMID: 34680372 PMCID: PMC8534084 DOI: 10.3390/cancers13205224] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/27/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive β cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to β cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating β cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD.
Collapse
Affiliation(s)
- Chamini J. Perera
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth 6102, Australia;
| | - Suresh T. Chari
- M.D Anderson Cancer Centre, Department of Gastroenterology, Hepatology and Nutrition, University of Texas, Houston, TX 75083, USA;
| | - Jerry R. Greenfield
- St Vincent Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia;
- Healthy Ageing, Garvan Institute of Medical Research, Darlinghurst 2830, Australia
- Department of Diabetes and Endocrinology, St Vincent’s Hospital, Darlinghurst 3065, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Romano C. Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| |
Collapse
|
|
18
|
Wang X, Carvalho V, Wang Q, Wang J, Li T, Chen Y, Ni C, Liu L, Yuan Y, Qiu S, Sun Z. Screening and Identification of Key Genes for Activation of Islet Stellate Cell. Front Endocrinol (Lausanne) 2021; 12:695467. [PMID: 34566887 PMCID: PMC8458934 DOI: 10.3389/fendo.2021.695467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/16/2021] [Indexed: 11/13/2022] Open
Abstract
Background It has been demonstrated that activated islet stellate cells (ISCs) play a critical role in islet fibrogenesis and significantly contribute to the progression of type 2 diabetes mellitus. However, the key molecules responsible for ISCs activation have not yet been determined. This study aimed to identify the potential key genes involved in diabetes-induced activation of ISCs. Method Stellate cells were isolated from three 10-week-old healthy male Wistar rats and three Goto-Kakizaki (GK) rats. Cells from each rat were primary cultured under the same condition. A Genome-wide transcriptional sequence of stellate cells was generated using the Hiseq3000 platform. The identified differentially expressed genes were validated using quantitative real-time PCR and western blotting in GK rats, high fat diet (HFD) rats, and their controls. Results A total of 204 differentially expressed genes (DEGs) between GK. ISCs and Wistar ISCs (W.ISCs) were identified, accounting for 0.58% of all the 35,362 genes detected. After the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, the mRNA levels of these genes were further confirmed by real-time PCR in cultured ISCs. We then selected Fos, Pdpn, Bad as the potential key genes for diabetes-induced activation of ISCs. Finally, we confirmed the protein expression levels of FOS, podoplanin, and Bad by western blotting and immunofluorescence in GK rats, HFD rats, and their controls. The results showed that the expression level of FOS was significantly decreased, while podoplanin and Bad were significantly increased in GK.ISCs and HFD rats compared with controls, which were consistent with the expression of α-smooth muscle actin. Conclusions A total of 204 DEGs were found between the GK.ISCs and W.ISCs. After validating the expression of potential key genes from GK rats and HFD rats, Fos, Pdpn, and Bad might be potential key genes involved in diabetes-induced activation of ISCs.
Collapse
Affiliation(s)
- Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Vladmir Carvalho
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Qianqian Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Jinbang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Tingting Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Chengming Ni
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Lili Liu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Yuan
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Shanhu Qiu
- Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| |
Collapse
|
|
19
|
Imamura Y, Kumagi T, Kuroda T, Koizumi M, Yoshida O, Kanemitsu K, Tada F, Tanaka Y, Hirooka M, Hiasa Y. Pancreas stiffness in liver cirrhosis is an indicator of insulin secretion caused by portal hypertension and pancreatic congestion. Hepatol Res 2021; 51:775-785. [PMID: 34018285 DOI: 10.1111/hepr.13672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/03/2021] [Accepted: 05/10/2021] [Indexed: 12/21/2022]
Abstract
AIM Portal hypertension induces pancreatic congestion and impaired insulin secretion in patients with liver cirrhosis (LC). However, its mechanism is unclear, with no established noninvasive imaging method for the evaluation of its pathogeneses. The present study focused on pancreas stiffness, as assessed by shear wave elastography (SWE), and examined its association with portal hypertension and insulin secretion. METHODS Shear wave elastography and contrast-enhanced ultrasonography were utilized to evaluate pancreas stiffness and congestion, respectively. A glucagon challenge test was used for insulin secretion assessment. Furthermore, rat models of carbon tetrachloride (CCl4 )-induced LC and portal hypertension were used to identify the direct effects of pancreatic congestion. Immunohistochemistry staining of the pancreas was carried out on human autopsy samples. RESULTS Pancreas stiffness measured by SWE was higher in patients with LC than in controls and showed significant correlation with pancreatic congestion. The glucagon challenge test indicated a lower value for the change in C-peptide immunoreactivity in the LC group, which was inversely correlated with pancreas stiffness and congestion. Additionally, portal hypertension and insulin secretion dysfunction were confirmed in CCl4 rat models. Autopsy of human samples revealed congestive and fibrotic changes in the pancreas and the relationship between insulin secretion and their factors in patients with LC. CONCLUSIONS In patients with LC, pancreas stiffness measured by SWE could be a potential noninvasive test for evaluating pancreatic congestion and fibrosis due to portal hypertension. Moreover, it was associated with impaired insulin secretion, and could aid in guiding the treatment for hepatogenous diabetes.
