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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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Grigorescu RR, Husar-Sburlan IA, Gheorghe C. Pancreatic Cancer: A Review of Risk Factors. Life (Basel) 2024; 14:980. [PMID: 39202722 PMCID: PMC11355429 DOI: 10.3390/life14080980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 09/03/2024] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.
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Affiliation(s)
- Raluca Roxana Grigorescu
- Gastroenterology Department, “Sfanta Maria” Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Cristian Gheorghe
- Center for Digestive Disease and Liver Transplantation, Fundeni Clinical Institute, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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Wayne CD, Benbetka C, Besner GE, Narayanan S. Challenges of Managing Type 3c Diabetes in the Context of Pancreatic Resection, Cancer and Trauma. J Clin Med 2024; 13:2993. [PMID: 38792534 PMCID: PMC11122338 DOI: 10.3390/jcm13102993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/04/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic or pancreoprivic diabetes, is a specific type of DM that often develops as a result of diseases affecting the exocrine pancreas, exhibiting an array of hormonal and metabolic characteristics. Several pancreatic exocrine diseases and surgical procedures may cause T3cDM. Diagnosing T3cDM remains difficult as the disease characteristics frequently overlap with clinical presentations of type 1 DM (T1DM) or type 2 DM (T2DM). Managing T3cDM is likewise challenging due to numerous confounding metabolic dysfunctions, including pancreatic endocrine and exocrine insufficiencies and poor nutritional status. Treatment of pancreatic exocrine insufficiency is of paramount importance when managing patients with T3cDM. This review aims to consolidate the latest information on surgical etiologies of T3cDM, focusing on partial pancreatic resections, total pancreatectomy, pancreatic cancer and trauma.
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Affiliation(s)
- Colton D. Wayne
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Surgery, Baylor University Medical Center, 3600 Gaston Ave, Dallas, TX 75246, USA
| | | | - Gail E. Besner
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Siddharth Narayanan
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
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Ungkulpasvich U, Hatakeyama H, Hirotsu T, di Luccio E. Pancreatic Cancer and Detection Methods. Biomedicines 2023; 11:2557. [PMID: 37760999 PMCID: PMC10526344 DOI: 10.3390/biomedicines11092557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The pancreas is a vital organ with exocrine and endocrine functions. Pancreatitis is an inflammation of the pancreas caused by alcohol consumption and gallstones. This condition can heighten the risk of pancreatic cancer (PC), a challenging disease with a high mortality rate. Genetic and epigenetic factors contribute significantly to PC development, along with other risk factors. Early detection is crucial for improving PC outcomes. Diagnostic methods, including imagining modalities and tissue biopsy, aid in the detection and analysis of PC. In contrast, liquid biopsy (LB) shows promise in early tumor detection by assessing biomarkers in bodily fluids. Understanding the function of the pancreas, associated diseases, risk factors, and available diagnostic methods is essential for effective management and early PC detection. The current clinical examination of PC is challenging due to its asymptomatic early stages and limitations of highly precise diagnostics. Screening is recommended for high-risk populations and individuals with potential benign tumors. Among various PC screening methods, the N-NOSE plus pancreas test stands out with its high AUC of 0.865. Compared to other commercial products, the N-NOSE plus pancreas test offers a cost-effective solution for early detection. However, additional diagnostic tests are required for confirmation. Further research, validation, and the development of non-invasive screening methods and standardized scoring systems are crucial to enhance PC detection and improve patient outcomes. This review outlines the context of pancreatic cancer and the challenges for early detection.
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Affiliation(s)
| | | | | | - Eric di Luccio
- Hirotsu Bioscience Inc., 22F The New Otani Garden Court, 4-1 Kioi-cho, Chiyoda-ku, Tokyo 102-0094, Japan; (U.U.); (H.H.); (T.H.)
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6
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Quijano JC, Wedeken L, Ortiz JA, Zook HN, LeBon JM, Luo A, Rawson J, Tremblay JR, Mares JM, Lopez K, Chen MH, Jou K, Mendez-Dorantes C, Al-Abdullah IH, Thurmond DC, Kandeel F, Riggs AD, Ku HT. Methylcellulose colony assay and single-cell micro-manipulation reveal progenitor-like cells in adult human pancreatic ducts. Stem Cell Reports 2023; 18:618-635. [PMID: 36868230 PMCID: PMC10031308 DOI: 10.1016/j.stemcr.2023.02.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 03/05/2023] Open
Abstract
Progenitor cells capable of self-renewal and differentiation in the adult human pancreas are an under-explored resource for regenerative medicine. Using micro-manipulation and three-dimensional colony assays we identify cells within the adult human exocrine pancreas that resemble progenitor cells. Exocrine tissues were dissociated into single cells and plated into a colony assay containing methylcellulose and 5% Matrigel. A subpopulation of ductal cells formed colonies containing differentiated ductal, acinar, and endocrine lineage cells, and expanded up to 300-fold with a ROCK inhibitor. When transplanted into diabetic mice, colonies pre-treated with a NOTCH inhibitor gave rise to insulin-expressing cells. Both colonies and primary human ducts contained cells that simultaneously express progenitor transcription factors SOX9, NKX6.1, and PDX1. In addition, in silico analysis identified progenitor-like cells within ductal clusters in a single-cell RNA sequencing dataset. Therefore, progenitor-like cells capable of self-renewal and tri-lineage differentiation either pre-exist in the adult human exocrine pancreas, or readily adapt in culture.
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Affiliation(s)
- Janine C Quijano
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| | - Lena Wedeken
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Jose A Ortiz
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
| | - Heather N Zook
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
| | - Jeanne M LeBon
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Angela Luo
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Jacob R Tremblay
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Jacob M Mares
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Kassandra Lopez
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Min-Hsuan Chen
- Integrative Genomics Core, City of Hope, Duarte, CA 91010, USA
| | - Kevin Jou
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Carlos Mendez-Dorantes
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
| | - Ismail H Al-Abdullah
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Debbie C Thurmond
- Department of Molecular & Cellular Endocrinology, City of Hope, Duarte, CA 91010, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA; Department of Clinical Diabetes, Endocrinology & Metabolism, City of Hope, Duarte, CA 91010, USA
| | - Arthur D Riggs
- Department of Diabetes & Drug Discovery, City of Hope, Duarte, CA 91010, USA
| | - Hsun Teresa Ku
- Department of Translational Research & Cellular Therapeutics, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
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7
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Kiss L, Fűr G, Pisipati S, Rajalingamgari P, Ewald N, Singh V, Rakonczay Z. Mechanisms linking hypertriglyceridemia to acute pancreatitis. Acta Physiol (Oxf) 2023; 237:e13916. [PMID: 36599412 DOI: 10.1111/apha.13916] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/25/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023]
Abstract
Hypertriglyceridemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important etiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG-induced AP and the clinically observed effects of HTG on the outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG-induced AP or AP in the presence of HTG and determining possible treatments are needed.
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Affiliation(s)
- Lóránd Kiss
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Gabriella Fűr
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Sailaja Pisipati
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Prasad Rajalingamgari
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Nils Ewald
- Institute for Endocrinology, Diabetology and Metabolism, University Hospital Minden, Minden, Germany.,Justus-Liebig-Universität Giessen, Giessen, Germany
| | - Vijay Singh
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Zoltán Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
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Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne) 2022; 13:800995. [PMID: 35222270 PMCID: PMC8873103 DOI: 10.3389/fendo.2022.800995] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies suggest associations between diabetes mellitus and some cancers. The risk of a number of cancers appears to be increased in diabetes mellitus. On the other hand, some cancer and cancer therapies could lead to diabetes mellitus. Genetic factors, obesity, inflammation, oxidative stress, hyperglycemia, hyperinsulinemia, cancer therapies, insulin and some oral hypoglycemic drugs appear to play a role in the crosstalk between diabetes mellitus and cancers. This review summarized the associations between various types of diabetes and cancers and updated available evidence of underlying mechanisms between diabetes and cancers.
