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Johnson-Pitt A, Catchpole B, Davison LJ. Exocrine pancreatic inflammation in canine diabetes mellitus - An active offender? Vet J 2024; 308:106241. [PMID: 39243807 DOI: 10.1016/j.tvjl.2024.106241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/27/2024] [Accepted: 09/01/2024] [Indexed: 09/09/2024]
Abstract
The purpose of this review is to examine the current scientific literature regarding the interplay between the exocrine and endocrine pancreas, specifically the role of the exocrine pancreas in the pathogenesis of canine diabetes mellitus. β-cell death caused by exocrine pancreatic inflammation is thought to be an under-recognised contributor to diabetes mellitus in dogs, with up to 30 % of canine diabetic patients with concurrent evidence of pancreatitis at post-mortem examination. Current diagnostics for pancreatitis are imprecise, and treatments for both diseases individually have their own limitations: diabetes through daily insulin injections, which has both welfare and financial implications for the stakeholders, and pancreatitis through treatment of clinical signs, such as analgesia and anti-emetics, rather than targeted treatment of the underlying cause. This review will consider the evidence for exocrine pancreatic inflammation making an active contribution to pancreatic β-cell loss and insulin-deficiency diabetes in the dog and explore current and potential future diagnostic and treatment avenues to improve outcomes for these patients.
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Affiliation(s)
- Arielle Johnson-Pitt
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK.
| | - Brian Catchpole
- Department of Pathobiology and Population Sciences, The Royal Veterinary College, Hertfordshire AL9 7TA, UK
| | - Lucy J Davison
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
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Di Piazza E, Todi L, Di Giuseppe G, Soldovieri L, Ciccarelli G, Brunetti M, Quero G, Alfieri S, Tondolo V, Pontecorvi A, Gasbarrini A, Nista EC, Giaccari A, Pani G, Mezza T. Advancing Diabetes Research: A Novel Islet Isolation Method from Living Donors. Int J Mol Sci 2024; 25:5936. [PMID: 38892122 PMCID: PMC11172646 DOI: 10.3390/ijms25115936] [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: 05/07/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors' clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches.
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Affiliation(s)
- Eleonora Di Piazza
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
| | - Laura Todi
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Laura Soldovieri
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Gea Ciccarelli
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Michela Brunetti
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Giuseppe Quero
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Digestive Surgery Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Digestive Surgery Unit, Ospedale Isola Tiberina—Gemelli Isola, 00186 Roma, Italy
| | - Sergio Alfieri
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Digestive Surgery Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Digestive Surgery Unit, Ospedale Isola Tiberina—Gemelli Isola, 00186 Roma, Italy
| | - Vincenzo Tondolo
- Digestive Surgery Unit, Ospedale Isola Tiberina—Gemelli Isola, 00186 Roma, Italy
| | - Alfredo Pontecorvi
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Antonio Gasbarrini
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
| | - Enrico Celestino Nista
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
| | - Andrea Giaccari
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Giovambattista Pani
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Teresa Mezza
- Department of Medicine and Translational Surgery, General Pathology Section, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Roma, Italy
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Omori K, Qi M, Salgado M, Gonzalez N, Hui LT, Chen KT, Rawson J, Miao L, Komatsu H, Isenberg JS, Al-Abdullah IH, Mullen Y, Kandeel F. A scalable human islet 3D-culture platform maintains cell mass and function long-term for transplantation. Am J Transplant 2024; 24:177-189. [PMID: 37813189 DOI: 10.1016/j.ajt.2023.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 10/11/2023]
Abstract
Present-day islet culture methods provide short-term maintenance of cell viability and function, limiting access to islet transplantation. Attempts to lengthen culture intervals remain unsuccessful. A new method was developed to permit the long-term culture of islets. Human islets were embedded in polysaccharide 3D-hydrogel in cell culture inserts or gas-permeable chambers with serum-free CMRL 1066 supplemented media for up to 8 weeks. The long-term cultured islets maintained better morphology, cell mass, and viability at 4 weeks than islets in conventional suspension culture. In fact, islets cultured in the 3D-hydrogel retained β cell mass and function on par with freshly isolated islets in vitro and, when transplanted into diabetic mice, restored glucose balance similar to fresh islets. Using gas-permeable chambers, the 3D-hydrogel culture method was scaled up over 10-fold and maintained islet viability and function, although the cell mass recovery rate was 50%. Additional optimization of scale-up methods continues. If successful, this technology could afford flexibility and expand access to islet transplantation, especially single-donor islet-after-kidney transplantation.
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Affiliation(s)
- Keiko Omori
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
| | - Meirigeng Qi
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Mayra Salgado
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Nelson Gonzalez
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Lauren T Hui
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Kuan-Tsen Chen
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jeffrey Rawson
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Lynn Miao
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Hirotake Komatsu
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jeffrey S Isenberg
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Ismail H Al-Abdullah
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yoko Mullen
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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Yildirim V, Sheraton VM, Brands R, Crielaard L, Quax R, van Riel NA, Stronks K, Nicolaou M, Sloot PM. A data-driven computational model for obesity-driven diabetes onset and remission through weight loss. iScience 2023; 26:108324. [PMID: 38026205 PMCID: PMC10665812 DOI: 10.1016/j.isci.2023.108324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/22/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Obesity is a major risk factor for the development of type 2 diabetes (T2D), where a sustained weight loss may result in T2D remission in individuals with obesity. To design effective and feasible intervention strategies to prevent or reverse T2D, it is imperative to study the progression of T2D and remission together. Unfortunately, this is not possible through experimental and observational studies. To address this issue, we introduce a data-driven computational model and use human data to investigate the progression of T2D with obesity and remission through weight loss on the same timeline. We identify thresholds for the emergence of T2D and necessary conditions for remission. We explain why remission is only possible within a window of opportunity and the way that window depends on the progression history of T2D, individual's metabolic state, and calorie restrictions. These findings can help to optimize therapeutic intervention strategies for T2D prevention or treatment.
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Affiliation(s)
- Vehpi Yildirim
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Vivek M. Sheraton
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Ruud Brands
- AMRIF B.V., Agro Business Park, 6708 PW Wageningen, the Netherlands
- Institute for Risk Assessment Sciences, Utrecht University, 3584 CL Utrecht, the Netherlands
| | - Loes Crielaard
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Rick Quax
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
| | - Natal A.W. van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, the Netherlands
- Department of Experimental and Vascular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Karien Stronks
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Mary Nicolaou
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Peter M.A. Sloot
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
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Glucose Homeostasis and Pancreatic Islet Size Are Regulated by the Transcription Factors Elk-1 and Egr-1 and the Protein Phosphatase Calcineurin. Int J Mol Sci 2023; 24:ijms24010815. [PMID: 36614256 PMCID: PMC9821712 DOI: 10.3390/ijms24010815] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
Pancreatic β-cells synthesize and secrete insulin. A key feature of diabetes mellitus is the loss of these cells. A decrease in the number of β-cells results in decreased biosynthesis of insulin. Increasing the number of β-cells should restore adequate insulin biosynthesis leading to adequate insulin secretion. Therefore, identifying proteins that regulate the number of β-cells is a high priority in diabetes research. In this review article, we summerize the results of three sophisticated transgenic mouse models showing that the transcription factors Elk-1 and Egr-1 and the Ca2+/calmodulin-regulated protein phosphatase calcineurin control the formation of sufficiently large pancreatic islets. Impairment of the biological activity of Egr-1 and Elk-1 in pancreatic β-cells leads to glucose intolerance and dysregulation of glucose homeostasis, the process that maintains glucose concentration in the blood within a narrow range. Transgenic mice expressing an activated calcineurin mutant also had smaller islets and showed hyperglycemia. Calcineurin induces dephosphorylation of Elk-1 which subsequently impairs Egr-1 biosynthesis and the biological functions of Elk-1 and Egr-1 to regulate islet size and glucose homeostasis.