Collapse
Affiliation(s)
- Yoshiki Imamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.,Postgraduate Medical Education Center, Ehime University Hospital, Ehime, Japan
| | - Taira Kuroda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Kozue Kanemitsu
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, Ehime, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| |
Collapse
|
|
20
|
Cole LK, Agarwal P, Doucette CA, Fonseca M, Xiang B, Sparagna GC, Seshadri N, Vandel M, Dolinsky VW, Hatch GM. Tafazzin Deficiency Reduces Basal Insulin Secretion and Mitochondrial Function in Pancreatic Islets From Male Mice. Endocrinology 2021; 162:bqab102. [PMID: 34019639 PMCID: PMC8197286 DOI: 10.1210/endocr/bqab102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Indexed: 12/13/2022]
Abstract
Tafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ affects both the species and content of CL in the inner mitochondrial membrane, which are essential for normal cellular respiration. In pancreatic β cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown. Male 4-month-old doxycycline-inducible TAZ knock-down (KD) mice and wild-type littermate controls were used. Immunohistochemistry was used to assess β-cell morphology in whole pancreas sections, whereas ex vivo insulin secretion, CL content, RNA-sequencing analysis, and mitochondrial oxygen consumption were measured from isolated islet preparations. Ex vivo insulin secretion under nonstimulatory low-glucose concentrations was reduced ~52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ~58% in islets from TAZ KD animals. TAZ deficiency in pancreatic islets was associated with significant alteration in CL molecular species and elevated polyunsaturated fatty acid CL content. In addition, RNA-sequencing of isolated islets showed that TAZ KD increased expression of extracellular matrix genes, which are linked to pancreatic fibrosis, activated stellate cells, and impaired β-cell function. These data indicate a novel role for TAZ in regulating pancreatic islet function, particularly under low-glucose conditions.
Collapse
Affiliation(s)
- Laura K Cole
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Prasoon Agarwal
- KTH Royal Institute of Technology, School of Electrical Engineering and Computer Science, 10044 Stockholm, Sweden
- Science for Life Laboratory, 16939 Solna, Sweden
| | - Christine A Doucette
- Physiology and Pathophysiology, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Mario Fonseca
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Bo Xiang
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Genevieve C Sparagna
- Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA
| | - Nivedita Seshadri
- Physiology and Pathophysiology, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Marilyne Vandel
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Vernon W Dolinsky
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| | - Grant M Hatch
- Department of Pharmacology, Winnipeg, R3E3P4, Canada
- Department of Therapeutics, Winnipeg, R3E3P4, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children’s Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada
| |
Collapse
|
|
21
|
Tissue Engineering Strategies for Improving Beta Cell Transplantation Outcome. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00333-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Beta cell replacement therapy as a form of islet transplantation is a promising alternative therapy with the possibility to make selected patients with type 1 diabetes (T1D) insulin independent. However, this technique faces challenges such as extensive activation of the host immune system post-transplantation, lifelong need for immunosuppression, and the scarcity of islet donor pancreas. Advancement in tissue engineering strategies can improve these challenges and allow for a more widespread application of this therapy. This review will discuss the recent development and clinical translation of tissue engineering strategies in beta cell replacement therapy.
Recent Findings
Tissue engineering offers innovative solutions for producing unlimited glucose responsive cells and fabrication of appropriate devices/scaffolds for transplantation applications. Generation of pancreatic organoids with supporting cells in biocompatible biomaterials is a powerful technique to improve the function of insulin-producing cell clusters. Fabrication of physical barriers such as encapsulation strategies can protect the cells from the host immune system and allow for graft retrieval, although this strategy still faces major challenges to fully restore physiological glucose regulation.
Summary
The three main components of tissue engineering strategies including the generation of stem cell-derived insulin-producing cells and organoids and the possibilities for therapeutic delivery of cell-seeded devices to extra-hepatic sites need to come together in order to provide safe and functional insulin-producing devices for clinical beta cell replacement therapy.
Collapse
|
|
22
|
Martinez-Useros J, Martin-Galan M, Garcia-Foncillas J. The Match between Molecular Subtypes, Histology and Microenvironment of Pancreatic Cancer and Its Relevance for Chemoresistance. Cancers (Basel) 2021; 13:322. [PMID: 33477288 PMCID: PMC7829908 DOI: 10.3390/cancers13020322] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/17/2022] Open
Abstract
In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt et al. 2015 and Bailey et al. 2016 have found specific gene signatures, which identify different molecular subtypes of pancreatic cancer and provide a comprehensive stratification for both a personalized treatment or to identify potential druggable targets. However, the routine clinical management of pancreatic cancer does not consider a broad molecular analysis of each patient, due probably to the lack of target therapies for this tumor. Therefore, the current treatment decision is taken based on patients´ clinicopathological features and performance status. Histopathological evaluation of tumor samples could reveal many other attributes not only from tumor cells but also from their microenvironment specially about the presence of pancreatic stellate cells, regulatory T cells, tumor-associated macrophages, myeloid derived suppressor cells and extracellular matrix structure. In the present article, we revise the four molecular subtypes proposed by Bailey et al. and associate each subtype with other reported molecular subtypes. Moreover, we provide for each subtype a potential description of the tumor microenvironment that may influence treatment response according to the gene expression profile, the mutational landscape and their associated histology.