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Affiliation(s)
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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Mohan S, Lafferty R, Tanday N, Flatt PR, Moffett RC, Irwin N. Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells. PLoS One 2021; 16:e0261608. [PMID: 34929019 PMCID: PMC8687525 DOI: 10.1371/journal.pone.0261608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 12/07/2021] [Indexed: 12/18/2022] Open
Abstract
Ac3IV (Ac-CYIQNCPRG-NH2) is an enzymatically stable vasopressin analogue that selectively activates Avpr1a (V1a) and Avpr1b (V1b) receptors. In the current study we have employed streptozotocin (STZ) diabetic transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, to evaluate the impact of sustained Ac3IV treatment on pancreatic islet cell morphology and transdifferentiation. Twice-daily administration of Ac3IV (25 nmol/kg bw) to STZ-diabetic Ins1Cre/+;Rosa26-eYFP mice for 12 days increased pancreatic insulin (p<0.01) and significantly reversed the detrimental effects of STZ on pancreatic islet morphology. Such benefits were coupled with increased (p<0.01) beta-cell proliferation and decreased (p<0.05) beta-cell apoptosis. In terms of islet cell lineage tracing, induction of diabetes increased (p<0.001) beta- to alpha-cell differentiation in Ins1Cre/+;Rosa26-eYFP mice, with Ac3IV partially reversing (p<0.05) such transition events. Comparable benefits of Ac3IV on pancreatic islet architecture were observed in STZ-diabetic GluCreERT2;ROSA26-eYFP transgenic mice. In this model, Ac3IV provoked improvements in islet morphology which were linked to increased (p<0.05-p<0.01) transition of alpha- to beta-cells. Ac3IV also increased (p<0.05-p<0.01) CK-19 co-expression with insulin in pancreatic ductal and islet cells. Blood glucose levels were unchanged by Ac3IV in both models, reflecting the severity of diabetes induced. Taken together these data indicate that activation of islet receptors for V1a and V1b positively modulates alpha- and beta-cell turnover and endocrine cell lineage transition events to preserve beta-cell identity and islet architecture.
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Affiliation(s)
- Shruti Mohan
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Ryan Lafferty
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Neil Tanday
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Peter R. Flatt
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - R. Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Nigel Irwin
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, United Kingdom
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10
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Hu JX, Zhao CF, Chen WB, Liu QC, Li QW, Lin YY, Gao F. Pancreatic cancer: A review of epidemiology, trend, and risk factors. World J Gastroenterol 2021; 27:4298-4321. [PMID: 34366606 PMCID: PMC8316912 DOI: 10.3748/wjg.v27.i27.4298] [Citation(s) in RCA: 296] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/18/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite rapid advances in modern medical technology and significant improvements in survival rates of many cancers, pancreatic cancer is still a highly lethal gastrointestinal cancer with a low 5-year survival rate and difficulty in early detection. At present, the incidence and mortality of pancreatic cancer are increasing year by year worldwide, no matter in the United States, Europe, Japan, or China. Globally, the incidence of pancreatic cancer is projected to increase to 18.6 per 100000 in 2050, with the average annual growth of 1.1%, meaning that pancreatic cancer will pose a significant public health burden. Due to the special anatomical location of the pancreas, the development of pancreatic cancer is usually diagnosed at a late stage with obvious clinical symptoms. Therefore, a comprehensive understanding of the risk factors for pancreatic cancer is of great clinical significance for effective prevention of pancreatic cancer. In this paper, the epidemiological characteristics, developmental trends, and risk factors of pancreatic cancer are reviewed and analyzed in detail.
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Affiliation(s)
- Jian-Xiong Hu
- Intensive Care Unit (ICU), Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Cheng-Fei Zhao
- School of Pharmacy and Medical Technology, Putian University, Putian 351100, Fujian Province, China
- Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine in University of Fujian Province, Putian University, Putian 351100, Fujian Province, China
| | - Wen-Biao Chen
- Department of Basic Medicine, Quanzhou Medical College, Quanzhou 362011, Fujian Province, China
| | - Qi-Cai Liu
- Department of Reproductive Medicine Centre, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China
| | - Qu-Wen Li
- Department of Priority Laboratory for Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou 350001, Fujian Province, China
| | - Yan-Ya Lin
- Intensive Care Unit (ICU), Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Feng Gao
- Department of Pathology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China
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11
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Hendley AM, Rao AA, Leonhardt L, Ashe S, Smith JA, Giacometti S, Peng XL, Jiang H, Berrios DI, Pawlak M, Li LY, Lee J, Collisson EA, Anderson MS, Fragiadakis GK, Yeh JJ, Ye CJ, Kim GE, Weaver VM, Hebrok M. Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree. eLife 2021; 10:e67776. [PMID: 34009124 PMCID: PMC8184217 DOI: 10.7554/elife.67776] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/18/2021] [Indexed: 12/25/2022] Open
Abstract
To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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Affiliation(s)
- Audrey M Hendley
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
- Center for Bioengineering and Tissue Regeneration, University of California, San FranciscoSan FranciscoUnited States
| | - Arjun A Rao
- CoLabs, University of California, San FranciscoSan FranciscoUnited States
- Bakar ImmunoX Initiative, University of California, San FranciscoSan FranciscoUnited States
| | - Laura Leonhardt
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Sudipta Ashe
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Jennifer A Smith
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Simone Giacometti
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Xianlu L Peng
- Department of Pharmacology, University of North Carolina at Chapel HillChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel HillUnited States
| | - Honglin Jiang
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoSan FranciscoUnited States
| | - David I Berrios
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Mathias Pawlak
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's HospitalBostonUnited States
| | - Lucia Y Li
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Jonghyun Lee
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Eric A Collisson
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoSan FranciscoUnited States
| | - Mark S Anderson
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Gabriela K Fragiadakis
- CoLabs, University of California, San FranciscoSan FranciscoUnited States
- Bakar ImmunoX Initiative, University of California, San FranciscoSan FranciscoUnited States
- Department of Medicine, Division of Rheumatology, University of California, San FranciscoSan FranciscoUnited States
| | - Jen Jen Yeh
- Department of Pharmacology, University of North Carolina at Chapel HillChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel HillUnited States
- Department of Surgery, University of North Carolina at Chapel HillChapel HillUnited States
| | - Chun Jimmie Ye
- Parker Institute for Cancer ImmunotherapySan FranciscoUnited States
| | - Grace E Kim
- Department of Pathology, University of California, San FranciscoSan FranciscoUnited States
| | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, University of California, San FranciscoSan FranciscoUnited States
| | - Matthias Hebrok
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
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12
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Identification of Individuals at Increased Risk for Pancreatic Cancer in a Community-Based Cohort of Patients With Suspected Chronic Pancreatitis. Clin Transl Gastroenterol 2021; 11:e00147. [PMID: 32352677 PMCID: PMC7263650 DOI: 10.14309/ctg.0000000000000147] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We lack reliable methods for identifying patients with chronic pancreatitis (CP) at increased risk for pancreatic cancer. We aimed to identify radiographic parameters associated with pancreatic cancer in this population.
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13
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Chua MWJ, Ng YK. Early onset of acute pancreatitis in a patient on low-dose liraglutide. Diabetes Metab Syndr 2021; 15:753-755. [PMID: 33823330 DOI: 10.1016/j.dsx.2021.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/27/2022]
Affiliation(s)
| | - Yi Kang Ng
- Department of General Medicine, Sengkang General Hospital, Singapore
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14
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Zanini S, Renzi S, Limongi AR, Bellavite P, Giovinazzo F, Bermano G. A review of lifestyle and environment risk factors for pancreatic cancer. Eur J Cancer 2021; 145:53-70. [PMID: 33423007 DOI: 10.1016/j.ejca.2020.11.040] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 11/04/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer (PaCa) is one of the deadliest cancers known and its incidence is increasing in the developed countries. Because of the lack of biomarkers that allow early detection and the tendency of the disease to be asymptomatic, the diagnosis comes often too late for effective surgical or chemotherapy intervention. Lifestyle factors, that may cause common genetic modifications occurring in the disease, interfere with pancreatic physiology or function, and play a role in PaCa development, have been of concern recently, since a strategy to prevent this severe cancer is needed. This review identifies the latest evidences related to increased risk of developing PaCa due to dietary habits such as high alcohol, fructose and red or processed meat intake, and pathological conditions such as diabetes, obesity and infections in addition to stress and smoking behaviour. It aims to highlight the importance of intervening on modifiable risk factors: the action on these factors could prevent a considerable number of new cases of PaCa.