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Sequeira IR, Yip W, Lu LW, Jiang Y, Murphy R, Plank LD, Cooper GJS, Peters CN, Aribsala BS, Hollingsworth KG, Poppitt SD. Exploring the relationship between pancreatic fat and insulin secretion in overweight or obese women without type 2 diabetes mellitus: A preliminary investigation of the TOFI_Asia cohort. PLoS One 2022; 17:e0279085. [PMID: 36584200 PMCID: PMC9803309 DOI: 10.1371/journal.pone.0279085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 10/02/2022] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE While there is an emerging role of pancreatic fat in the aetiology of type 2 diabetes mellitus (T2DM), its impact on the associated decrease in insulin secretion remains controversial. We aimed to determine whether pancreatic fat negatively affects β-cell function and insulin secretion in women with overweight or obesity but without T2DM. METHODS 20 women, with normo- or dysglycaemia based on fasting plasma glucose levels, and low (< 4.5%) vs high (≥ 4.5%) magnetic resonance (MR) quantified pancreatic fat, completed a 1-hr intravenous glucose tolerance test (ivGTT) which included two consecutive 30-min square-wave steps of hyperglycaemia generated by using 25% dextrose. Plasma glucose, insulin and C-peptide were measured, and insulin secretion rate (ISR) calculated using regularisation deconvolution method from C-peptide kinetics. Repeated measures linear mixed models, adjusted for ethnicity and baseline analyte concentrations, were used to compare changes during the ivGTT between high and low percentage pancreatic fat (PPF) groups. RESULTS No ethnic differences in anthropomorphic variables, body composition, visceral adipose tissue (MR-VAT) or PPF were measured and hence data were combined. Nine women (47%) were identified as having high PPF values. PPF was significantly associated with baseline C-peptide (p = 0.04) and ISR (p = 0.04) in all. During the 1-hr ivGTT, plasma glucose (p<0.0001), insulin (p<0.0001) and ISR (p = 0.02) increased significantly from baseline in both high and low PPF groups but did not differ between the two groups at any given time during the test (PPF x time, p > 0.05). Notably, the incremental areas under the curves for both first and second phase ISR were 0.04 units lower in the high than low PPF groups, but this was not significant (p > 0.05). CONCLUSION In women with overweight or obesity but without T2DM, PPF did not modify β-cell function as determined by ivGTT-assessed ISR. However, the salient feature in biphasic insulin secretion in those with ≥4.5% PPF may be of clinical importance, particularly in early stages of dysglycaemia may warrant further investigation.
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Affiliation(s)
- Ivana R. Sequeira
- Human Nutrition Unit, School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- * E-mail:
| | - Wilson Yip
- Human Nutrition Unit, School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Louise W. Lu
- Human Nutrition Unit, School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Yannan Jiang
- Department of Statistics, Faculty of Science, University of Auckland, Auckland, New Zealand
| | - Rinki Murphy
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Auckland District Health Board, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Lindsay D. Plank
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Garth J. S. Cooper
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics (CADET), Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- Division of Medical Sciences, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Carl N. Peters
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Waitemata District Health Board, Auckland, New Zealand
| | - Benjamin S. Aribsala
- Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Science, Newcastle University, Newcastle Upon Tyne, United Kingdom
- Department of Computer Science, Faculty of Science, Lagos State University, Lagos, Nigeria
| | - Kieren G. Hollingsworth
- Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Science, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Sally D. Poppitt
- Human Nutrition Unit, School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Riddet Centre of Research Excellence (CoRE) for Food and Nutrition, Palmerston North, New Zealand
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Tsuchiya T, Saisho Y, Inaishi J, Sasaki H, Sato M, Nishikawa M, Masugi Y, Yamada T, Itoh H. Increased alpha cell to beta cell ratio in patients with pancreatic cancer. Endocr J 2022; 69:1407-1414. [PMID: 35934795 DOI: 10.1507/endocrj.ej22-0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age- and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.
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Affiliation(s)
- Tami Tsuchiya
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Saisho Diabetes Clinic, Tokyo 164-0001, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Midori Sato
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masaru Nishikawa
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Taketo Yamada
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pathology, Saitama Medical University, Saitama 350-0495, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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8
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Yoshino M, Yoshino J, Smith GI, Stein RI, Bittel AJ, Bittel DC, Reeds DN, Sinacore DR, Cade WT, Patterson BW, Cho K, Patti GJ, Mittendorfer B, Klein S. Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes. Cell Metab 2022; 34:1431-1441.e5. [PMID: 36084645 PMCID: PMC9728552 DOI: 10.1016/j.cmet.2022.08.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/01/2022] [Accepted: 08/16/2022] [Indexed: 11/03/2022]
Abstract
Lifestyle therapy (energy restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, β cell function, and multi-organ insulin sensitivity, which were associated with changes in muscle NAD+ biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, which are likely mediated by specific alterations in skeletal muscle and adipose tissue biology.
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Affiliation(s)
- Mihoko Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - Jun Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA; Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Gordon I Smith
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - Richard I Stein
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - Adam J Bittel
- Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, USA
| | - Daniel C Bittel
- Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, USA
| | - Dominic N Reeds
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - David R Sinacore
- Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, USA; Department of Physical Therapy, High Point University, High Point, NC, USA
| | - W Todd Cade
- Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, USA
| | - Bruce W Patterson
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - Kevin Cho
- Department of Chemistry, Washington University School of Medicine, St Louis, MO, USA
| | - Gary J Patti
- Department of Chemistry, Washington University School of Medicine, St Louis, MO, USA
| | - Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA; Sansum Diabetes Research Institute, Santa Barbara, CA, USA.
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9
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Pretransplant HOMA-β Is Predictive of Insulin Independence in 7 Patients With Chronic Pancreatitis Undergoing Islet Autotransplantation. Transplant Direct 2022; 8:e1367. [PMID: 36204182 PMCID: PMC9529061 DOI: 10.1097/txd.0000000000001367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 06/24/2022] [Accepted: 07/13/2022] [Indexed: 11/26/2022] Open
Abstract
Islet and β-cell function is intrinsic to glucose homeostasis. Pancreatectomy and islet autotransplantation (PIAT) for chronic pancreatitis (CP) treatment is a useful model for assessing islet function in the absence of immune-suppression and to perform extensive presurgical metabolic evaluations not possible from deceased donors. We recently showed that in CP-PIAT patients, preoperative islet identity loss presented with postoperative glycemic loss. Here, we examine presurgical islet function using Homeostatic Model Assessment-Beta Cell Function (%) (HOMA-β) and glycemic variables and compared them with postsurgical insulin independence and their predicted alignment with Secretory Unit of Islet Transplant Objects (SUITO) and beta cell score after transplantation (BETA-2) scores.
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10
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Bi XJ, Lv YQ, Yang XH, Ge Y, Han H, Feng JS, Zhang M, Chen L, Xu MZ, Guan FY. A New Berberine Preparation Protects Pancreatic Islet Cells from Apoptosis Mediated by Inhibition of Phospholipase A2/p38 MAPK Pathway. Bull Exp Biol Med 2022; 173:346-353. [DOI: 10.1007/s10517-022-05547-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Indexed: 11/30/2022]
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11
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Is Type 2 Diabetes a Primary Mitochondrial Disorder? Cells 2022; 11:cells11101617. [PMID: 35626654 PMCID: PMC9140179 DOI: 10.3390/cells11101617] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/27/2022] [Accepted: 04/20/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is the most common endocrine disturbance in inherited mitochondrial diseases. It is essential to increase awareness of the correct diagnosis and treatment of diabetes in these patients and screen for the condition in family members, as diabetes might appear with distinctive clinical features, complications and at different ages of onset. The severity of mitochondrial-related diabetes is likely to manifest on a large scale of phenotypes depending on the location of the mutation and whether the number of affected mitochondria copies (heteroplasmy) reaches a critical threshold. Regarding diabetes treatment, the first-choice treatment for type 2 diabetes (T2D), metformin, is not recommended because of the risk of lactic acidosis. The preferred treatment for diabetes in patients with mitochondrial disorders is SGLT-2i and mitochondrial GLP-1-related substances. The tight relationship between mitochondrial dysfunction, reduced glucose-stimulated insulin secretion (GSIS), and diabetes development in human patients is acknowledged. However, despite the well-characterized role of mitochondria in GSIS, there is a relative lack of data in humans implicating mitochondrial dysfunction as a primary defect in T2D. Our recent studies have provided data supporting the significant role of the mitochondrial respiratory-chain enzyme, cytochrome c oxidase (COX), in regulating GSIS in a rodent model of T2D, the Cohen diabetic sensitive (CDs) rat. The nutritionally induced diabetic CDs rat demonstrates several features of mitochondrial diseases: markedly reduced COX activity in several tissues, increased reactive oxygen production, decreased ATP generation, and increased lactate dehydrogenase expression in islets. Moreover, our data demonstrate that reduced islet-COX activity precedes the onset of diabetes, suggesting that islet-COX deficiency is the primary defect causing diabetes in this model. This review examines the possibility of including T2D as a primary mitochondrial-related disease. Understanding the critical interdependence between diabetes and mitochondrial dysfunction, centering on the role of COX, may open novel avenues to diagnose and treat diabetes in patients with mitochondrial diseases and mitochondrial dysfunction in diabetic patients.