Collapse
|
|
23
|
Kim JJ, Lee E, Ryu GR, Ko SH, Ahn YB, Song KH. Hypoxia Increases β-Cell Death by Activating Pancreatic Stellate Cells within the Islet. Diabetes Metab J 2020; 44:919-927. [PMID: 32431113 PMCID: PMC7801750 DOI: 10.4093/dmj.2019.0181] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/06/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hypoxia can occur in pancreatic islets in type 2 diabetes mellitus. Pancreatic stellate cells (PSCs) are activated during hypoxia. Here we aimed to investigate whether PSCs within the islet are also activated in hypoxia, causing β-cell injury. METHODS Islet and primary PSCs were isolated from Sprague Dawley rats, and cultured in normoxia (21% O2) or hypoxia (1% O2). The expression of α-smooth muscle actin (α-SMA), as measured by immunostaining and Western blotting, was used as a marker of PSC activation. Conditioned media (hypoxia-CM) were obtained from PSCs cultured in hypoxia. RESULTS Islets and PSCs cultured in hypoxia exhibited higher expressions of α-SMA than did those cultured in normoxia. Hypoxia increased the production of reactive oxygen species. The addition of N-acetyl-L-cysteine, an antioxidant, attenuated the hypoxia-induced PSC activation in islets and PSCs. Islets cultured in hypoxia-CM showed a decrease in cell viability and an increase in apoptosis. CONCLUSION PSCs within the islet are activated in hypoxia through oxidative stress and promote islet cell death, suggesting that hypoxia-induced PSC activation may contribute to β-cell loss in type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Jong Jin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Esder Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Gyeong Ryul Ryu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu-Bae Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Ho Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
24
|
Chang WT, Ragazzi E, Liu PY, Wu SN. Effective block by pirfenidone, an antifibrotic pyridone compound (5-methyl-1-phenylpyridin-2[H-1]-one), on hyperpolarization-activated cation current: An additional but distinctive target. Eur J Pharmacol 2020; 882:173237. [PMID: 32525005 PMCID: PMC7276140 DOI: 10.1016/j.ejphar.2020.173237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 12/26/2022]
Abstract
Pirfenidone (PFD), a pyridone compound, is well recognized as an antifibrotic agent tailored for the treatment of idiopathic pulmonary fibrosis. Recently, through its anti-inflammatory and anti-oxidant effects, PFD based clinical trial has also been launched for the treatment of coronavirus disease (COVID-19). To what extent this drug can perturb membrane ion currents remains largely unknown. Herein, the exposure to PFD was observed to depress the amplitude of hyperpolarization-activated cation current (Ih) in combination with a considerable slowing in the activation time of the current in pituitary GH3 cells. In the continued presence of ivabradine or zatebradine, subsequent application of PFD decreased Ih amplitude further. The presence of PFD resulted in a leftward shift in Ih activation curve without changes in the gating charge. The addition of this compound also led to a reduction in area of voltage-dependent hysteresis evoked by long-lasting inverted triangular (downsloping and upsloping) ramp pulse. Neither the amplitude of M-type nor erg-mediated K+ current was altered by its presence. In whole-cell potential recordings, addition of PFD reduced the firing frequency, and this effect was accompanied by the depression in the amplitude of sag voltage elicited by hyperpolarizing current stimulus. Overall, this study highlights evidence that PFD is capable of perturbing specific ionic currents, revealing a potential additional impact on functional activities of different excitable cells.
Collapse
Affiliation(s)
- Wei-Ting Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Division of Cardiology, Internal Medicine, Chi-Mei Medical Center, Tainan, 71004, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, 71004, Taiwan.
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy
| | - Ping-Yen Liu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Division of Cardiology, Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, 70401, Taiwan.
| | - Sheng-Nan Wu
- Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| |
Collapse
|
|
25
|
Hadden M, Mittal A, Samra J, Zreiqat H, Sahni S, Ramaswamy Y. Mechanically stressed cancer microenvironment: Role in pancreatic cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188418. [PMID: 32827581 DOI: 10.1016/j.bbcan.2020.188418] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/21/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in the world due to its insensitivity to current therapies and its propensity to metastases from the primary tumor mass. This is largely attributed to its complex microenvironment composed of unique stromal cell populations and extracellular matrix (ECM). The recruitment and activation of these cell populations cause an increase in deposition of ECM components, which highly influences the behavior of malignant cells through disrupted forms of signaling. As PDAC progresses from premalignant lesion to invasive carcinoma, this dynamic landscape shields the mass from immune defenses and cytotoxic intervention. This microenvironment influences an invasive cell phenotype through altered forms of mechanical signaling, capable of enacting biochemical changes within cells through activated mechanotransduction pathways. The effects of altered mechanical cues on malignant cell mechanotransduction have long remained enigmatic, particularly in PDAC, whose microenvironment significantly changes over time. A more complete and thorough understanding of PDAC's physical surroundings (microenvironment), mechanosensing proteins, and mechanical properties may help in identifying novel mechanisms that influence disease progression, and thus, provide new potential therapeutic targets.
Collapse
Affiliation(s)
- Matthew Hadden
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia
| | - Anubhav Mittal
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Jaswinder Samra
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Hala Zreiqat
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia; ARC Training Centre for Innovative Bioengineering, The University of Sydney, NSW 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia.
| | - Yogambha Ramaswamy
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia.
| |
Collapse
|
|
26
|
Mateus Gonçalves L, Pereira E, Werneck de Castro JP, Bernal-Mizrachi E, Almaça J. Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis. Diabetologia 2020; 63:1564-1575. [PMID: 32424539 PMCID: PMC7354906 DOI: 10.1007/s00125-020-05168-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/02/2020] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS Islet vascular fibrosis may play an important role in the progression of type 2 diabetes, but there are no mouse models allowing detailed mechanistic studies to understand how a dysfunctional islet microvasculature contributes to diabetes pathogenesis. Here we report that the transgenic AktTg mouse, unlike other mouse strains, shows an increased deposition of extracellular matrix (ECM) proteins in perivascular regions, allowing us to study the cellular mechanisms that lead to islet vascular fibrosis. METHODS Using immunohistochemistry, we labelled the islet microvasculature and ECM in pancreas sections of AktTg mice and human donors and performed lineage tracing to follow the fate of islet pericytes. We compared islet microvascular responses in living pancreas slices from wild-type and AktTg mice. RESULTS We found that vascular pericytes proliferate extensively, convert into profibrotic myofibroblasts and substantially contribute to vascular fibrosis in the AktTg mouse model. The increased deposition of collagen I, fibronectin and periostin within the islet is associated with diminished islet perfusion as well as impaired capillary responses to noradrenaline (norepinephrine) and to high glucose in living pancreas slices. CONCLUSIONS/INTERPRETATION Our study thus illustrates how the AktTg mouse serves to elucidate a cellular mechanism in the development of islet vascular fibrosis, namely a change in pericyte phenotype that leads to vascular dysfunction. Because beta cells in the AktTg mouse are more numerous and larger, and secrete more insulin, in future studies we will test the role beta cell secretory products play in determining the phenotype of pericytes and other cells residing in the islet microenvironment under physiological and pathophysiological conditions. Graphical abstract.