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Affiliation(s)
- Sara Zanini
- Centre for Obesity Research and Education [CORE], School of Pharmacy & Life Sciences, Robert Gordon University, Aberdeen, UK
| | - Serena Renzi
- Centre for Obesity Research and Education [CORE], School of Pharmacy & Life Sciences, Robert Gordon University, Aberdeen, UK
| | - Antonina R Limongi
- Department of Science, University of Basilicata, Potenza, Italy; BioInnova Srl, Potenza, Italy
| | - Paolo Bellavite
- Department of Medicine, Section of General Pathology, University of Verona, Italy
| | | | - Giovanna Bermano
- Centre for Obesity Research and Education [CORE], School of Pharmacy & Life Sciences, Robert Gordon University, Aberdeen, UK.
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15
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Abstract
PURPOSE OF REVIEW Type 1 and type 2 diabetes are often accompanied by mostly mild forms of exocrine pancreatic insufficiency. Despite high prevalence, little is known about the clinical consequences of exocrine pancreatic insufficiency and its optimal (nutritional) treatment. Even less is known if and to what extent exocrine pancreas insufficiency also affects glycemic control in diabetes. This article aims for summarizing current clinical knowledge on screening, diagnosis, and treatment and gives an overview on the pathophysiology of exocrine pancreatic insufficiency in diabetes. RECENT FINDINGS Recent studies reveal novel insights into the close interaction of acinar, ductal, and endocrine cells and the gut-pancreas axis. Exocrine pancreatic insufficiency is a clinically relevant, frequent but poorly understood disorder in both type 1 and type 2 diabetes.
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Affiliation(s)
- Bernhard Radlinger
- Department of Internal Medicine 1, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Gabriele Ramoser
- Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria
| | - Susanne Kaser
- Department of Internal Medicine 1, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
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16
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Morphological advantages of endoscopic treatment in obstructive chronic pancreatitis. Pancreatology 2020; 20:199-204. [PMID: 31899135 DOI: 10.1016/j.pan.2019.12.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 08/09/2019] [Accepted: 12/17/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND and study aims: Chronic pancreatitis is associated with recurrent or persistent abdominal pain over the course of the disease. Ductal hypertension showing obstructed and dilated pancreatic duct has been suggested as a major factor in the mechanism of pain in chronic pancreatitis. Many studies investigating pain relief after endoscopic treatment of pancreatic duct (PD) are available, but the number of studies regarding the morphological changes to pancreas such as changes in PD caliber, pancreatic parenchyma, and especially pancreatic volume is far fewer. As such, we analyzed the changes of ductal caliber and parenchymal volume after endoscopic treatment of PD in patients with obstructive chronic pancreatitis. PATIENTS AND METHODS In this retrospective study, we compared two groups of patients with obstructive chronic pancreatitis that either received endoscopic management of PD or conservative treatment without such endoscopic management. After we obtained age, sex, etiology of chronic pancreatitis, diabetic status, smoking and alcohol abuse status from the database, we compared the incidence for changes in pancreatic parenchymal volume and PD caliber between two groups. RESULT In our study population, total of 480 patients was diagnosed with chronic pancreatitis between January 2006 and December 2016, and 166 (34.5%) of these patients were diagnosed with obstructive chronic pancreatitis with obstructed and dilated PD. After reviewing the population with the exclusion criteria, 71 patients were available for the final analysis. 28 of those patient received endoscopic treatment of pancreatic duct and 43 received conservative treatment without any endoscopic treatment of PD. Statistical analysis with Cox proportional hazards models showed that diabetes and endoscopic PD management were significant predictors for progression of PD caliber and in pancreatic parenchyma, and that only PD management influenced the pancreatic volume loss. CONCLUSION Endoscopic management of PD in obstructive chronic pancreatitis have advantages on morphologic change such as pancreatic volume loss and progression of PD caliber in long follow-up period.
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17
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Deng H, Yang F, Ma X, Wang Y, Chen Q, Yuan L. Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice. Cell Transplant 2020; 29:963689720927392. [PMID: 32584149 PMCID: PMC7563804 DOI: 10.1177/0963689720927392] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/23/2022] Open
Abstract
In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.
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Affiliation(s)
- Hongjun Deng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Fengying Yang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Xiaoyi Ma
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Ying Wang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Qi Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
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18
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Wang J, Li HQ, Xu XH, Kong XC, Sun R, Jing T, Ye L, Su XF, Ma JH. The Effects of Once-Weekly Dulaglutide and Insulin Glargine on Glucose Fluctuation in Poorly Oral-Antidiabetic Controlled Patients with Type 2 Diabetes Mellitus. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2682657. [PMID: 31950036 PMCID: PMC6943972 DOI: 10.1155/2019/2682657] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/30/2019] [Accepted: 08/10/2019] [Indexed: 12/25/2022]
Abstract
Aim. To compare the effects of once-weekly Dulaglutide with once-daily glargine in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM). Method. A total of 25 patients with T2DM admitted into Department of Endocrinology from December 2012 to August 2013 were randomly assigned into two groups: Dulaglutide group (n = 16) and glargine group (n = 9). All patients received either Dulaglutide or glargine treatments for 52 weeks. Continuous glucose monitoring systems (CGMS) were applied to them for two 72 h periods at before and after the treatment each. Patient general clinical data were collected and analyzed. Result. Fast blood glucose (FBG) of the glargine group declined more significantly than the Dulaglutide group after treatment (p < 0.05). The mean blood glucose (MBG), standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE) within a day, the largest amplitude of glycemic excursion (LAGE), M-value, absolute means of daily difference (MODD) of glycemic excursion, the percentage of time (≤2.8 mmol/L, ≤3.9 mmol/L, ≥10.0 mmol/L, ≥13.9 mmol/L, 3.9-7.8 mmol/L, and 9-10.0 mmol/L), maximum glycemic value, and minimum glycemic value were similar between the two groups (p > 0.05). The incidence of hypoglycemia was also similar between the two groups (p > 0.05). Though serum levels of TNF-α, IL-6, and 8-PGF2α all decreased, significant reduction was found in TNF-α and 8-PGF2α. TNF-α was only significantly reduced in the Dulaglutide group, while 8-PGF2α was seen in both groups. Conclusion. For T2DM patients with poorly controlled oral antidiabetic drugs, once-weekly Dulaglutide not only has the same effect on glucose fluctuation as once-daily glargine but also significantly reduced TNF-α and 8-PGF2α after a 52 week treatment protocol. This trial is registered with ClinicalTrials.gov NCT01648582.
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Affiliation(s)
- Jie Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Hui-qin Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Xiao-hua Xu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Xiao-cen Kong
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Rui Sun
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Ting Jing
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Lei Ye
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Xiao-fei Su
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Jian-hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China
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19
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Sun X, Sun S, Yang S. An Efficient and Flexible Method for Deconvoluting Bulk RNA-Seq Data with Single-Cell RNA-Seq Data. Cells 2019; 8:E1161. [PMID: 31569701 PMCID: PMC6830085 DOI: 10.3390/cells8101161] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 12/25/2022] Open
Abstract
Estimating cell type compositions for complex diseases is an important step to investigate the cellular heterogeneity for understanding disease etiology and potentially facilitate early disease diagnosis and prevention. Here, we developed a computationally statistical method, referring to Multi-Omics Matrix Factorization (MOMF), to estimate the cell-type compositions of bulk RNA sequencing (RNA-seq) data by leveraging cell type-specific gene expression levels from single-cell RNA sequencing (scRNA-seq) data. MOMF not only directly models the count nature of gene expression data, but also effectively accounts for the uncertainty of cell type-specific mean gene expression levels. We demonstrate the benefits of MOMF through three real data applications, i.e., Glioblastomas (GBM), colorectal cancer (CRC) and type II diabetes (T2D) studies. MOMF is able to accurately estimate disease-related cell type proportions, i.e., oligodendrocyte progenitor cells and macrophage cells, which are strongly associated with the survival of GBM and CRC, respectively.
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Affiliation(s)
- Xifang Sun
- Department of Mathematics, School of Science, Xi'an Shiyou University, 710065 Xi'an, China.
| | - Shiquan Sun
- School of Computer Science, Northwestern Polytechnical University, 710072 Xi'an, China.
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Sheng Yang
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 211166 Nanjing, China.