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12
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Exercise targeted on maximal lipid oxidation has long-term weight-reducing effects but improves insulin secretion and lipid oxidation before reducing fat mass. Sci Sports 2022. [DOI: 10.1016/j.scispo.2021.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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13
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Hu Q, Mu J, Liu Y, Yang Y, Liu Y, Pan Y, Zhang Y, Li L, Liu D, Chen J, Zhang F, Jin L. Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-Cell Proliferation Through the CPEB1/CDKN1B Pathway. Diabetes 2022; 71:394-411. [PMID: 35029277 DOI: 10.2337/db21-0134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022]
Abstract
Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.
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Affiliation(s)
- Qianxing Hu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Jinming Mu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yuhong Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
- Pancreatic Research Institute, Southeast University, Nanjing, Jiangsu Province, China
| | - Dechen Liu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Jianqiu Chen
- College of Engineering, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China
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14
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Bartolomé A, Suda N, Yu J, Zhu C, Son J, Ding H, Califano A, Accili D, Pajvani UB. Notch-mediated Ephrin signaling disrupts islet architecture and β cell function. JCI Insight 2022; 7:157694. [PMID: 35167496 PMCID: PMC8986078 DOI: 10.1172/jci.insight.157694] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/09/2022] [Indexed: 11/23/2022] Open
Abstract
Altered islet architecture is associated with β cell dysfunction and type 2 diabetes (T2D) progression, but molecular effectors of islet spatial organization remain mostly unknown. Although Notch signaling is known to regulate pancreatic development, we observed “reactivated” β cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, β cell–specific Notch gain-of-function mice. As predicted, we found that Notch activation in postnatal β cells impaired glucose-stimulated insulin secretion and glucose intolerance, but we observed a surprising remnant glucose intolerance after doxycycline withdrawal and cessation of Notch activity, associated with a marked disruption of normal islet architecture. Transcriptomic screening of Notch-active islets revealed increased Ephrin signaling. Commensurately, exposure to Ephrin ligands increased β cell repulsion and impaired murine and human pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible β cells in patients with T2D. These studies suggest that β cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life.
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Affiliation(s)
- Alberto Bartolomé
- Departamento de Fisiopatología Endocrina y del Sistema Nervioso, IIBm Alberto Sols (CSIC/UAM), Madrid, Spain
| | - Nina Suda
- Department of Medicine, Columbia University, New York, United States of America
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, United States of America
| | - Changyu Zhu
- Department of Medicine, Columbia University, New York, United States of America
| | - Jinsook Son
- Department of Medicine, Columbia University, New York, United States of America
| | - Hongxu Ding
- Systems Biology, Columbia University College of Physicians & Surgeons, New York, United States of America
| | - Andrea Califano
- Systems Biology, Columbia University College of Physicians & Surgeons, New York, United States of America
| | - Domenico Accili
- Department of Medicine, Columbia University, New York, United States of America
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, United States of America
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15
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Oyenihi OR, Cerf ME, Matsabisa MG, Brooks NL, Oguntibeju OO. Effect of kolaviron on islet dynamics in diabetic rats. Saudi J Biol Sci 2022; 29:324-330. [PMID: 35002425 PMCID: PMC8716911 DOI: 10.1016/j.sjbs.2021.08.095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/23/2021] [Accepted: 08/29/2021] [Indexed: 10/25/2022] Open
Abstract
Kolaviron, a biflavonoid isolated from the edible seeds of Garcinia kola, lowers blood glucose in experimental models of diabetes; however, the underlying mechanisms are not yet fully elucidated. The objective of the current study was to assess the effects of kolaviron on islet dynamics in streptozotocin-induced diabetic rats. Using double immunolabeling of glucagon and insulin, we identified insulin-producing β- and glucagon-producing α-cells in the islets of diabetic and control rats and determined the fractional β-cell area, α-cell area and islet number. STZ challenged rats presented with islet hypoplasia and reduced β-cell area concomitant with an increase in α-cell area. Kolaviron restored some islet architecture in diabetic rats through the increased β-cell area. Overall, kolaviron-treated diabetic rats presented a significant (p < 0.05) increase in the number of large and very large islets compared to diabetic control but no difference in islet number and α-cell area. The β-cell replenishment potential of kolaviron and its overall positive effects on glycemic control suggest that it may be a viable target for diabetes treatment.
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Affiliation(s)
- Omolola R Oyenihi
- Phytomedicine and Phytochemistry Group, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville 7535, South Africa
| | - Marlon E Cerf
- Grants, Innovation and Product Development, South African Medical Research Council, Tygerberg, South Africa.,Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - Motlalepula G Matsabisa
- Pharmacology Department, School of Clinical Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa
| | - Nicole L Brooks
- Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa
| | - Oluwafemi O Oguntibeju
- Phytomedicine and Phytochemistry Group, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville 7535, South Africa
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16
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Bonetti S, Zusi C, Rinaldi E, Boselli ML, Csermely A, Malerba G, Trabetti E, Bonora E, Bonadonna R, Trombetta M. Role of monogenic diabetes genes on beta cell function in Italian patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 13. DIABETES & METABOLISM 2022; 48:101323. [DOI: 10.1016/j.diabet.2022.101323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/27/2021] [Accepted: 11/25/2021] [Indexed: 10/19/2022]
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17
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Wang G, Song J, Huang Y, Li X, Wang H, Zhang Y, Suo H. Lactobacillus plantarum SHY130 isolated from yak yogurt attenuates hyperglycemia in C57BL/6J mice by regulating the enteroinsular axis. Food Funct 2021; 13:675-687. [PMID: 34935020 DOI: 10.1039/d1fo02387j] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes, one of the most serious and common chronic metabolic diseases affecting people worldwide in the 21st century, has become a major problem that needs to be addressed urgently. This study was designed to elucidate the anti-diabetic effect of yak yogurt-derived Lactobacillus (L.) plantarum SHY130 on C57BL/6J mice fed high-fat diet and streptozotocin (HFD/STZ), and the potential regulatory mechanisms involved. Mice were divided into 3 groups: normal control, diabetes, and diabetes treated with L. plantarum SHY130 (SHY130). Treatment with L. plantarum SHY130 had a regulatory effect on blood glucose and clearly ameliorated insulin resistance in T2DM mice. L. plantarum SHY130 inhibited the reduction in β-cell mass and α-cell proliferation in the pancreas and increased the expression of the short-chain fatty acid (SCFA) receptors GPR43 and GPR41 in the colon of T2DM mice. Furthermore, L. plantarum SHY130 treatment readjusted intestinal flora structure, enhanced the abundance of SCFA-producing bacteria, such as Faecalibaculum, Odoribacter, Alistipes, and increased the levels of SCFAs in diabetic mice. In summary, L. plantarum SHY130 ameliorated hyperglycemia in HFD/STZ-induced diabetic mice by regulating the enteroinsular axis.
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Affiliation(s)
- Guangqi Wang
- College of Food Science, Southwest University, Chongqing 400715, China.
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing 400715, China.
| | - Yechuan Huang
- College of Bioengineering, Jingchu University of Technology, Jingmen 448000, China
| | - Xueqiong Li
- Chongqing Agricultural Product Quality and Safety Center, Chongqing 400020, China
| | - Hongwei Wang
- College of Food Science, Southwest University, Chongqing 400715, China.
| | - Yu Zhang
- College of Food Science, Southwest University, Chongqing 400715, China.
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing 400715, China.