Collapse
Affiliation(s)
- Luciana Mateus Gonçalves
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Obesity and Comorbidities Research Center, Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Elizabeth Pereira
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - João Pedro Werneck de Castro
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Miami VA Health Care System, Miami, FL, 33136, USA
| | - Joana Almaça
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| |
Collapse
|
|
27
|
Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
Collapse
Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| |
Collapse
|
|
28
|
Bovolini A, Garcia J, Silva AF, Andrade MA, Duarte JA. Islets of Langerhans phenotype alterations induced by fatty diet and physical activity levels in Wistar rats. Nutrition 2020; 79-80:110838. [PMID: 32569951 DOI: 10.1016/j.nut.2020.110838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Physical inactivity (PIn) and a fatty diet (FD) are closely linked to development of metabolic syndrome (MetS), overloading the endocrine pancreas seeking energy homeostasis. However, the relative contribution of FD and PIn to the pancreatic overload is unknown. The aim of this study was to verify the isolated and conjugated influence of FD and PIn in the islets of Langer hans (islets) structure and function related to overload in Wistar rats. METHODS Male Wistar rats were divided into four groups (n = 10/group): active groups, fed with fat (AFD) or standard (ASD) diet; and physically inactive groups, fed with fat (SFD) or standard (SSD) diet for 21 wk. Glucose tolerance (GT) and insulin sensitivity (IS) were assessed before sacrifice. Retroperitoneal adipose tissue and pancreas were weighted (PW), and pancreas samples processed for histologic analyses. RESULTS Only the FD-fed animals presented MS. Compared with standard diet, FD impaired GT and IS, decreased PW, and enlarged islets dimensions, with islets cellular death, inflammatory response, and enhanced collagen content, which were attenuated in AFD. Independent of the diet, PIn groups presented higher amounts of islets connective tissue, but without influence on inflammatory reaction and cellular death. The GT impairment was higher in the FD-fed groups, whereas the decreased IS was more pronounced in the PIn groups. CONCLUSION FD induced MS with detrimental effects on pancreas overload, inducing islets morphologic and functional maladaptation, which were attenuated in active animals. Physical activity was not able to prevent FD-induced MS. FD showed a negative influence on GT, whereas PIn mainly affected IS.
Collapse
Affiliation(s)
- Antonio Bovolini
- CIAFEL Laboratory of Biochemistry and Experimental Morphology, Sports Faculty, University of Porto, Porto, Portugal
| | - Juliana Garcia
- CITAB Centre for the Research and Technology of Agro-Environment and Biological Sciences, University of Trás-os-Montes e Alto Douro, Vila Real, Portugal.
| | - Ana Filipa Silva
- Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | - José Alberto Duarte
- CIAFEL Laboratory of Biochemistry and Experimental Morphology, Sports Faculty, University of Porto, Porto, Portugal
| |
Collapse
|
|
29
|
Yang Y, Kim J, Park H, Lee E, Yoon K. Pancreatic stellate cells in the islets as a novel target to preserve the pancreatic β-cell mass and function. J Diabetes Investig 2020; 11:268-280. [PMID: 31872946 PMCID: PMC7078117 DOI: 10.1111/jdi.13202] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022] Open
Abstract
There are numerous lines of clinical evidence that inhibition of the renin-angiotensin system (RAS) can prevent and delay the development of diabetes. Also, the role of RAS in the pathogenesis of diabetes, including insulin resistance and β-cell dysfunction, has been extensively investigated. Nevertheless, this role had not yet been fully shown. A variety of possible protective mechanisms for RAS blockers in the regulation of glucose homeostasis have been suggested. However, the direct effect on pancreatic islet fibrosis has only recently been spotlighted. Various degrees of islet fibrosis are often observed in the islets of patients with type 2 diabetes mellitus, which can be associated with a decrease in β-cell mass and function in these patients. Pancreatic stellate cells are thought to be deeply involved in this islet fibrosis. In this process, the activation of RAS in islets is shown to transform quiescent pancreatic stellate cells into the activated form, stimulates their proliferation and consequently leads to islet fibrotic destruction. In this article, we introduce existing clinical and experimental evidence for diabetes prevention through inhibition of RAS, and review the responsible local RAS signaling pathways in pancreatic stellate cells. Finally, we propose possible targets for the prevention of islet fibrosis.
Collapse
Affiliation(s)
- Yeoree Yang
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Ji‐Won Kim
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Heon‐Seok Park
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Eun‐Young Lee
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Kun‐Ho Yoon
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| |
Collapse
|
|
30
|
Trojanowski BM, Salem HH, Neubauer H, Simon E, Wagner M, Dorajoo R, Boehm BO, Labriola L, Wirth T, Baumann B. Elevated β-cell stress levels promote severe diabetes development in mice with MODY4. J Endocrinol 2020; 244:323-337. [PMID: 31682591 PMCID: PMC6933809 DOI: 10.1530/joe-19-0208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022]
Abstract
Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating β-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting β-cell stress and ultimately leading to cell death, we asked whether additional β-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge β-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/- mice were found glucose intolerant without progressing to diabetes, additional challenge of β-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of β-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling β-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and β-cell mass. Our findings implicate that the avoidance of additional β-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when β-cell stress is normalized.