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20
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HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27. Biochem J 2018; 475:3997-4010. [PMID: 30322885 DOI: 10.1042/bcj20180465] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/12/2018] [Accepted: 10/14/2018] [Indexed: 12/18/2022]
Abstract
The homeobox transcription factor Nkx6.1 is sufficient to increase functional β-cell mass, where functional β-cell mass refers to the combination of β-cell proliferation, glucose-stimulated insulin secretion (GSIS) and β-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional β-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase β-cell proliferation in primary rat islets and the INS-1 832/13 β-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing β-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated β-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional β-cell mass.
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21
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Pothuraju R, Rachagani S, Junker WM, Chaudhary S, Saraswathi V, Kaur S, Batra SK. Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:319. [PMID: 30567565 PMCID: PMC6299603 DOI: 10.1186/s13046-018-0963-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure. MAIN BODY Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression. CONCLUSIONS Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC.
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Affiliation(s)
- Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Sanguine Diagnostics and Therapeutics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Viswanathan Saraswathi
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. .,Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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22
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Arthur R, Kabat GC, Kim MY, Ho GYF, Chlebowski RT, Pan K, Rohan TE. Adiposity, history of diabetes, and risk of pancreatic cancer in postmenopausal women. Ann Epidemiol 2018; 29:23-29.e1. [PMID: 30449532 DOI: 10.1016/j.annepidem.2018.09.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 09/05/2018] [Accepted: 09/12/2018] [Indexed: 11/29/2022]
Abstract
PURPOSE The purpose of this study was to examine the association of type II diabetes and anthropometric variables with risk of pancreatic cancer among postmenopausal women. METHODS Weight, height, waist circumference, and hip circumference were measured by trained personnel, whereas history of diabetes and weight earlier in life were self-reported. Pancreatic cancer was ascertained via central review of medical records by physician adjudicators. After exclusions, 1045 cases of pancreatic cancer were diagnosed among 156,218 women over a median follow-up of approximately 18 years. Cox proportional hazards models were used to estimate the associations of study factors with pancreatic cancer risk. RESULTS Diabetes (hazards ratio (HR): 1.30; 95% confidence intervals (95% CI): 1.01-1.66), and in particular, waist circumference, waist-to-hip ratio, and waist-to-height ratio showed positive associations with pancreatic cancer risk (HRs for highest vs. lowest level 1.38; 95% CI: 1.14-1.66, 1.40; 1.17-1.68; and 1.36; 1.13-1.64, respectively). Body mass index at the baseline showed only a borderline positive association with risk (HR: 1.21; 95% CI: 0.97-1.51). Body mass index at age 50 years, but not at ages 18 and 35 years, was also associated with increased pancreatic cancer risk. CONCLUSIONS In this study of postmenopausal women, central adiposity and, to a lesser extent, general adiposity and a history of diabetes, were associated with increased pancreatic cancer risk.
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Affiliation(s)
- Rhonda Arthur
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
| | | | - Mimi Y Kim
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
| | - Gloria Y F Ho
- Center for Health Innovations and Outcomes Research, Feinstein Institute for Medical Research, Northwell Health, Great Neck, NY
| | - Rowan T Chlebowski
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA
| | - Kathy Pan
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA; Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
| | - Thomas E Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
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23
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Dietary oleic acid is inversely associated with pancreatic cancer - Data from food diaries in a cohort study. Pancreatology 2018; 18:655-660. [PMID: 30031691 DOI: 10.1016/j.pan.2018.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 07/06/2018] [Accepted: 07/08/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Dietary oleic acid may prevent pancreatic ductal adenocarcinoma (PDA) by reducing hyperinsulinaemia which can otherwise promote DNA damage and tumour growth. Results from previous epidemiological studies investigating oleic acid are inconsistent. This study aims to clarify the relationship between dietary oleic acid intake and the risk of developing PDA using nutritional information from food diaries plus published serum biomarker data from HbA1c. METHODS 23,658 participants, aged 40-74 years, were recruited into EPIC-Norfolk and completed 7-day food diaries which recorded; foods, brands and portion sizes to calculate nutrient intakes. Serum HbA1c was measured at recruitment in 11,147 participants (48.7% of cohort). Hazard ratios (HRs) for quintiles of dietary oleic acid intake and serum HbA1c were estimated using Cox regression. Additional analyses were made according to whether body mass index (BMI) was greater or less than 25 kg/m2 as this influences hyperinsulinaemia. RESULTS 88 participants (55% women) developed PDA after a mean follow-up of 8.4 years (SD = 3.9) (mean age at diagnosis = 72.6 years, SD = 8.8). A decreased risk of PDA was associated with increased dietary oleic acid intake (highest vs lowest quintile, HR = 0.29, 95% CI = 0.10-0.81, P trend across quintiles = 0.011), with statistical significance maintained when BMI>25 kg/m2 but not if BMI<25 kg/m2. An elevated serum HbA1c was associated with increased risk of disease (highest vs lowest quintiles, HR = 6.32, 95% CI = 1.38-28.89, P for trend = 0.004). CONCLUSIONS The data supports a protective role of oleic acid against development of PDA in those with higher BMIs possibly through influencing hyperinsulinaemia. Oleic acid intake should be accurately measured in future aetiological studies.
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Eibl G, Cruz-Monserrate Z, Korc M, Petrov MS, Goodarzi MO, Fisher WE, Habtezion A, Lugea A, Pandol SJ, Hart PA, Andersen DK. Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet 2018; 118:555-567. [PMID: 28919082 PMCID: PMC5845842 DOI: 10.1016/j.jand.2017.07.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.
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Zare M, Rastegar S, Ebrahimi E, Roohipoor A, Shirali S. Role of pancreatic duct cell in beta cell neogenesis: A mini review study. Diabetes Metab Syndr 2017; 11 Suppl 1:S1-S4. [PMID: 27578621 DOI: 10.1016/j.dsx.2016.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 08/22/2016] [Indexed: 12/16/2022]
Abstract
Today diabetes mellitus is known as main threatening for health society. Beta cells have pivotal role in energy homeostasis by balance in blood glucose. Proliferation and neogenesis are two factors for preservation of beta cell mass but these have lower rate during adulthood rather than neonatal. Beta cell destruction occurs during diabetes that leads to hyperglycemia. Continues production of beta cell is a therapeutic strategy to keep normal blood glucose and pancreatic duct cell can be one of the sources of new beta cells. Here, we reviewed the role of pancreatic duct cell in production of beta cell based on a chronological order of conducted studies.
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Affiliation(s)
- Mahsa Zare
- Department of Pharmacology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahdokht Rastegar
- Department of Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esmaeel Ebrahimi
- Department of Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Azade Roohipoor
- Department of Biochemistry, Taft University of Payame-Noor, Yazd, Iran
| | - Saeed Shirali
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Hyperlipidemia Research Center, Department of Laboratory Sciences, School of Paramedical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Frič P, Šedo A, Škrha J, Bušek P, Laclav M, Škrha P, Zavoral M. Early detection of sporadic pancreatic cancer: time for change. Eur J Gastroenterol Hepatol 2017; 29:885-891. [PMID: 28471824 DOI: 10.1097/meg.0000000000000904] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sporadic pancreatic cancer amounts to ∼90% of all pancreatic cancers. It is a gloomy depressive disease and the most recalcitrant malignancy, with a very low 5-year survival (3-6%). At present, diagnostic methods are commonly applied, as used half a century ago, after the appearance of local and systemic symptoms (abdominal and back pain, cholestasis, painless jaundice, fatigue, anorexia, weight loss, anemia, peripheral phlebitis, and cachexia). Unfortunately, these symptoms are harbingers of an advanced disease. The subsequent imaging methods may offer additional information on the location, size, and morphology of the lesion, but they do not influence the prognosis. Radical surgery may be offered to 15-20% of patients. The relapses after surgery are frequent and chemotherapy may be palliative. Preventive programs represent the only possibility of improvement. We propose the first multistep and multidisciplinary preventive program for early detection of sporadic pancreatic cancer for the differential identification of average-risk patients who probably have the disease from those who do not.