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18
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Ogawa Y, Kimura H, Fujimoto H, Kawashima H, Toyoda K, Mukai E, Yagi Y, Ono M, Inagaki N, Saji H. Development of novel radioiodinated exendin-4 derivatives targeting GLP-1 receptor for detection of β-cell mass. Bioorg Med Chem 2021; 52:116496. [PMID: 34808404 DOI: 10.1016/j.bmc.2021.116496] [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: 07/23/2021] [Revised: 10/15/2021] [Accepted: 11/02/2021] [Indexed: 10/19/2022]
Abstract
In subjects with type 2 diabetes mellitus (T2DM), pancreatic β-cell mass decreases; however, it is unknown to what extent this decrease contributes to the pathophysiology of T2DM. Therefore, the development of a method for noninvasive detection of β-cell mass is underway. We previously reported that glucagon-like peptide-1 receptor (GLP-1R) is a promising target molecule for β-cell imaging. In this study, we attempted to develop a probe targeting GLP-1R for β-cell imaging using single-photon emission computed tomography (SPECT). For this purpose, we selected exendin-4 as the lead compound and radiolabeled lysine at residue 12 in exendin-4 or additional lysine at the C-terminus using [123I]iodobenzoylation. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Biodistribution study was performed in normal ddY mice. Ex vivo autoradiography was performed in transgenic mice expressing green fluorescent protein under control of the mouse insulin I gene promoter. Additionally, SPECT imaging was performed in normal ddY mice. The affinity of novel synthesized derivatives toward pancreatic β-cells was not affected by iodobenzoylation. The derivatives accumulated in the pancreas after intravenous administration specifically via GLP-1R expressed on the pancreatic β-cells. Extremely high signal-to-noise ratio was observed during evaluation of biodistribution of [123I]IB12-Ex4. SPECT images using normal mice showed that [123I]IB12-Ex4 accumulated in the pancreas with high contrast between the pancreas and background. These results indicate that [123I]IB12-Ex4 for SPECT is useful for clinical applications because of its preferable kinetics in vivo.
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Affiliation(s)
- Yu Ogawa
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hiroyuki Kimura
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
| | - Hiroyuki Fujimoto
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hidekazu Kawashima
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Radioisotope Research Center, Kyoto Pharmaceutical University, 1 Misasagi-shichono-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Kentaro Toyoda
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Mukai
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yusuke Yagi
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Masahiro Ono
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hideo Saji
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
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19
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Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest 2021; 132:154068. [PMID: 34905513 PMCID: PMC8803344 DOI: 10.1172/jci154068] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/08/2021] [Indexed: 12/02/2022] Open
Abstract
Background It is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity. Methods We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D). Results Glucose-stimulated insulin secretion (GSIS), an assessment of β cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. Conclusion Increased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in β cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560. FUNDING NIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559).
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Affiliation(s)
- Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Bruce W Patterson
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Gordon I Smith
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Mihoko Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
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20
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Pancreatogenic Diabetes, 2 Onset Forms and Lack of Metabolic Syndrome Components Differentiate It From Type 2 Diabetes. Pancreas 2021; 50:1376-1381. [PMID: 35041336 DOI: 10.1097/mpa.0000000000001930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES We compared pancreatogenic (DM3c) and type 2 diabetes mellitus. METHODS We compared age-, sex-, and diabetes mellitus duration-matched DM3c cases (n = 142) and type 2 diabetes mellitus (n = 142). Pancreatogenic diabetes was considered when it appeared after the diagnosis of pancreatitis or after pancreatic surgery. RESULTS Pancreatogenic diabetes presented lower body mass index (BMI) [odds ratio (OR), 1.2; 95% confidence interval (CI), 1.13-1.28; P < 0.001], worse glycemic control (OR, 1.196; 95% CI, 1.058-1.35; P = 0.004), required insulin more frequently (OR, 4.21; 95% CI, 2.57-6.93; P = 0.0001), had more hypoglycemic episodes (OR, 3.65; 95% CI, 1.64-8.16; P = 0.001) but lower frequency of dyslipidemia (OR, 0.42; 95% CI, 0.26-0.68; P = 0.001) and arterial hypertension (OR, 0.52; 95% CI, 0.32-0.86; P = 0.01). Pancreatogenic diabetes cases on pancreatic enzyme replacement therapy had lower glycosylated hemoglobin (8.52% vs 9.44%; P = 0.026), serum carotenes (79.1 vs 116.1; P = 0.03), and BMI (23.4 vs 26.1; P = 0.0005) than those not on pancreatic enzyme replacement therapy. Pancreatogenic diabetes onset occurred earlier in necrotizing pancreatitis and after pancreatic surgery. CONCLUSIONS Pancreatogenic diabetes presents with low BMI and lacks metabolic syndrome components. The type of pancreatic disease or surgery defines its onset time.
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21
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Sasaki H, Saisho Y, Inaishi J, Itoh H. Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes. J Endocr Soc 2021; 5:bvab128. [PMID: 34405128 PMCID: PMC8361804 DOI: 10.1210/jendso/bvab128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell–centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.
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Affiliation(s)
- Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Nagy A, Juhász MF, Görbe A, Váradi A, Izbéki F, Vincze Á, Sarlós P, Czimmer J, Szepes Z, Takács T, Papp M, Fehér E, Hamvas J, Kárász K, Török I, Stimac D, Poropat G, Ince AT, Erőss B, Márta K, Pécsi D, Illés D, Váncsa S, Földi M, Faluhelyi N, Farkas O, Nagy T, Kanizsai P, Márton Z, Szentesi A, Hegyi P, Párniczky A. Glucose levels show independent and dose-dependent association with worsening acute pancreatitis outcomes: Post-hoc analysis of a prospective, international cohort of 2250 acute pancreatitis cases. Pancreatology 2021; 21:1237-1246. [PMID: 34332908 DOI: 10.1016/j.pan.2021.06.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/31/2021] [Accepted: 06/17/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Metabolic risk factors, such as obesity, hypertension, and hyperlipidemia are independent risk factors for the development of various complications in acute pancreatitis (AP). Hypertriglyceridemia dose-dependently elicits pancreatotoxicity and worsens the outcomes of AP. The role of hyperglycemia, as a toxic metabolic factor in the clinical course of AP, has not been examined yet. METHODS We analyzed a prospective, international cohort of 2250 AP patients, examining associations between (1) glycosylated hemoglobin (HbA1c), (2) on-admission glucose, (3) peak in-hospital glucose and clinically important outcomes (mortality, severity, complications, length of hospitalization (LOH), maximal C-reactive protein (CRP)). We conducted a binary logistic regression accounting for age, gender, etiology, diabetes, and our examined variables. Receiver Operating Characteristic Curve (ROC) was applied to detect the diagnostic accuracy of the three variables. RESULTS Both on-admission and peak serum glucose are independently associated with AP severity and mortality, accounting for age, gender, known diabetes and AP etiology. They show a dose-dependent association with severity (p < 0.001 in both), mortality (p < 0.001), LOH (p < 0.001), maximal CRP (p < 0.001), systemic (p < 0.001) and local complications (p < 0.001). Patients with peak glucose >7 mmol/l had a 15 times higher odds for severe AP and a five times higher odds for mortality. We found a trend of increasing HbA1c with increasing LOH (p < 0.001), severity and local complications. CONCLUSIONS On-admission and peak in-hospital glucose are independently and dose-dependently associated with increasing AP severity and mortality. In-hospital laboratory control of glucose and adequate treatment of hyperglycemia are crucial in the management of AP.
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Affiliation(s)
- Anikó Nagy
- Heim Pál National Pediatric Institute, Budapest, Hungary; Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Márk Félix Juhász
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Anikó Görbe
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Alex Váradi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Ferenc Izbéki
- Szent György University Teaching Hospital of Fejér County, Székesfehérvár, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Patrícia Sarlós
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - József Czimmer
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zoltán Szepes
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Takács
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Mária Papp
- Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary
| | - Eszter Fehér
- Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary
| | | | | | - Imola Török
- County Emergency Clinical Hospital - Gastroenterology and University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
| | - Davor Stimac
- Clinical Hospital Center Rijeka, Rijeka, Croatia
| | | | - Ali Tüzün Ince
- Hospital of Bezmialem Vakif University, School of Medicine, Istanbul, Turkey
| | - Bálint Erőss
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Katalin Márta
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Dániel Pécsi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Dóra Illés
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Szilárd Váncsa
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Mária Földi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary
| | - Nándor Faluhelyi
- Department of Medical Imaging, Clinical Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Orsolya Farkas
- Department of Medical Imaging, Clinical Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Tamás Nagy
- Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Kanizsai
- Department of Emergency Medicine, Clinical Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Zsolt Márton
- First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andrea Szentesi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Andrea Párniczky
- Heim Pál National Pediatric Institute, Budapest, Hungary; Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary.