Collapse
Affiliation(s)
| | - Heba H Salem
- Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Faculty of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Heike Neubauer
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Eric Simon
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Martin Wagner
- Division of Endocrinology, Diabetes and Metabolism, Ulm University Medical Centre, Ulm University, Ulm, Germany
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
| | - Bernhard O Boehm
- Lee Kong Chiang School of Medicine, Nanyang Technological University, Singapore, Singapore
- Imperial College London, London, UK
| | - Leticia Labriola
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Thomas Wirth
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Bernd Baumann
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Correspondence should be addressed to B Baumann:
| |
Collapse
|
|
31
|
Zhou Y, Zhou J, Sun B, Xu W, Zhong M, Li Y, He C, Chen Y, Wang X, Jones PM, Sun Z. Vitamin A deficiency causes islet dysfunction by inducing islet stellate cell activation via cellular retinol binding protein 1. Int J Biol Sci 2020; 16:947-956. [PMID: 32140064 PMCID: PMC7053333 DOI: 10.7150/ijbs.37861] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Vitamin A (VA) plays an essential role in pancreatic homeostasis. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. Herein, we have investigated the effect of VA on glucose homeostasis trough regulation of ISCs function in dietary VA deficiency model mice. Methods: Male C57BL/6 mice were randomly fed a VA-sufficient, a VA-deficient (VAD) or a VAD-rescued diet. Glucose metabolism was assessed by glucose tolerance tests and immunohistochemistry. ISCs activation degree was evaluated by immunofluorescence, quantitative PCR and western blotting in both, retinol-treated cultured ISCs and model mice. Changes in ISCs phenotype and their effect on islets were assessed by lentiviral transduction and enzyme-linked immunosorbent assays in a co-culture system. Results: VAD mice showed irregular shaped islet, glucose intolerance, islet size distribution excursions, and upregulated expression of α-smooth muscle actin (α-SMA, marker of ISCs activation). Reintroduction of dietary VA restored pancreatic VA levels, endocrine hormone profiles, and inhibited ISCs activation. Incubation with retinol increased the expression of VA signaling factors in ISCs, including cellular retinol binding protein 1 (CRBP1). The knockdown of CRBP1 maintained the quiescent ISCs phenotype and reduced the damage of activated ISCs on islet function. Conclusions: VA deficiency reduced islet function by activating ISCs in VAD mice. Restoring ISCs quiescence via CRBP1 inhibition could reverse the impairment of islet function caused by activated ISCs exposure.
Collapse
Affiliation(s)
- Yunting Zhou
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Junming Zhou
- Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Wei Xu
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, UK
| | - Ming Zhong
- Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, China
| | - Yumin Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, UK
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| |
Collapse
|
|
32
|
Bynigeri RR, Mitnala S, Talukdar R, Singh SS, Duvvuru NR. Pancreatic stellate cell-potentiated insulin secretion from Min6 cells is independent of interleukin 6-mediated pathway. J Cell Biochem 2020; 121:840-855. [PMID: 31452250 DOI: 10.1002/jcb.29329] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 07/15/2019] [Indexed: 02/07/2025]
Abstract
Pancreatic stellate cells (PSCs) secrete various factors, which can influence the β-cell function. The identification of stellate cell infiltration into the islets in pancreatic diseases suggests possible existence of cross-talk between these cells. To elucidate the influence of PSCs on β-cell function, mouse PSCs were cocultured with Min6 cells using the Transwell inserts. Glucose-stimulated insulin secretion from Min6 cells in response to PSCs was quantified by enzyme-linked immunosorbent assay and insulin gene expression was measured by quantitative polymerase chain reaction. Upon cytometric identification of IL6 in PSC culture supernatants, Min6 cells were cultured with IL6 to assess its influence on the insulin secretion and gene expression. PLC-IP3 pathway inhibitors were added in the cocultures, to determine the influence of PSC-secreted IL6 on Glucose-stimulated insulin secretion from Min6 cells. Increased insulin secretion with a concomitant decrease in total insulin content was noticed in PSC-cocultured Min6 cells. Although increased GSIS was noted from IL6-treated Min6 cells, no change in the total insulin content was noted. Coculture of Min6 cells with PSCs or their exposure to IL6 did not alter either the expression of β-cell-specific genes or that of miRNA-375. PSC-cocultured Min6 cells, in the presence of PLC-IP3 pathway inhibitors (U73122, Neomycin, and Xestospongin C), did not revoke the observed increase in GSIS. In conclusion, the obtained results indicate that augmented insulin secretion from Min6 cells in response to PSC secretions is independent of IL6-mediated PLC-IP3 pathway.
Collapse
Affiliation(s)
| | - Sasikala Mitnala
- Department of Basic Sciences, Asian Healthcare Foundation, Hyderabad, India
| | - Rupjyoti Talukdar
- Department of Basic Sciences, Asian Healthcare Foundation, Hyderabad, India
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Surya S Singh
- Department of Biochemistry, Osmania University, Hyderabad, India
| | | |
Collapse
|
|
33
|
Paternoster S, Falasca M. The intricate relationship between diabetes, obesity and pancreatic cancer. Biochim Biophys Acta Rev Cancer 2019; 1873:188326. [PMID: 31707038 DOI: 10.1016/j.bbcan.2019.188326] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 09/28/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the leading determinants of global cancer mortality, and its incidence is predicted to increase, to become in 2030 the second most common cause of cancer-related death. Obesity and diabetes are recognized risk factors for the development of pancreatic cancer. In the last few decades an epidemic of diabetes and obesity has been spreading worldwide, forewarning an increase in incidence of pancreatic cancer. This review considers the most recent literature, covering the multiple molecular axis linking these three pathologies, aiming to draw a more comprehensive view of pancreatic cancer for a better theragnostic stratification of the population.