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Affiliation(s)
- Přemysl Frič
- aDepartment of Medicine/Gastroenterology, Military University Hospital bInstitute of Biochemistry and Experimental Oncology cLaboratory of Endocrinology and Metabolism, General University Hospital, First Faculty of Medicine dSecond Department of Medicine, University Hospital, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Schludi B, Moin ASM, Montemurro C, Gurlo T, Matveyenko AV, Kirakossian D, Dawson DW, Dry SM, Butler PC, Butler AE. Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes. JCI Insight 2017; 2:92282. [PMID: 28679961 DOI: 10.1172/jci.insight.92282] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 05/23/2017] [Indexed: 12/26/2022] Open
Abstract
Pancreatitis is more frequent in type 2 diabetes mellitus (T2DM), although the underlying cause is unknown. We tested the hypothesis that ongoing β cell stress and apoptosis in T2DM induces ductal tree proliferation, particularly the pancreatic duct gland (PDG) compartment, and thus potentially obstructs exocrine outflow, a well-established cause of pancreatitis. PDG replication was increased 2-fold in human pancreas from individuals with T2DM, and was associated with increased pancreatic intraepithelial neoplasia (PanIN), lesions associated with pancreatic inflammation and with the potential to obstruct pancreatic outflow. Increased PDG replication in the prediabetic human-IAPP-transgenic (HIP) rat model of T2DM was concordant with increased β cell stress but preceded metabolic derangement. Moreover, the most abundantly expressed chemokines released by the islets in response to β cell stress in T2DM, CXCL1, -4, and -10, induced proliferation in human pancreatic ductal epithelium. Also, the diabetes medications reported as potential modifiers for the risk of pancreatitis in T2DM modulated PDG proliferation accordingly. We conclude that chronic stimulation and proliferation of the PDG compartment in response to islet inflammation in T2DM is a potentially novel mechanism that serves as a link to the increased risk for pancreatitis in T2DM and may potentially be modified by currently available diabetes therapy.
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Affiliation(s)
| | | | | | | | | | | | - David W Dawson
- Department of Pathology and Laboratory Medicine.,Jonsson Comprehensive Cancer Center, UCLA, David Geffen School of Medicine, Los Angeles, California, USA
| | - Sarah M Dry
- Department of Pathology and Laboratory Medicine.,Jonsson Comprehensive Cancer Center, UCLA, David Geffen School of Medicine, Los Angeles, California, USA
| | - Peter C Butler
- Larry L. Hillblom Islet Research Center.,Jonsson Comprehensive Cancer Center, UCLA, David Geffen School of Medicine, Los Angeles, California, USA
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Ito M, Makino N, Matsuda A, Ikeda Y, Kakizaki Y, Saito Y, Ueno Y, Kawata S. High Glucose Accelerates Cell Proliferation and Increases the Secretion and mRNA Expression of Osteopontin in Human Pancreatic Duct Epithelial Cells. Int J Mol Sci 2017; 18:ijms18040807. [PMID: 28417915 PMCID: PMC5412391 DOI: 10.3390/ijms18040807] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 04/05/2017] [Accepted: 04/08/2017] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The incidence of pancreatic cancer is increasing year-by-year in Japan. Among the diseases that complicate pancreatic cancer, diabetes is the most common. Recently, it has become evident that patients suffering from diabetes and obesity show increased expression of osteopontin (OPN). The purpose of this study was to investigate the effect of high glucose and high insulin culture conditions on a human pancreatic duct epithelial cell line (HPDE-6), focusing particularly on OPN expression. METHODS HPDE-6 were cultured under various conditions, employing several combinations of glucose (normal, 6 mM high, 30 mM, and 60 mM) and insulin (0.1 nM, 1 nM) concentration. RESULTS HPDE-6 cell proliferation was significantly accelerated under high glucose culture conditions in comparison to samples in 6 mM glucose, and was more prominent under high insulin conditions. At the same time, the expression of OPN mRNA was also increased significantly. In comparison with 6 mM glucose, the expression of 8-OHdG DNA was increased in high glucose culture. CONCLUSION HPDE-6 cells show accelerated proliferation and increased OPN expression when cultured under high glucose and high insulin conditions. Furthermore, the cells show increased oxidative stress in the presence of high glucose.
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Affiliation(s)
- Miho Ito
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Naohiko Makino
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Akiko Matsuda
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Yushi Ikeda
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Yasuharu Kakizaki
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Yoshihiko Saito
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | - Sumio Kawata
- Hyogo Prefectural Nishinomiya Hospital, Nishinomiya 662-0918, Japan.
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Barone E, Corrado A, Gemignani F, Landi S. Environmental risk factors for pancreatic cancer: an update. Arch Toxicol 2016; 90:2617-2642. [PMID: 27538405 DOI: 10.1007/s00204-016-1821-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/04/2016] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.
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Affiliation(s)
- Elisa Barone
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Alda Corrado
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Federica Gemignani
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Stefano Landi
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy.
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Akalestou E, Christakis I, Solomou AM, Minnion JS, Rutter GA, Bloom SR. Proglucagon-Derived Peptides Do Not Significantly Affect Acute Exocrine Pancreas in Rats. Pancreas 2016; 45:967-73. [PMID: 26731187 PMCID: PMC4820085 DOI: 10.1097/mpa.0000000000000585] [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] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. METHODS Glucagon-like peptide 1, oxyntomodulin, glucagon, and exendin-4 were infused into anesthetized rats to measure plasma amylase concentration changes. In addition, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. RESULTS Plasma amylase did not increase postpeptide infusion, compared with vehicle and cholecystokinin; however, oxyntomodulin inhibited plasma amylase when coadministered with cholecystokinin. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. CONCLUSIONS The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin seems to be a potent inhibitor of amylase release, potentially making it a safer antiobesity agent regarding pancreatitis, compared with GLP-1 agonists.
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Affiliation(s)
- Elina Akalestou
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Ioannis Christakis
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Antonia M. Solomou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - James S. Minnion
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Stephen R. Bloom
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
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Early pancreatic carcinogenesis - risk factors, early symptoms, and the impact of antidiabetic drugs. Eur J Gastroenterol Hepatol 2016; 28:e19-25. [PMID: 27120389 DOI: 10.1097/meg.0000000000000646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC.
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Abstract
The recent recognition of the clinical association between type 2 diabetes (T2D) and several types of human cancer has been further highlighted by reports of antidiabetic drugs treating or promoting cancer. At the cellular level, a plethora of molecules operating within distinct signaling pathways suggests cross-talk between the multiple pathways at the interface of the diabetes–cancer link. Additionally, a growing body of emerging evidence implicates homeostatic pathways that may become imbalanced during the pathogenesis of T2D or cancer or that become chronically deregulated by prolonged drug administration, leading to the development of cancer in diabetes and vice versa. This notion underscores the importance of combining clinical and basic mechanistic studies not only to unravel mechanisms of disease development but also to understand mechanisms of drug action. In turn, this may help the development of personalized strategies in which drug doses and administration durations are tailored to individual cases at different stages of the disease progression to achieve more efficacious treatments that undermine the diabetes–cancer association.
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Affiliation(s)
- Slavica Tudzarova
- Wolfson Institute for Biomedical Research, University College London, London WC1E6BT, UK
| | - Mahasin A Osman
- Department of Molecular Physiology, Pharmacology and Biotechnology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912 Department of Chemistry and Forensic Sciences, College of Sciences and Technology, Savannah State University, Savannah, GA 41404
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Draney C, Hobson AE, Grover SG, Jack BO, Tessem JS. Cdk5r1 Overexpression Induces Primary β-Cell Proliferation. J Diabetes Res 2016; 2016:6375804. [PMID: 26788519 PMCID: PMC4691621 DOI: 10.1155/2016/6375804] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/15/2015] [Accepted: 08/18/2015] [Indexed: 02/07/2023] Open
Abstract
Decreased β-cell mass is a hallmark of type 1 and type 2 diabetes. Islet transplantation as a method of diabetes therapy is hampered by the paucity of transplant ready islets. Understanding the pathways controlling islet proliferation may be used to increase functional β-cell mass through transplantation or by enhanced growth of endogenous β-cells. We have shown that the transcription factor Nkx6.1 induces β-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to define Nkx6.1-independent mechanisms by which Nr4a1 and Nr4a3 induce β-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 but not by Nkx6.1. Overexpression of Cdk5r1 is sufficient to induce primary rat β-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 in β-cells confers protection against apoptosis induced by etoposide and thapsigargin, but not camptothecin. The Cdk5 kinase complex inhibitor roscovitine blocks islet proliferation, suggesting that Cdk5r1 mediated β-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 kinase complex is sufficient to induce β-cell proliferation while maintaining glucose stimulated insulin secretion.