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23
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DI Giuseppe G, Ciccarelli G, Cefalo CM, Cinti F, Moffa S, Improta F, Capece U, Pontecorvi A, Giaccari A, Mezza T. Prediabetes: how pathophysiology drives potential intervention on a subclinical disease with feared clinical consequences. Minerva Endocrinol (Torino) 2021; 46:272-292. [PMID: 34218657 DOI: 10.23736/s2724-6507.21.03405-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder whose rising incidence suggests the epidemic proportions of the disease. Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) - alone or combined - represent two intermediate metabolic condition between Normal Glucose Tolerance (NGT) and overt T2DM. Several studies have demonstrated that insulin resistance and beta-cell impairment can be identified even in normoglycemic prediabetic individuals. Worsening of these two conditions may lead to progression of IGT and/or IFG status to overt diabetes. Starting from these assumptions, it seems logical to suppose that interventions aimed at improving metabolic conditions, even in prediabetes, could represent an effective target to halt transition from IGT/IFG to manifest T2DM. Starting from pathophysiological knowledge, in this review we evaluate two possible interventions (lifestyle modifications and pharmacological agents) eligible as prediabetes therapy since they have been demonstrated to improve insulin resistance and beta-cell impairment. Detecting high-risk people and treating them could represent an effective strategy to slow down progression to overt diabetes, normalize glucose tolerance, and even prevent micro- and macrovascular complications.
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Affiliation(s)
- Gianfranco DI Giuseppe
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gea Ciccarelli
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M Cefalo
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simona Moffa
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Flavia Improta
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Capece
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy - .,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
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24
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Cao G, González J, Ortiz Fragola JP, Muller A, Tumarkin M, Moriondo M, Azzato F, Blanco MV, Milei J. Structural changes in endocrine pancreas of male Wistar rats due to chronic cola drink consumption. Role of PDX-1. PLoS One 2021; 16:e0243340. [PMID: 34115756 PMCID: PMC8195359 DOI: 10.1371/journal.pone.0243340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 05/27/2021] [Indexed: 12/26/2022] Open
Abstract
AIM The objective of this work was to analyze the structural changes of the pancreatic islets in rats, after 6 month consuming regular and light cola for 6 months. Also, we have analyzed the possible role of PDX-1 in that process. Finally, with the available knowledge, we propose a general working hypothesis that explains the succession of phenomena observed. Previously, we reported evidence showing that chronic cola consumption in rats impairs pancreatic metabolism of insulin and glucagon and produces some alterations typically observed in the metabolic syndrome, with an increase in oxidative stress. Of note It is worth mentioning that no apoptosis nor proliferation of islet cells could be demonstrated. In the present study, 36 male Wistar rats were divided into three groups to and given free access to freely drink regular cola (C), light cola (L), or water (W, control). We assessed the impact of the three different beverages in on glucose tolerance, lipid levels, creatinine levels and immunohistochemical changes addressed for the expression of insulin, glucagon, PDX-1 and NGN3 in islet cells, to evaluate the possible participation of PDX-1 in the changes observed in α and β cells after 6 months of treatment. Moreover, we assessed by stereological methods, the mean volume of islets (Vi) and three important variables: the fractional β -cell area, the cross-sectional area of alpha (A α-cell) and beta cells (A β-cell), and the number of β and α cell per body weight. Data were analyzed by two-way ANOVA followed by Bonferroni's multiple t-test or by Kruskal-Wallis test, then followed by Dunn's test (depending on distribution). Statistical significance was set at p<0.05. Cola drinking caused impaired glucose tolerance as well as fasting hyperglycemia (mean:148; CI:137-153; p<0.05 vs W) and an increase of in insulin immunolabeling (27.3±19.7; p<0.05 vs W and L). Immunohistochemical expression for PDX-1 was significantly high in C group compared to W (0.79±0.71; p<0.05). In this case, we observed cytoplasmatic and nuclear localization. Likewise, a mild but significant decrease of in Vi was detected after 6 months in C compared to W group (8.2±2.5; p<0.05). Also, we observed a significant decrease of in the fractional β cell area (78.2±30.9; p<0.05) compared to W. Accordingly, a reduced mean value of islet α and β cell number per body weight (0.05±0.02 and 0.08±0.04 respectively; both p<0.05) compared to W was detected. Interestingly, consumption of light cola increased the Vi (10.7±3.6; p<0.05) compared to W. In line with this, a decreased cross-sectional area of β-cells was observed after chronic consumption of both, regular (78.2±30.9; p<0.05) and light cola (110.5±24.3; p<0.05), compared to W. As for, NGN3, it was negative in all three groups. Our results support the idea that PDX-1 plays a key role in the dynamics of the pancreatic islets after chronic consumption of sweetened beverages. In this experimental model, the loss of islets cells might be attributed to autophagy, favored by the local metabolic conditions and oxidative stress.
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Affiliation(s)
- Gabriel Cao
- Centro de Altos Estudios en Ciencias Humanas y de La Salud (CAECIHS), Universidad Abierta Interamericana, Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Julián González
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
| | - Juan P. Ortiz Fragola
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
| | - Angélica Muller
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
| | - Mariano Tumarkin
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
| | - Marisa Moriondo
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
| | - Francisco Azzato
- Facultad de Medicina, Sexta Cátedra de Medicina, Hospital de Clínicas, Buenos Aires, Argentina
| | - Manuel Vazquez Blanco
- Facultad de Medicina, Sexta Cátedra de Medicina, Hospital de Clínicas, Buenos Aires, Argentina
| | - José Milei
- Facultad de Medicina, CONICET, Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina
- Facultad de Medicina, Sexta Cátedra de Medicina, Hospital de Clínicas, Buenos Aires, Argentina
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25
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Parveen N, Dhawan S. DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis. Front Endocrinol (Lausanne) 2021; 12:651258. [PMID: 34025578 PMCID: PMC8137853 DOI: 10.3389/fendo.2021.651258] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/21/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.
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Affiliation(s)
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States
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26
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Lorenzo PI, Cobo-Vuilleumier N, Martín-Vázquez E, López-Noriega L, Gauthier BR. Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes? Int J Mol Sci 2021; 22:4239. [PMID: 33921851 PMCID: PMC8073058 DOI: 10.3390/ijms22084239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β-cells to allow the re-establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet β-cells with several subpopulations of β-cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus-mediated transcriptome alterations that trigger the transdifferentiation of islet non-β-cells into β-cells; and finally, the possibility of using agents that promote a fully functional/mature β-cell phenotype to reduce and reverse the process of dedifferentiation of β-cells during diabetes.
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Affiliation(s)
- Petra I. Lorenzo
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Eugenia Martín-Vázquez
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Livia López-Noriega
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
| | - Benoit R. Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain; (N.C.-V.); (E.M.-V.); (L.L.-N.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 028029 Madrid, Spain
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27
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Quast DR, Breuer TGK, Nauck MA, Janot-Matuschek M, Uhl W, Meier JJ. Insulinbedarf und Glukosehomöostase bei Menschen nach partieller und totaler Pankreatektomie im Vergleich zu Menschen mit anderen Diabetesformen. DIABETOL STOFFWECHS 2021. [DOI: 10.1055/a-1344-0323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Zusammenfassung
Einleitung Pankreasresektionen werden bei schwerwiegenden Pankreaserkrankungen durchgeführt. Bei Komplikationen einer chronischen Pankreatitis, teilweise jedoch auch bei Raumforderungen, kann eine Pankreasteilresektion sinnvoll sein. Eine totale Pankreatektomie führt zum absoluten Insulinmangel und der Notwendigkeit einer Insulintherapie. Bei Teilresektionen (partielle Pankreatektomie) werden weniger gravierende Konsequenzen für den Glukosemetabolismus erwartet. Es ist das Ziel der vorliegenden Arbeit, die Insulinregime nach Pankreatektomie mit denen anderer Diabetesformen zu vergleichen.
Material und Methodik Es wurden Patientencharakteristika und Details der postoperativen Insulintherapie von pankreasoperierten Patienten einer spezialisierten Universitätsklinik für Viszeralchirurgie ausgewertet. Diese Daten wurden mit Kohorten nicht operierter Patienten mit Typ-1-Diabetes (T1DM; absoluter Insulinmangel) bzw. Typ-2-Diabetes (T2DM; Insulinresistenz und relativer Insulinmangel), jeweils unter Insulintherapie, verglichen. Ergänzt wurde diese Datenanalyse durch eine Literaturrecherche zu den Stichworten „pancreatogenic diabetes“, „type 3c diabetes“ und „pancreatectomy diabetes“.