Collapse
Affiliation(s)
- Silvano Paternoster
- Metabolic Signalling Group, School Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley 6102, Perth, Western Australia, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley 6102, Perth, Western Australia, Australia.
| |
Collapse
|
|
34
|
Li W, Zhou Y, Wang X, Cai M, Gao F, Carlsson PO, Sun Z. A modified in vitro tool for isolation and characterization of rat quiescent islet stellate cells. Exp Cell Res 2019; 384:111617. [PMID: 31505166 DOI: 10.1016/j.yexcr.2019.111617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Islet stellate cells (ISCs) play a critical role in islet fibrosis, contributing to the progression of pancreatic diseases. Previous studies have focused on fibrosis-associated activated ISCs obtained by standard islet explant techniques. However, in vitro models of quiescent ISCs (qISCs) are lacking. This study aims to develop a method to isolate qISCs and analyze their phenotype during activation. METHODS Immunofluorescence staining was applied to localize ISCs in normal human, rat, and mouse islets. qISCs were isolated from rat islets using density gradient centrifugation (DGC) method. qRT-PCR, immunoblotting, proliferation, and migration assays were employed for their characterization. RESULTS Desmin-positive ISCs were detected in normal human, rat, and mouse islets. Freshly isolated qISCs, obtained by density gradient centrifugation, displayed a polygonal appearance with refringent cytoplasmic lipid droplets and expressed transcriptional markers indicating a low activation/quiescent state. With increasing culture time, the marker expression pattern changed, reflecting ISC activation. qISCs contained more lipid droplets and exhibited lower proliferation and migration abilities compared to spindle-shaped ISCs obtained by traditional explant techniques. CONCLUSIONS This study describes a new method for efficient isolation of qISCs from rat islets, representing a useful in vitro tool to study the biology of ISCs in more physiological conditions.
Collapse
Affiliation(s)
- Wei Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yunting Zhou
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Min Cai
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Feng Gao
- Graduate Innovation Platform of Southeast University, Nanjing, China
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China.
| |
Collapse
|
|
35
|
Abstract
PURPOSE OF REVIEW The goal of this manuscript is to review the current literature related to fibrogenesis in the pancreatobiliary system and how this process contributes to pancreatic and biliary diseases. In particular, we seek to define the current state of knowledge regarding the epigenetic mechanisms that govern and regulate tissue fibrosis in these organs. A better understanding of these underlying molecular events will set the stage for future epigenetic therapeutics. RECENT FINDINGS We highlight the significant advances that have been made in defining the pathogenesis of pancreatobiliary fibrosis as it relates to chronic pancreatitis, pancreatic cancer, and the fibro-obliterative cholangiopathies. We also review the cell types involved as well as concepts related to epithelial-mesenchymal crosstalk. Furthermore, we outline important signaling pathways (e.g., TGFβ) and diverse epigenetic processes (i.e., DNA methylation, non-coding RNAs, histone modifications, and 3D chromatin remodeling) that regulate fibrogenic gene networks in these conditions. We review a growing body of scientific evidence linking epigenetic regulatory events to fibrotic disease states in the pancreas and biliary system. Advances in this understudied area will be critical toward developing epigenetic pharmacological approaches that may lead to more effective treatments for these devastating and difficult to treat disorders.
Collapse
Affiliation(s)
- Sayed Obaidullah Aseem
- Division of Gastroenterology and Hepatology, Rochester, FL, USA
- Gastroenterology Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Rochester, FL, USA.
- Gastroenterology Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Mayo Clinic Foundation, Rochester, MN, USA.
| |
Collapse
|
|
36
|
Lipotoxicity reduces β cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules. Exp Cell Res 2019; 380:1-8. [DOI: 10.1016/j.yexcr.2019.04.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/22/2019] [Accepted: 04/10/2019] [Indexed: 12/17/2022]
|
|
37
|
Effects of Sting Plant Extracts as Penetration Enhancers on Transdermal Delivery of Hypoglycemic Compounds. ACTA ACUST UNITED AC 2019; 55:medicina55050121. [PMID: 31067805 PMCID: PMC6572286 DOI: 10.3390/medicina55050121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/17/2019] [Accepted: 04/17/2019] [Indexed: 11/17/2022]
Abstract
Background and objectives: The percutaneous route is an interesting and inventive investigation field of drug delivery. However, it is challenging for drug molecules to pass through the skins surface, which is a characterized by its permeability barrier. The purpose of this study is to look at the effect of some penetration enhancers on in vivo permeation of insulin and insulin sensitizers (curcumin and rutin) through diabetes-induced mouse skin. Materials and Methods: Sting crude extracts of Dendrocnide meyeniana, Urtica thunbergiana Sieb. and Zucc, and Alocasia odora (Lodd.) Spach were used as the penetration enhancers. Mouse skin irritation was tested by smearing the enhancers for the measurements at different time points and the cell viability of the HaCaT human skin keratinocytes, which was determined by Trypan blue exclusion and MTT assays to evaluate human biosafety for these extracts after the mouse skin permeation experiments. Results: All enhancers induced a slight erythema without edema on the mouse skin that completely recovered after 6 h from the enhancer smears as compared with normal mouse skin. Furthermore, no damaged cells were found in the HaCaT keratinocytes under sting crude extract treatments. The blood sugar level in the diabetic mice treated with the insulin or insulin sensitizers, decreased significantly (p < 0.05) in the presence of enhancers. The area under the curve (AUC) values of transdermal drug delivery (TDD) ranged from 42,000 ± 5000 mg/dL x min without enhancers, to 30,000 ± 2000 mg/dL x min in the presence of enhancers. Conclusions: This study exhibited that natural plant extracts could be preferred over the chemically synthesized molecules and are safe and potent penetration enhancers for stimulating the transdermal absorption of drugs.