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Affiliation(s)
- Carrie Draney
- Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
| | - Amanda E. Hobson
- Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
| | - Samuel G. Grover
- Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
| | - Benjamin O. Jack
- Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
| | - Jeffery S. Tessem
- Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
- *Jeffery S. Tessem:
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3-D imaging of islets in obesity: formation of the islet-duct complex and neurovascular remodeling in young hyperphagic mice. Int J Obes (Lond) 2015; 40:685-97. [PMID: 26499436 DOI: 10.1038/ijo.2015.224] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 09/15/2015] [Accepted: 10/10/2015] [Indexed: 01/30/2023]
Abstract
BACKGROUND Obesity and insulin resistance lead to islet hyperplasia. However, how the islet remodeling influences the pancreatic environment and the associated neurovascular networks is largely unknown. The lack of information is primarily due to the difficulty of global visualization of the hyperplasic islet (>200 μm) and the neurovascular environment with high definition. METHODS We modulated the pancreatic optical property to achieve 3-dimensional (3-D) whole-islet histology and to integrate transmitted light microscopy (which provides the ground-truth tissue information) with confocal fluorescence imaging. The new optical and imaging conditions were used to globally examine the hyperplastic islets of the young (2 months) obese db/db and ob/ob mice, which otherwise cannot be easily portrayed by the standard microtome-based histology. The voxel-based islet micrographs were digitally processed for stereo projection and qualitative and quantitative analyses of the islet tissue networks. RESULTS Paired staining and imaging of the pancreatic islets, ducts and neurovascular networks reveal the unexpected formation of the 'neuro-insular-ductal complex' in the young obese mice. The complex consists of the peri- and/or intra-islet ducts and prominent peri-ductal sympathetic nerves; the latter contributes to a marked increase in islet sympathetic innervation. In vascular characterization, we identify a decreased perivascular density of the ob/ob islet pericytes, which adapt to ensheathing the dilated microvessels with hypertrophic processes. CONCLUSIONS Modulation of pancreatic optical property enables 3-D panoramic examination of islets in the young hyperphagic mice to reveal the formation of the islet-duct complex and neurovascular remodeling. On the basis of the morphological proximity of the remodeled tissue networks, we propose a reactive islet microenvironment consisting of the endocrine cells, ductal epithelium and neurovascular tissues in response to the metabolic challenge that is experienced early in life.
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Usborne A, Byrd RA, Meehan J, Blackbourne JL, Sullivan J, Poitout-Belissent F, Prefontaine A, Martin JA, Vahle JL. An Investigative Study of Pancreatic Exocrine Biomarkers, Histology, and Histomorphometry in Male Zucker Diabetic Fatty (ZDF) Rats Given Dulaglutide by Subcutaneous Injection Twice Weekly for 13 Weeks. Toxicol Pathol 2015; 43:1093-102. [PMID: 26269615 DOI: 10.1177/0192623315596857] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonist therapy has been implicated as a possible risk factor for acute pancreatitis in patients with type 2 diabetes. Dulaglutide is a long-acting GLP-1 receptor agonist in development for treatment of type 2 diabetes. The effects of dulaglutide were evaluated in male Zucker diabetic fatty (ZDF) rats to examine whether dulaglutide may induce or modulate pancreatitis. Rats were randomized to dose groups receiving twice-weekly subcutaneously administered dulaglutide 0.5, 1.5, and 5.0 mg/kg/dose (corresponding human plasma exposures following twice-weekly dosing are 3-, 8-, and 30-fold, respectively) for 13 weeks or to vehicle control. Following termination, serially trimmed sections of pancreases were stained with hematoxylin and eosin or co-stained with an epithelial marker and a marker of either proliferation or apoptosis. Efficacious reductions in glucose and hemoglobin A1c occurred at all dulaglutide doses. Lipase activity was unaffected, and there were modest increases in total and pancreatic amylase activities at all doses without individual microscopic inflammatory correlates. Microscopic dulaglutide-related pancreatic changes included increased interlobular ductal epithelium without ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased incidence/severity of neutrophilic acinar pancreatic inflammation (5.0 mg/kg). In summary, dulaglutide treatment was associated with mild alterations in ductal epithelium and modest exacerbation of spontaneous lesions of the exocrine pancreas typically found in the ZDF rat model.
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Affiliation(s)
- Amy Usborne
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
| | - Richard A Byrd
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
| | - James Meehan
- Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada
| | - Jamie L Blackbourne
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
| | - John Sullivan
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
| | | | - Annick Prefontaine
- Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada
| | - Jennifer A Martin
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
| | - John L Vahle
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
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Haluzík M, Mráz M, Svačina Š. Balancing benefits and risks in patients receiving incretin-based therapies: focus on cardiovascular and pancreatic side effects. Drug Saf 2015; 37:1003-10. [PMID: 25391858 DOI: 10.1007/s40264-014-0238-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.
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Affiliation(s)
- Martin Haluzík
- 3rd Dept. of Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, U Nemocnice 1, 128 08, Prague 2, Czech Republic,
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Salvatore T, Marfella R, Rizzo MR, Sasso FC. Pancreatic cancer and diabetes: A two-way relationship in the perspective of diabetologist. Int J Surg 2015; 21 Suppl 1:S72-7. [PMID: 26123386 DOI: 10.1016/j.ijsu.2015.06.063] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 03/25/2015] [Accepted: 04/10/2015] [Indexed: 12/31/2022]
Abstract
Diabetes is a risk factor for pancreatic cancer as roughly half of all patients with pancreatic cancer are found to have diabetes at time of diagnosis. Moreover, an around 2-fold risk of pancreatic malignancy in diabetic patients has even be recently resulted from two meta-analysis. Actually, there is a bidirectional association between the two entities that implies a complex and reverse causality. In fact, while the risk for pancreatic cancer is modestly but significantly increased in patients with long-standing diabetes, recent-onset diabetes appears to be very frequently associated with pancreatic malignancy. Therefore, diabetes could serve as an excellent clue for early detection of pancreatic cancer. Moreover, recent epidemiological findings support the hypothesis that chronic exposure to hyperglycemia, higher insulin concentrations, and insulin resistance may be responsible for the enhanced risk of developing pancreatic cancer. Epidemiological data suggest that the type of anti-diabetic therapy may affect the risk of developing pancreatic cancer. In particular, metformin has been shown to reduce the risk of pancreatic cancer, as well as several other malignancies. On the other hand, some hypoglycemic agents could determine an increase of pancreatic cancer risk. These last findings were not confirmed. Finally, pancreatic cancer necessitates of a multidisciplinary management, primarily including surgeons and oncologists. In this context, the diabetologist plays an important role, given that his actions may influence the prevention and early diagnosis of pancreatic cancer, the perioperative complications associated to glycemic derangement, as well as the proper treatment of postpancreactomy diabetes.
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Affiliation(s)
- Teresa Salvatore
- Depart. of Internal and Experimental Medicine "Magrassi - Lanzara", Second University of Naples, Italy.
| | - Raffaele Marfella
- Depart. of Medicine, Surgery, Neurology, Metabolism and Geriatrics, Second University of Naples, Italy.
| | - Maria Rosaria Rizzo
- Depart. of Medicine, Surgery, Neurology, Metabolism and Geriatrics, Second University of Naples, Italy.
| | - Ferdinando Carlo Sasso
- Depart. of Internal and Experimental Medicine "Magrassi - Lanzara", Second University of Naples, Italy.
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Liao WC, Tu YK, Wu MS, Lin JT, Wang HP, Chien KL. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. BMJ 2015; 350:g7371. [PMID: 25556126 PMCID: PMC4282179 DOI: 10.1136/bmj.g7371] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2014] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. DESIGN Systematic review and dose-response meta-analysis of prospective observational studies. DATA SOURCES Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. ELIGIBILITY CRITERIA Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. DATA EXTRACTION AND SYNTHESIS Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. RESULTS Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. CONCLUSIONS Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer.