Ergebnisse Daten von 32 (68,8 % Frauenanteil) bzw. 41 (43,9 % Frauenanteil) Patienten nach totaler bzw. partieller Pankreatektomie wurden analysiert. Vor der totalen Pankreatektomie hatten 56,3 % der Patienten einen Diabetes mellitus, postoperativ bestand bei allen Patienten eine Insulinpflichtigkeit. Dabei waren die Insulindosierungen im Vergleich mit Patienten mit T1DM (unter intensivierter Insulintherapie) signifikant niedriger (p < 0,0001). Die Dosierungen von Basal- (48,6 % weniger) und Mahlzeiteninsulin (38,1 % weniger) waren gleichermaßen betroffen. Eine partielle Pankreatektomie führte deutlich seltener zu einem Diabetes mellitus, und eine Insulintherapie war nur bei 26,8 % der Patienten erforderlich.
Diskussion Der basale und prandiale Insulinbedarf nach Pankreatektomie ist niedriger als bei einem T1DM und einem T2DM. Dies sollte bei der Blutzuckereinstellung nach Pankreatektomie berücksichtigt werden.
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Affiliation(s)
- Daniel Robert Quast
- Diabeteszentrum Bochum/Hattingen, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
| | - Thomas Georg Karl Breuer
- Diabeteszentrum Bochum/Hattingen, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
| | - Michael Albrecht Nauck
- Diabeteszentrum Bochum/Hattingen, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz
| | - Monika Janot-Matuschek
- Klinik für Allgemein- und Viszeralchirurgie, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
| | - Waldemar Uhl
- Klinik für Allgemein- und Viszeralchirurgie, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
| | - Juris Jendrik Meier
- Diabeteszentrum Bochum/Hattingen, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Bochum
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28
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Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review. Nutrients 2020; 12:nu12123846. [PMID: 33339276 PMCID: PMC7766247 DOI: 10.3390/nu12123846] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/14/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.
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29
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Pancreatic Islet Changes in Human Whole Organ Pancreas Explants: What Can Be Learned From Explanted Samples? Transplant Direct 2020; 6:e613. [PMID: 33134489 PMCID: PMC7575169 DOI: 10.1097/txd.0000000000001059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/24/2020] [Accepted: 07/14/2020] [Indexed: 01/09/2023] Open
Abstract
Background. Whole pancreas transplantation (Tx) is a successful treatment for type 1 diabetes resulting in independence from antidiabetic therapies. Transplant-related factors contributing to pancreatic islet failure are largely unknown; both recurring insulitis and pancreatitis have been implicated. The aim was to determine if cellular changes in islets and exocrine tissue are evident early in Tx, which could contribute to eventual graft failure using well-preserved tissue of grafts explanted from largely normoglycemic recipients. Methods. Histological specimens of explants (n = 31), Tx duration 1 day–8 years (median 29 d), cold ischemia time 7.2–17.3 hours (median 11.1 h), donor age 13–54 years (median 38 y) were examined; sections were labeled for inflammation, islet amyloidosis, and tissue fibrosis, and morphometry performed on immunolabeled insulin and glucagon positive islet cells. Data were related to clinical details of donor, recipient, and features of Tx. Results. Islet inflammation consistent with recurrent insulitis was not seen in any sample. Insulin-labeled islet cell proportion decreased with donor age (P < 0.05) and cold ischemia (P < 0.01) in explants from 26 normoglycemic patients; glucagon-labeled area proportion increased with cold ischemia (P < 0.05). Clinical pancreatitis was the explant reason in 12 of 28 normoglycemic cases. Exocrine fibrotic area/pancreas was variable (0.7%–55%) and unrelated to clinical/pathological features. Islet amyloid was present in 3 normoglycemic cases (donor ages 58, 42, and 31 y; Tx duration 8 y, 31 and 33 d, respectively). In 1 patient receiving antidiabetic therapy, the insulin-labeled area was reduced but with no evidence of islet inflammation. Conclusions. Explant histological changes after short-term Tx are similar to those seen in type 2 diabetes and occur in the absence of immunologic rejection without causing hyperglycemia. This suggests that factors associated with Tx affect islet stability; persistent deterioration of islet integrity and exocrine tissue fibrosis could impact on sustainability of islet function.
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Yang K, Lee M, Jones PA, Liu SS, Zhou A, Xu J, Sreekanth V, Wu JLY, Vo L, Lee EA, Pop R, Lee Y, Wagner BK, Melton DA, Choudhary A, Karp JM. A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells. SCIENCE ADVANCES 2020; 6:eabc3207. [PMID: 33208361 PMCID: PMC7673808 DOI: 10.1126/sciadv.abc3207] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 10/07/2020] [Indexed: 06/11/2023]
Abstract
Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)-a high-fidelity culture system where stem cell-derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation-so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.
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Affiliation(s)
- Kisuk Yang
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
- Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02142, USA
| | - Miseon Lee
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Peter Anthony Jones
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Sophie S Liu
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Angela Zhou
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jun Xu
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Vedagopuram Sreekanth
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Jamie L Y Wu
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Lillian Vo
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Eunjee A Lee
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Ramona Pop
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Yuhan Lee
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Bridget K Wagner
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Douglas A Melton
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Amit Choudhary
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA
- Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA
| | - Jeffrey M Karp
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Center for Nanomedicine, Harvard Stem Cell Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
- Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Bharmal SH, Cho J, Alarcon Ramos GC, Ko J, Stuart CE, Modesto AE, Singh RG, Petrov MS. Trajectories of glycaemia following acute pancreatitis: a prospective longitudinal cohort study with 24 months follow-up. J Gastroenterol 2020; 55:775-788. [PMID: 32494905 DOI: 10.1007/s00535-020-01682-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND New-onset diabetes is the most common sequela of acute pancreatitis (AP). Yet, prospective changes in glycaemia over time have never been investigated comprehensively in this study population. The primary aim was to determine the cumulative incidence of new-onset prediabetes and new-onset diabetes after AP over 24 months of follow-up in a prospective cohort study. The secondary aim was to identify trajectories of glycaemia during follow-up and their predictors at the time of hospitalisation. METHODS Patients with a prospective diagnosis of AP and no diabetes based on the American Diabetes Association criteria were followed up every 6 months up to 24 months after hospital discharge. Incidence of new-onset prediabetes/diabetes over each follow-up period was calculated. Group-based trajectory modelling was used to identify common changes in glycaemia. Multinomial regression analyses were conducted to investigate the associations between a wide array of routinely available demographic, anthropometric, laboratory, imaging, and clinical factors and membership in the trajectory groups. RESULTS A total of 152 patients without diabetes were followed up. The cumulative incidence of new-onset prediabetes and diabetes was 20% at 6 months after hospitalisation and 43% over 24 months of follow-up (p trend < 0.001). Three discrete trajectories of glycaemia were identified: normal-stable glycaemia (32%), moderate-stable glycaemia (60%), and high-increasing glycaemia (8%). Waist circumference was a significant predictor of moderate-stable glycaemia. None of the studied predictors were significantly associated with high-increasing glycaemia. CONCLUSIONS This first prospective cohort study of changes in glycaemia (determined at structured time points in unselected AP patients) showed that at least one out of five patients develops new-onset prediabetes or diabetes at 6 months of follow-up and more than four out of ten-in the first 2 years. Changes in glycaemia after AP follow three discrete trajectories. This may inform prevention or early detection of critical changes in blood glucose metabolism following an attack of AP and, hence, reduce the burden of new-onset diabetes after acute pancreatitis.
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Affiliation(s)
- Sakina Huseni Bharmal
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | - Jaelim Cho
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | | | - Juyeon Ko
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | - Charlotte Elizabeth Stuart
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | - Andre Eto Modesto
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | - Ruma Girish Singh
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand
| | - Maxim Sergey Petrov
- School of Medicine, University of Auckland, Room 12.085 A, Level 12, Auckland City Hospital, Auckland, 1142, New Zealand.
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Saisho Y. An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective. Expert Opin Pharmacother 2020; 21:1565-1578. [PMID: 32521177 DOI: 10.1080/14656566.2020.1776262] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM. AREAS COVERED Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective. EXPERT OPINION Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.