Collapse
|
|
38
|
Zhou Y, Sun B, Li W, Zhou J, Gao F, Wang X, Cai M, Sun Z. Pancreatic Stellate Cells: A Rising Translational Physiology Star as a Potential Stem Cell Type for Beta Cell Neogenesis. Front Physiol 2019; 10:218. [PMID: 30930789 PMCID: PMC6424017 DOI: 10.3389/fphys.2019.00218] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
The progressive decline and eventual loss of islet β-cell function underlies the pathophysiological mechanism of the development of both type 1 and type 2 diabetes mellitus. The recovery of functional β-cells is an important strategy for the prevention and treatment of diabetes. Based on similarities in developmental biology and anatomy, in vivo induction of differentiation of other types of pancreatic cells into β-cells is a promising avenue for future diabetes treatment. Pancreatic stellate cells (PSCs), which have attracted intense research interest due to their effects on tissue fibrosis over the last decade, express multiple stem cell markers and can differentiate into various cell types. In particular, PSCs can successfully differentiate into insulin- secreting cells in vitro and can contribute to tissue regeneration. In this article, we will brings together the main concepts of the translational physiology potential of PSCs that have emerged from work in the field and discuss possible ways to develop the future renewable source for clinical treatment of pancreatic diseases.
Collapse
Affiliation(s)
- Yunting Zhou
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Wei Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Junming Zhou
- Department of Outpatient, Army Engineering University, Jingling Hospital, Nanjing University, Nanjing, China
| | - Feng Gao
- Graduate Innovation Platform of Southeast University, Nanjing, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Min Cai
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| |
Collapse
|
|
39
|
Çelik S, Baysal B, Şen S. Resveratrol Attenuates Benzo(a)pyrene-Induced Dysfunctions, Oxidative Stress and Apoptosis in Pancreatic Beta-Cells. ACTA ACUST UNITED AC 2019. [DOI: 10.4236/abb.2019.1011029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|
|
40
|
Xu W, Liang J, Geng HF, Lu J, Li R, Wang XL, Lv Q, Liu Y, Wang J, Liu XK, Jones PM, Sun Z. Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function. Int J Endocrinol 2019; 2019:7870109. [PMID: 31097962 PMCID: PMC6487103 DOI: 10.1155/2019/7870109] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/18/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Emerging evidence suggests that T2DM is attributable to the dysfunction of β-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on β-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. METHODS iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. RESULTS We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. CONCLUSION Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.
Collapse
Affiliation(s)
- Wei Xu
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, UK
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Jun Liang
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - H. F. Geng
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - Jun Lu
- Key Laboratory of Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - Rui Li
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - X. L. Wang
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - Qian Lv
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - Ying Liu
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - Jie Wang
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - X. K. Liu
- Department of Endocrinology of Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China
| | - Peter M. Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, UK
| | - Zl Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| |
Collapse
|
|
41
|
Olaniru OE, Pingitore A, Giera S, Piao X, Castañera González R, Jones PM, Persaud SJ. The adhesion receptor GPR56 is activated by extracellular matrix collagen III to improve β-cell function. Cell Mol Life Sci 2018; 75:4007-4019. [PMID: 29855662 PMCID: PMC6182347 DOI: 10.1007/s00018-018-2846-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 05/11/2018] [Accepted: 05/24/2018] [Indexed: 12/19/2022]
Abstract
AIMS G-protein coupled receptor 56 (GPR56) is the most abundant islet-expressed G-protein coupled receptor, suggesting a potential role in islet function. This study evaluated islet expression of GPR56 and its endogenous ligand collagen III, and their effects on β-cell function. METHODS GPR56 and collagen III expression in mouse and human pancreas sections was determined by fluorescence immunohistochemistry. Effects of collagen III on β-cell proliferation, apoptosis, intracellular calcium ([Ca2+]i) and insulin secretion were determined by cellular BrdU incorporation, caspase 3/7 activities, microfluorimetry and radioimmunoassay, respectively. The role of GPR56 in islet vascularisation and innervation was evaluated by immunohistochemical staining for CD31 and TUJ1, respectively, in pancreases from wildtype (WT) and Gpr56-/- mice, and the requirement of GPR56 for normal glucose homeostasis was determined by glucose tolerance tests in WT and Gpr56-/- mice. RESULTS Immunostaining of mouse and human pancreases revealed that GPR56 was expressed by islet β-cells while collagen III was confined to the peri-islet basement membrane and islet capillaries. Collagen III protected β-cells from cytokine-induced apoptosis, triggered increases in [Ca2+]i and potentiated glucose-induced insulin secretion from WT islets but not from Gpr56-/- islets. Deletion of GPR56 did not affect glucose-induced insulin secretion in vitro and it did not impair glucose tolerance in adult mice. GPR56 was not required for normal islet vascularisation or innervation. CONCLUSION We have demonstrated that collagen III improves islet function by increasing insulin secretion and protecting against apoptosis. Our data suggest that collagen III may be effective in optimising islet function to improve islet transplantation outcomes, and GPR56 may be a target for the treatment of type 2 diabetes.
Collapse
Affiliation(s)
- Oladapo E Olaniru
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Attilio Pingitore
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Stefanie Giera
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Xianhua Piao
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Ramón Castañera González
- Department of General Surgery, Rio Carrión Hospital, University Hospital Complex of Palencia, Palencia, Spain
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Shanta J Persaud
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK.
| |
Collapse
|
|
42
|
Xue R, Jia K, Wang J, Yang L, Wang Y, Gao L, Hao J. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol 2018; 9:754. [PMID: 29967585 PMCID: PMC6015921 DOI: 10.3389/fphys.2018.00754] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/29/2018] [Indexed: 12/17/2022] Open
Abstract
Pancreatic stellate cell (PSC) is a type of pluripotent cell located between pancreatic lobules and the surrounding area of acinars. When activated, PSC can be transformed into myofibroblast-like cell. A number of evidences suggest that activated PSC is the main source of the accumulation of extracellular matrix (ECM) protein under the pathological conditions, which lead to pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. Recent studies have found that PSC also plays an important role in the endocrine cell function, islet fibrosis and diabetes. In order to provide new strategies for the treatment of pancreatic diseases, this paper systematically summarizes the recent researches about the biological behaviors of PSC, including its stem/progenitor cell characteristics, secreted exosomes, cellular senescence, epithelial mesenchymal transformation (EMT), energy metabolism and direct mechanical reprogramming.