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Affiliation(s)
- Wei-Chih Liao
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
| | - Yu-Kang Tu
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, 510 Zhongzheng Road, New Taipei City 242, Taiwan
| | - Hsiu-Po Wang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan
| | - Kuo-Liong Chien
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
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Hobson A, Draney C, Stratford A, Becker TC, Lu D, Arlotto M, Tessem JS. Aurora Kinase A is critical for the Nkx6.1 mediated β-cell proliferation pathway. Islets 2015; 7:e1027854. [PMID: 26030060 PMCID: PMC4588548 DOI: 10.1080/19382014.2015.1027854] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Type 1 and type 2 diabetes are ultimately characterized by depleted β-cell mass. Characterization of the molecular pathways that control β-cell proliferation could be harnessed to restore these cells. The homeobox β-cell transcription factor Nkx6.1 induces β-cell proliferation by activating the orphan nuclear receptors Nr4a1 and Nr4a3. Here, we demonstrate that Nkx6.1 localizes to the promoter of the mitotic kinase AURKA (Aurora Kinase A) and induces its expression. Adenovirus mediated overexpression of AURKA is sufficient to induce proliferation in primary rat islets while maintaining glucose stimulated insulin secretion. Furthermore, AURKA is necessary for Nkx6.1 mediated β-cell proliferation as demonstrated by shRNA mediated knock down and pharmacological inhibition of AURKA kinase activity. AURKA preferentially induces DNA replication in β-cells as measured by BrdU incorporation, and enhances the rate of histone H3 phosphorylation in primary β-cells, demonstrating that AURKA induces the replicative and mitotic cell cycle phases in rat β-cells. Finally, overexpression of AURKA results in phosphorylation of the cell cycle regulator p53, which targets p53 for degradation and permits cell cycle progression. These studies define a pathway by which AURKA upregulation by Nkx6.1 results in phosphorylation and degradation of p53, thus removing a key inhibitory factor and permitting engagement of the β-cell proliferation pathway.
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Key Words
- AURKA
- AURKA, Aurora Kinase A
- BrdU, bromodeoxyuridine
- ChIP, chromatin immunoprecipitation
- Nkx6.1
- Nkx6.1, NK Homeobox 1
- Nr4a1, Nuclear receptor subfamily 4, group A, member 1
- Nr4a3, Nuclear receptor subfamily 4, group A, member 3
- cell cycle
- islet
- p53
- proliferation
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Affiliation(s)
- Amanda Hobson
- Nutrition; Dietetics and Food Science Department; College of Life Sciences; Brigham Young University, Provo, Utah USA
| | - Carrie Draney
- Nutrition; Dietetics and Food Science Department; College of Life Sciences; Brigham Young University, Provo, Utah USA
| | - Andrew Stratford
- Nutrition; Dietetics and Food Science Department; College of Life Sciences; Brigham Young University, Provo, Utah USA
| | - Thomas C Becker
- Duke Molecular Physiology Institute; Duke University Medical Center; Durham, NC USA
| | - Danhong Lu
- Duke Molecular Physiology Institute; Duke University Medical Center; Durham, NC USA
| | - Michelle Arlotto
- Duke Molecular Physiology Institute; Duke University Medical Center; Durham, NC USA
| | - Jeffery S Tessem
- Nutrition; Dietetics and Food Science Department; College of Life Sciences; Brigham Young University, Provo, Utah USA
- Correspondence to: Jeffery Sivert Tessem;
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40
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Riley KG, Gannon M. Pancreas Development and Regeneration. PRINCIPLES OF DEVELOPMENTAL GENETICS 2015:565-590. [DOI: 10.1016/b978-0-12-405945-0.00031-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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He XD, Wu Q, Liu W, Hong T, Li JJ, Miao RY, Zhao HT. Association of metabolic syndromes and risk factors with ampullary tumors development: A case-control study in China. World J Gastroenterol 2014; 20:9541-9548. [PMID: 25071350 PMCID: PMC4110587 DOI: 10.3748/wjg.v20.i28.9541] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 02/22/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the risk factors for ampullary adenoma and ampullary cancer.
METHODS: This case-control study included ampullary tumor patients referred to Peking Union Medical College Hospital. Controls were randomly selected from an existing database of healthy individuals at the Health Screening Center of the same hospital. Data on metabolic syndromes, medical conditions, and family history were collected by retrospective review of the patients’ records and health examination reports, or by interview.
RESULTS: A total of 181 patients and 905 age- and sex-matched controls were enrolled. We found that a history of diabetes, cholecystolithiasis, low-density lipoprotein, and apolipoprotein A were significantly related to ampullary adenomas. Diabetes, cholecystolithiasis, chronic pancreatitis, total cholesterol, high-density lipoprotein, and apolipoprotein A were also significantly related to ampullary cancer.
CONCLUSION: Some metabolic syndrome components and medical conditions are potential risk factors for the development of ampullary tumors. Cholelithiasis, diabetes, and apolipoprotein A may contribute to the malignant transformation of benign ampullary adenomas into ampullary cancer.
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Nichols RJ, New C, Annes JP. Adult tissue sources for new β cells. Transl Res 2014; 163:418-31. [PMID: 24345765 PMCID: PMC3976738 DOI: 10.1016/j.trsl.2013.11.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 11/04/2013] [Accepted: 11/20/2013] [Indexed: 12/25/2022]
Abstract
The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies-from implantable insulin delivery devices to transplantation-based cell replacement therapy, to β-cell regeneration-focus on replacing the lost insulin-producing capacity of individuals with diabetes. Among these, β-cell regeneration remains promising but heretofore unproved. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of β-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new β cells from existing cells. First, β cells, long thought to be postmitotic, have demonstrated the potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating β cells from other differentiated cell types. Here, we review the exciting developments surrounding endogenous sources of β-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues.
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Affiliation(s)
| | - Connie New
- Department of Medicine, Stanford University Medical School, Stanford, Calif
| | - Justin P Annes
- Department of Medicine, Stanford University Medical School, Stanford, Calif.
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Preziosi G, Oben JA, Fusai G. Obesity and pancreatic cancer. Surg Oncol 2014; 23:61-71. [PMID: 24746917 DOI: 10.1016/j.suronc.2014.02.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 02/21/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Pancreatic cancer is an invariably fatal malignancy. Cigarette smoking and diabetes are established risk factors, but over the last two decades studies have shown that excess adiposity is an additional independent risk factor with 30-50% of cases thought to be attributed to nutritional factors. The aim of this narrative review is to analyze all the epidemiological evidence on the topic and possible pathophysiology. METHODS We searched PubMed, Embase, Cochrane Library and Medline, and all available evidence was included. We firstly analyze meta- and pooled analysis. Then we discuss individual studies to identify sources of discrepancies between studies and attempt to delineate pathophysiology. RESULTS It is estimated that obese individuals have a relative risk (RR) ranging between 1.19 and 1.47, when compared with those of normal weight, regardless of diabetes or smoking status. No significant differences were found between gender. CONCLUSION There is a measurable increased risk of developing pancreatic cancer in obese individuals, and excess adiposity is related to the condition with a "dose-response" curve. Hyperinsulinemia and possibly hyperestrogenism secondary to a metabolic syndrome, and independently from diabetes status, appear to be the key elements of the pathogenesis in pancreatic cancer secondary to excess body fat. Increased efforts should therefore be made in tackling the epidemic levels of obesity in the Western world countries.
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Affiliation(s)
- Giuseppe Preziosi
- Hepato-Pancreatico-Biliary Surgery and Liver Transplant Unit, Royal Free Hospital, London, United Kingdom.
| | - Jude A Oben
- Centre for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom
| | - Giuseppe Fusai
- Hepato-Pancreatico-Biliary Surgery and Liver Transplant Unit, Royal Free Hospital, London, United Kingdom
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Nakamura T, Ito T, Uchida M, Hijioka M, Igarashi H, Oono T, Kato M, Nakamura K, Suzuki K, Jensen RT, Takayanagi R. PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist. J Transl Med 2014; 94:63-78. [PMID: 24217090 PMCID: PMC3879597 DOI: 10.1038/labinvest.2013.133] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 10/02/2013] [Accepted: 10/21/2013] [Indexed: 12/20/2022] Open
Abstract
There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.