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Affiliation(s)
- Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine , Tokyo, Japan
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Lesch A, Backes TM, Langfermann DS, Rössler OG, Laschke MW, Thiel G. Ternary complex factor regulates pancreatic islet size and blood glucose homeostasis in transgenic mice. Pharmacol Res 2020; 159:104983. [PMID: 32504838 DOI: 10.1016/j.phrs.2020.104983] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 05/05/2020] [Accepted: 05/29/2020] [Indexed: 12/13/2022]
Abstract
A hallmark of diabetes mellitus is the inability of pancreatic β-cells to secrete sufficient amounts of insulin for maintaining normoglycemia. The formation of smaller islets may underlie the development of a diabetic phenotype, as a decreased β-cell mass will produce an insufficient amount of insulin. For a pharmacological intervention it is crucial to identify the proteins determining β-cell mass. Here, we identified the ternary complex factor (TCF) Elk-1 as a regulator of the size of pancreatic islets. Elk-1 mediates, together with a dimer of the serum-response factor (SRF), serum response element-regulated gene transcription. Elk-1 is activated in glucose-treated pancreatic β-cells but the biological functions of this protein in β-cells are so far unknown. Elk-1 and homologous TCF proteins are expressed in islets and insulinoma cells. Gene targeting experiments revealed that the TCF proteins show redundant activities. To solve the problem of functional redundancy of these homologous proteins, we generated conditional transgenic mice expressing a dominant-negative mutant of Elk-1 in pancreatic β-cells. The mutant competes with the wild-type TCFs for DNA and SRF-binding. Expression of the Elk-1 mutant in pancreatic β-cells resulted in the generation of significantly smaller islets and increased caspase-3 activity, indicating that apoptosis was responsible for the reduction of the pancreatic islet size. Glucose tolerance tests revealed that transgenic mice expressing the dominant-negative mutant of Elk-1 in pancreatic β-cells displayed impaired glucose tolerance. Thus, we show here for the first time that TCF controls important functions of pancreatic β-cells in vivo. Elk-1 may be considered as a new therapeutic target for the treatment of diabetes.
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Affiliation(s)
- Andrea Lesch
- Department of Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Tobias M Backes
- Department of Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Daniel S Langfermann
- Department of Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Oliver G Rössler
- Department of Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, D-66421, Homburg, Germany
| | - Gerald Thiel
- Department of Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany.
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Zhyzhneuskaya SV, Al-Mrabeh A, Peters C, Barnes A, Aribisala B, Hollingsworth KG, McConnachie A, Sattar N, Lean MEJ, Taylor R. Time Course of Normalization of Functional β-Cell Capacity in the Diabetes Remission Clinical Trial After Weight Loss in Type 2 Diabetes. Diabetes Care 2020; 43:813-820. [PMID: 32060017 DOI: 10.2337/dc19-0371] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 12/29/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To assess functional β-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss. RESEARCH DESIGN AND METHODS A Stepped Insulin Secretion Test with Arginine was used to quantify functional β-cell capacity by hyperglycemia and arginine stimulation. Thirty-nine of 57 participants initially achieved remission (HbA1c <6.5% [<48 mmol/mol] and fasting plasma glucose <7 mmol/L on no antidiabetic drug therapy) with a 16.4 ± 7.7 kg weight loss and were followed up with supportive advice on avoidance of weight regain. At 2 years, 20 participants remained in remission in the study. A nondiabetic control (NDC) group, matched for age, sex, and weight after weight loss with the intervention group, was studied once. RESULTS During remission, median (interquartile range) maximal rate of insulin secretion increased from 581 (480-811) pmol/min/m2 at baseline to 736 (542-998) pmol/min/m2 at 5 months, 942 (565-1,240) pmol/min/m2 at 12 months (P = 0.028 from baseline), and 936 (635-1,435) pmol/min/m2 at 24 months (P = 0.023 from baseline; n = 20 of 39 of those initially in remission). This was comparable to the NDC group (1,016 [857-1,507] pmol/min/m2) by 12 (P = 0.064) and 24 (P = 0.244) months. Median first-phase insulin response increased from baseline to 5 months (42 [4-67] to 107 [59-163] pmol/min/m2; P < 0.0001) and then remained stable at 12 and 24 months (110 [59-201] and 125 [65-166] pmol/min/m2, respectively; P < 0.0001 vs. baseline) but lower than that of the NDC group (250 [226-429] pmol/min/m2; P < 0.0001). CONCLUSIONS A gradual increase in assessed functional β-cell capacity occurred after weight loss, becoming similar to that of NDC group participants by 12 months. This result was unchanged at 2 years with continuing remission of type 2 diabetes.
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Affiliation(s)
- Sviatlana V Zhyzhneuskaya
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Ahmad Al-Mrabeh
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Carl Peters
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Alison Barnes
- Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K
| | | | - Kieren G Hollingsworth
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Alex McConnachie
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, U.K
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Michael E J Lean
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, U.K
| | - Roy Taylor
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K.
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Sehrawat A, Shiota C, Mohamed N, DiNicola J, Saleh M, Kalsi R, Zhang T, Wang Y, Prasadan K, Gittes GK. SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice. J Biol Chem 2020; 295:4858-4869. [PMID: 32122971 DOI: 10.1074/jbc.ra119.011011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 02/18/2020] [Indexed: 12/19/2022] Open
Abstract
The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-β-inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal β-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a β cell-specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β-cell function in adult islets when SMAD7 was either absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in β cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-β signaling and modulates β-cell proliferation but does not appear to alter β-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance β-cell proliferation without negative effects on β-cell function.
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Affiliation(s)
- Anuradha Sehrawat
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Chiyo Shiota
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Nada Mohamed
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Julia DiNicola
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Mohamed Saleh
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Ranjeet Kalsi
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Ting Zhang
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Yan Wang
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - Krishna Prasadan
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
| | - George K Gittes
- Department of Pediatric Surgery, Children's Hospital of University of Pittsburgh, Pittsburgh, Pennsylvania 15224
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Pancreatic Hormone Responses to Mixed Meal Test in New-onset Prediabetes/Diabetes After Non-necrotizing Acute Pancreatitis. J Clin Gastroenterol 2020; 54:e11-e20. [PMID: 30480566 DOI: 10.1097/mcg.0000000000001145] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIM To investigate the pancreatic hormone responses to mixed meal test, in particular changes in insulin secretion, insulin sensitivity, and their interrelationship, in individuals with new-onset prediabetes or diabetes after non-necrotizing acute pancreatitis (NODAP) compared with healthy controls. METHODS Twenty-nine individuals with NODAP and 29 age-and sex-matched healthy controls were recruited. All participants (after fasting for at least 8 h) were given 12 oz. of BOOST drink and blood samples were collected before and after stimulation to measure insulin, C-peptide, glucagon, and pancreatic polypeptide. Indices of insulin sensitivity (HOMA-IS, 1/fasting insulin, Raynaud, and Matsuda) and insulin secretion (HOMA-β, Stumvoll, insulinogenic index 30' and 60') were calculated. Repeated measures analyses were conducted in the unadjusted and adjusted models. RESULTS Insulin and C-peptide levels were significantly higher in individuals with NODAP compared with controls during mixed meal test in both the unadjusted (P=0.001 for both) and adjusted (P=0.004 and P=0.006, respectively) models. HOMA-IS (P=0.005), 1/fasting insulin (P=0.018), Raynaud index (P=0.018), and Matsuda index (P=0.021) were significantly lower in individuals with NODAP, whereas HOMA-β (P=0.028) and Stumvoll index (P=0.013) were significantly higher. Glucagon and pancreatic polypeptide levels did not differ significantly between NODAP and controls during mixed meal test in both the unadjusted (P=0.345 and P=0.206, respectively) and adjusted (P=0.359 and P=0.158, respectively) models. CONCLUSIONS Decreased insulin sensitivity, β-cell compensation, and no significant change in postprandial levels of glucagon and pancreatic polypeptide characterize NODAP. The above findings may help develop an evidence-based protocol with a view to optimize control of glucose homeostasis in NODAP.
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Faulk C, Mueller KR, Cheishvili D, Colwell M, Pepin AS, Syzf M, Hering BJ, Burlak C. Epigenetic biomarkers indicate islet cell death in xenotransplantation. Xenotransplantation 2020; 27:e12570. [PMID: 31984530 DOI: 10.1111/xen.12570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Xenotransplantation of porcine islets has emerged in recent decades as a potential treatment for type 1 diabetes (T1D). Current methods of detection, indicative of successful engraftment, occur downstream of actual islet death. Epigenetic biomarkers can be detected in circulating cell-free DNA (cfDNA) to provide an earlier indication of graft dysfunction. AIMS The present study identified a biomarker of islet death using differential methylation of the insulin gene, INS, originating from β-cells in porcine islets. MATERIALS & METHODS Pyrosequencing primers specific for porcine INS were designed to quantify hypomethylation along 12 cysteine-guanine dinucleotide (CpG) sites, including three sites in the cyclic adenosine monophosphate (cAMP) response element (CRE) binding protein 2 (CRE2) binding region of the 5' untranslated region (UTR) and nine sites within intron 2. RESULTS PCR amplification of bisulfite-converted DNA combined with pyrosequencing data support the conclusion that hypomethylated porcine INS is specific to islet origin. CONCLUSION Moreover, the results of this study indicate a highly specific epigenetic biomarker, capable of detecting a single islet, supporting the measurement of cfDNA as a biomarker for transplanted islet death. Defining the epigenetic characteristics of porcine-derived islets within cfDNA will be crucial to develop a better understanding of graft survival immunology for transplantation.