Collapse
Affiliation(s)
- Ran Xue
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Kai Jia
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianxin Wang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lixin Yang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yanbin Wang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lingyun Gao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
43
|
Tosta ADM, Borges MDC, Silva ÉMCD, Takeuti TD, Terra Júnior JA, Crema E. Pulmonary function evaluation in type 2 diabetes mellitus patients submitted to metabolic surgery. FISIOTERAPIA EM MOVIMENTO 2018. [DOI: 10.1590/1980-5918.031.ao20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Abstract Introduction: Diabetes Mellitus (DM) is a multifactorial metabolic disorder. As considered a public health problem needing additional treatment options. Objective: This prospective study aimed at evaluating pulmonary function through spirometry, before and after metabolic surgery without gastric resection in type 2 DM patients. Methods: Sample was composed by 17 type 2 DM females. They were analyzed in pre (24 hours before surgical procedure), immediate post-operative period POST1 (24 hours after surgical procedure) and in the late postoperative period POST2 (two years after surgical procedure). Besides statistical analysis, it was evaluated the following spirometric parameters: forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and the FEV1 / FVC ratio (%). Results: Spirometric parameters showed a value increase when compared PRE and POS2 values, except for FVC and FEV1, which was not statistically significant. Conclusion: Type 2 DM women submitted to metabolic surgery without gastric resection showed spirometric value increased after two-year surgical procedure, when compared to preoperative period values. It is important additional studies about pulmonary function, diabetic patients and metabolic surgery without gastric resection.
Collapse
|
|
44
|
Um J, Jung N, Kim D, Choi S, Lee SH, Son Y, Park KS. Substance P preserves pancreatic β-cells in type 1 and type 2 diabetic mice. Biochem Biophys Res Commun 2018; 499:960-966. [PMID: 29626466 DOI: 10.1016/j.bbrc.2018.04.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 01/09/2023]
Abstract
Preservation of pancreatic β-cells is required for the development of therapies for type 1 and type 2 diabetes (T1D and T2D, respectively). Our previous study demonstrated that substance P (SP) preserves β-cell populations in mice with streptozotocin-induced T1D. Here, we demonstrated that chronic systemic treatment with SP restored the mass of β-cells both in nonobese diabetic (NOD) mice with T1D or db/db mice with T2D. SP delayed the onset of T1D in NOD mice via immune modulation. SP inhibited immune infiltration into islets and the salivary glands of NOD mice. In db/db mice, SP treatment rescued glucose intolerance. Moreover, SP inhibited apoptosis, as well as the activation of pancreatic stellate cells in pancreatic islets of db/db mice. SP downregulated the number of α-smooth muscle actin (α-SMA) expressing cells in db/db pancreatic islets. Cleaved-caspase-3 expression was reduced in islets of SP-treated db/db mice compared to that in the control. Therefore, these results suggested that SP may preserve pancreatic β-cells through immune modulation and protection from the stimulated activation of pancreatic stellate cells and apoptosis in T1D and T2D, respectively.
Collapse
Affiliation(s)
- Jihyun Um
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, South Korea
| | - Nunggum Jung
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, South Korea
| | - Dongjin Kim
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, South Korea
| | - Sanghyuk Choi
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, South Korea
| | - Sang-Ho Lee
- Kyung Hee University Hospital at Gangdong, Seoul 05278, South Korea
| | - Youngsook Son
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, South Korea
| | - Ki-Sook Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, South Korea; East-West Medical Research Institute, Kyung Hee University, Seoul 02447, South Korea; College of Medicine, Kyung Hee University, Seoul 02447, South Korea; Kyung Hee University Medical Center, Seoul 02447, South Korea.
| |
Collapse
|
|
45
|
Wang X, Li W, Chen J, Zhao S, Qiu S, Yin H, Carvalho V, Zhou Y, Shi R, Hu J, Li S, Nijiati M, Sun Z. A Transcriptional Sequencing Analysis of Islet Stellate Cell and Pancreatic Stellate Cell. J Diabetes Res 2018; 2018:7361684. [PMID: 29619382 PMCID: PMC5830286 DOI: 10.1155/2018/7361684] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 11/22/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Our previous studies have shown that islet stellate cell (ISC), similar to pancreatic stellate cell (PSC) in phenotype and biological characters, may be responsible for the islet fibrosis in type 2 diabetes. To further identify the differences between PSC and ISC and for better understanding of the physiological function of ISC, we employed genome-wide transcriptional analysis on the PSCs and ISCs of Wistar rats. METHOD PSCs and ISCs from each rat were primarily cultured at the same condition. Genome-wide transcriptional sequence of stellate cells was generated. The identified differentially expressed genes were validated using RT-PCR. RESULTS 32 significant differentially expressed genes between PSCs and ISCs were identified. Moreover, collagen type 11a1 (COL11A1), was found to be expressed 2.91-fold higher in ISCs compared with PSCs, indicating that COL11A1 might be a potential key gene modulating the differences between PSC and ISC. CONCLUSIONS Our study identified and validated the differences between PSC and ISC in genome-wide transcriptional scale, confirming the assumption that ISC and PSC are similar other than identical. Moreover, our data might be instrumental for further investigation of ISC and islet fibrosis, and some differential expressed genes may provide an insight into new therapeutic targets for type 2 diabetes.
Collapse
Affiliation(s)
- Xiaohang Wang
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Wei Li
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Juan Chen
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Sheng Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, China
| | - Shanhu Qiu
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Han Yin
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Vladmir Carvalho
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yunting Zhou
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Ruifeng Shi
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jiannan Hu
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Shenyi Li
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Munire Nijiati
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| |
Collapse
|