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Affiliation(s)
- Taichi Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
| | - Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masahiko Uchida
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masayuki Hijioka
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Takamasa Oono
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Koichi Suzuki
- Department of Leprosy Research Center, National Institute of Infectious Diseases, Tokyo Japan
| | - Robert T. Jensen
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
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Abstract
Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5-8-fold increased risk of being diagnosed with pancreatic cancer within 1-3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.
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The effects of dipeptidyl-peptidase-IV inhibitor, vildagliptin, on the exocrine pancreas in spontaneously diabetic Goto-Kakizaki rats. Pancreas 2013; 42:786-94. [PMID: 23774700 DOI: 10.1097/mpa.0b013e318287c9b5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES The risk of adverse effects of dipeptidyl peptidase-4 inhibitors on the exocrine pancreas, particularly the high risk of pancreatitis, is controversial. In this study, we examined the exocrine pancreatic function and structure in spontaneously diabetic Goto-Kakizaki (GK) rats treated with a dipeptidyl peptidase-4 inhibitor. METHODS Male GK rats and normal Wistar rats 4 weeks of age were treated with vildagliptin (VG; 30 mg/kg/d) for 18 weeks. Subsequently, exocrine pancreatic pathology and function in treated animals were compared to those in untreated animals. RESULTS In GK rats, VG treatment suppressed elevated serum concentrations of amylase and lipase, reduced lymphocytic infiltration around ducts, around vessels, and in acinar areas, and reduced the frequency of apoptotic acinar cells and ductule formation (both of which occurred more frequently in GK rats than Wistar rats). However, VG treatment had no effect on the proliferation rate of pancreatic duct glandular cells (which was low in GK rats) and of cells in the main ducts, peripheral ducts, and acini (which was similar in all groups). CONCLUSIONS Perturbations of exocrine pancreatic function and structure in GK rats are ameliorated by long-term VG treatment.
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Campos GM, Ziemelis M, Paparodis R, Ahmed M, Davis DB. Laparoscopic reversal of Roux-en-Y gastric bypass: technique and utility for treatment of endocrine complications. Surg Obes Relat Dis 2013; 10:36-43. [PMID: 24120983 DOI: 10.1016/j.soard.2013.05.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 04/24/2013] [Accepted: 05/25/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND The anatomic and physiologic changes with Roux-en-Y gastric bypass (RYGB) may lead to uncommon but occasionally difficult to treat complications such as hyperinsulinemic hypoglycemia with neuroglycopenia and recalcitrant hypocalcemia associated to hypoparathyroidism. Medical management of these complications is challenging. Laparoscopic reversal of RYGB anatomy with restoration of pyloric function and duodenal continuity is a potential treatment. The objective of this study was to present the indications, surgical technique, and clinical outcomes of laparoscopic reversal of RYGB. METHODS Prospective study of consecutive patients offered laparoscopic reversal of RYGB. RESULTS Five patients with remote laparoscopic RYGB underwent laparoscopic reversal of RYGB to normal anatomy (n = 2) or modified sleeve gastrectomy (n = 3). Indications were medically refractory hyperinsulinemic hypoglycemia with neuroglycopenia (n = 3), recalcitrant hypocalcemia with hypoparathyroidism (n = 1), and both conditions simultaneously (n = 1). Before reversal, all patients had a gastrostomy tube placed in the excluded stomach to document improvement of symptoms. Laparoscopic reversal was accomplished successfully in all patients. Three postoperative complications occurred: bleeding that required transfusion, gallstone pancreatitis, and a superficial trocar site infection. Average length of stay was 3 days. At a mean follow-up of 12 months (range 3 to 22), no additional episodes of neuroglycopenia occurred, average number of hypoglycemic episodes per week decreased from 18.5 ± 12.4 to 1.5 ± 1.9 (P = .05), and hypocalcemia became responsive to oral replacement therapy in both patients. CONCLUSIONS Laparoscopic reversal of RYGB to normal anatomy or modified sleeve gastrectomy is feasible and may be a therapeutic option for selected patients with medically refractory hyperinsulinemic hypoglycemia and/or recalcitrant hypocalcemia associated with hypoparathyroidism.
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Affiliation(s)
- Guilherme M Campos
- Department of Surgery, Division of General Surgery, Section of Foregut and Bariatric Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
| | - Martynas Ziemelis
- Department of Surgery, Division of General Surgery, Section of Foregut and Bariatric Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Rodis Paparodis
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Muhammed Ahmed
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Dawn Belt Davis
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
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Ninov N, Hesselson D, Gut P, Zhou A, Fidelin K, Stainier DYR. Metabolic regulation of cellular plasticity in the pancreas. Curr Biol 2013; 23:1242-50. [PMID: 23791726 DOI: 10.1016/j.cub.2013.05.037] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 03/21/2013] [Accepted: 05/21/2013] [Indexed: 12/27/2022]
Abstract
Obese individuals exhibit an increase in pancreatic β cell mass; conversely, scarce nutrition during pregnancy has been linked to β cell insufficiency in the offspring [reviewed in 1, 2]. These phenomena are thought to be mediated mainly through effects on β cell proliferation, given that a nutrient-sensitive β cell progenitor population in the pancreas has not been identified. Here, we employed the fluorescent ubiquitination-based cell-cycle indicator system to investigate β cell replication in real time and found that high nutrient concentrations induce rapid β cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β cell differentiation from progenitors in the intrapancreatic duct (IPD). Furthermore, using a new zebrafish line where β cells are constitutively ablated, we show that β cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a downregulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic target of rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. Thus, this study reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient-sensitive progenitors in the mature pancreas.
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Affiliation(s)
- Nikolay Ninov
- Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4(th) Street, San Francisco, CA 94158, USA.
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Abstract
The importance of the IGF system in carcinogenesis has been established for many solid cancers. It is well known that individuals with higher circulating levels of the IGF1 ligand present an increased risk of cancer. However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR), which appears to be at least equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, IGF1, and IGF2. Although the connection between insulin, diabetes, and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer is missing. In this review, we focus on the contribution of insulin and IGFs to carcinogenesis in the insulin-producing organ, the pancreas. We give a short summary on the complexity of insulin and the IGF system in the pancreas and their potential roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma. Finally, we discuss drug-targeting options of this system and the rationale of simultaneous targeting of both the insulin and the IGF systems.
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Affiliation(s)
- Marija Trajkovic-Arsic
- II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr 22, 81675 Munich, Germany.
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Tatarkiewicz K, Belanger P, Gu G, Parkes D, Roy D. No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks. Diabetes Obes Metab 2013; 15:417-26. [PMID: 23163898 PMCID: PMC3654567 DOI: 10.1111/dom.12040] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 09/29/2012] [Accepted: 11/12/2012] [Indexed: 12/18/2022]
Abstract
AIMS The potential association of glucagon-like peptide receptor agonists (GLP-1RAs) with the development of pancreatitis or pancreatic malignancies in patients with diabetes has been suggested. This study evaluated the long-term effects of the GLP-1RA exenatide on pancreatic exocrine structure and function in the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. METHODS Rats received subcutaneous twice-daily injections of 0 (control), 6, 40 and 250 µg/kg/day exenatide for 3 months. Clinical signs, body and pancreas weight, food consumption, HbA1c, fasting serum amylase, lipase, glucose and insulin concentrations were evaluated during treatment and after a 28-day off-drug period to assess the reversibility of any observed effects. Morphometric analysis of pancreatic ductal cell proliferation and apoptosis were performed. RESULTS Plasma exenatide concentrations were several-fold higher than therapeutic levels observed in humans. No exenatide-related effects were observed on clinical signs, lipase concentration, pancreatic weight, pancreatic histology, ductal cell proliferation or apoptosis. Exenatide improved animal survival, physical condition, glucose concentrations and HbA1c, decreased food intake, and increased serum insulin concentration. Total amylase concentrations, although within normal ranges, were slightly higher in exenatide-treated rats; following the off-drug period, total amylase concentrations were comparable in treated and untreated rats. Exenatide-related minimal-to-moderate islet hypertrophy was observed at doses ≥6 µg/kg/day, with dose-related increases in incidence and degree. These changes were still present after the off-drug period. CONCLUSIONS Chronic administration of exenatide in ZDF rats resulted in the expected metabolic benefits and improved animal survival, with no adverse effects noted on pancreatic exocrine structure and function.
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