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Affiliation(s)
- Christopher Faulk
- Department of Animal Sciences, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, Saint Paul, MN, USA
| | - Kate R Mueller
- Department of Surgery, Schulze Diabetes Institute, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - David Cheishvili
- Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada
| | - Mathia Colwell
- Department of Animal Sciences, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, Saint Paul, MN, USA
| | - Anne-Sophie Pepin
- Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada
| | - Moshe Syzf
- Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada
| | - Bernhard J Hering
- Department of Surgery, Schulze Diabetes Institute, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Christopher Burlak
- Department of Surgery, Schulze Diabetes Institute, School of Medicine, University of Minnesota, Minneapolis, MN, USA
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Close AF, Dadheech N, Lemieux H, Wang Q, Buteau J. Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3. Cells 2020; 9:cells9010168. [PMID: 31936632 PMCID: PMC7017372 DOI: 10.3390/cells9010168] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/03/2020] [Accepted: 01/04/2020] [Indexed: 12/14/2022] Open
Abstract
Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks.
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Affiliation(s)
- Anne-Françoise Close
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Nidheesh Dadheech
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Hélène Lemieux
- Faculty Saint-Jean, Department of Medicine, University of Alberta, Edmonton, AB T6C 4G9, Canada
| | - Qian Wang
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Jean Buteau
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence: ; Tel.: +1-780-492-8386
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Lai X, Zhang L, Fang J, Li G, Xu L, Ma J, Xiong Y, Liu L, Chen Z. OGTT 2-hour serum C-peptide index as a predictor of post-transplant diabetes mellitus in kidney transplant recipients. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:538. [PMID: 31807520 DOI: 10.21037/atm.2019.10.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Background The high incidence of post-transplant diabetes mellitus (PTDM) necessitates the identification of new factors to explain its pathogenesis. This study aimed to clarify the association between the C-peptide index (CPI) and PTDM. Methods A total of 290 non-diabetic kidney transplant patients were analyzed. All subjects underwent a 75 g oral glucose tolerance test (OGTT). Plasma glucose concentrations, serum C-peptide levels, hemoglobin A1c (HbA1c), and other biochemical indicators were measured. CPI was calculated as the ratio of serum C-peptide to plasma glucose. Results Among the 290 patients, 36 (12.4%) developed PTDM at the end of 1 year. Patients with PTDM had older age (P<0.001), higher levels of body mass index (BMI) (P=0.004) and HbA1c (P=0.001), a higher proportion of deceased donors (P=0.045), and lower levels of 2 h-CPI (P=0.02) than those without PTDM. The OGTT 2 h-CPI was positively correlated with BMI, HbA1c, type of calcineurin inhibitor, albumin, and triglyceride. Multivariate logistic regression and Cox hazard model analysis showed that pre-transplant OGTT 2 h-CPI was an independent predictor for the development of PTDM, together with age, BMI, and HbA1c. Conclusions Of the pre-transplant factors studied, OGTT 2 h-CPI proved to be an independent predictor of PTDM.
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Affiliation(s)
- Xingqiang Lai
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Lei Zhang
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Jiali Fang
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Guanghui Li
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Lu Xu
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Junjie Ma
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yunyi Xiong
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Luhao Liu
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zheng Chen
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
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Li L, Krznar P, Erban A, Agazzi A, Martin-Levilain J, Supale S, Kopka J, Zamboni N, Maechler P. Metabolomics Identifies a Biomarker Revealing In Vivo Loss of Functional β-Cell Mass Before Diabetes Onset. Diabetes 2019; 68:2272-2286. [PMID: 31537525 DOI: 10.2337/db19-0131] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 09/10/2019] [Indexed: 11/13/2022]
Abstract
Identification of individuals with decreased functional β-cell mass is essential for the prevention of diabetes. However, in vivo detection of early asymptomatic β-cell defect remains unsuccessful. Metabolomics has emerged as a powerful tool in providing readouts of early disease states before clinical manifestation. We aimed at identifying novel plasma biomarkers for loss of functional β-cell mass in the asymptomatic prediabetes stage. Nontargeted and targeted metabolomics were applied in both lean β-Phb2-/- (β-cell-specific prohibitin-2 knockout) mice and obese db/db (leptin receptor mutant) mice, two distinct mouse models requiring neither chemical nor dietary treatments to induce spontaneous decline of functional β-cell mass promoting progressive diabetes development. Nontargeted metabolomics on β-Phb2-/- mice identified 48 and 82 significantly affected metabolites in liver and plasma, respectively. Machine learning analysis pointed to deoxyhexose sugars consistently reduced at the asymptomatic prediabetes stage, including in db/db mice, showing strong correlation with the gradual loss of β-cells. Further targeted metabolomics by gas chromatography-mass spectrometry uncovered the identity of the deoxyhexose, with 1,5-anhydroglucitol displaying the most substantial changes. In conclusion, this study identified 1,5-anhydroglucitol as associated with the loss of functional β-cell mass and uncovered metabolic similarities between liver and plasma, providing insights into the systemic effects caused by early decline in β-cells.
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Affiliation(s)
- Lingzi Li
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
- Faculty Diabetes Centre, University of Geneva Medical Centre, Geneva, Switzerland
| | - Petra Krznar
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
- PhD Program in Systems Biology, Life Science Zurich Graduate School, Zurich, Switzerland
| | - Alexander Erban
- Max Planck Institute of Molecular Plant Physiology, Potsdam, Germany
| | - Andrea Agazzi
- Theoretical Physics Department, University of Geneva, Geneva, Switzerland
| | - Juliette Martin-Levilain
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
- Faculty Diabetes Centre, University of Geneva Medical Centre, Geneva, Switzerland
| | - Sachin Supale
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
- Faculty Diabetes Centre, University of Geneva Medical Centre, Geneva, Switzerland
| | - Joachim Kopka
- Max Planck Institute of Molecular Plant Physiology, Potsdam, Germany
| | - Nicola Zamboni
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
- Faculty Diabetes Centre, University of Geneva Medical Centre, Geneva, Switzerland
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Elevated Hedgehog-Interacting Protein Levels in Subjects with Prediabetes and Type 2 Diabetes. J Clin Med 2019; 8:jcm8101635. [PMID: 31590446 PMCID: PMC6832111 DOI: 10.3390/jcm8101635] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 09/30/2019] [Accepted: 10/03/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of cancers. In order to prevent diabetes, early diagnosis of prediabetes is important. However, biomarkers for prediabetes diagnosis are still scarce. The hedgehog-interacting protein (Hhip) is important in embryogenesis and is known to be a biomarker of several cancers. However, Hhip levels in subjects with diabetes are still unknown. METHODS In total, 314 participants were enrolled and divided into normal glucose tolerance (NGT; n = 75), impaired fasting glucose (IFG; n = 66), impaired glucose tolerance (IGT; n = 86), and newly diagnosed diabetes (NDD; n = 87) groups. Plasma Hhip levels were determined by an ELISA. The association between the Hhip and the presence of diabetes was examined by a multivariate linear regression analysis. RESULTS There were significant differences in the body mass index, systolic and diastolic blood pressure, fasting plasma glucose (FPG), post-load 2-h glucose, hemoglobin A1c (A1C), C-reactive protein, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels among the groups. Concentrations of the Hhip were 2.45 ± 2.12, 4.40 ± 3.22, 4.44 ± 3.64, and 6.31 ± 5.35 ng/mL in subjects in the NGT, IFG, IGT, and NDD groups, respectively. In addition, we found that A1C and FPG were independently associated with Hhip concentrations. Using NGT as a reference group, IFG, IGT, and NDD were all independently associated with Hhip concentrations. CONCLUSIONS Hhip was positively associated with prediabetes and type 2 diabetes mellitus.
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Saisho Y. Changing the Concept of Type 2 Diabetes: Beta Cell Workload Hypothesis Revisited. Endocr Metab Immune Disord Drug Targets 2019; 19:121-127. [PMID: 30173655 PMCID: PMC7360903 DOI: 10.2174/1871530318666180821161825] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 07/12/2018] [Accepted: 07/12/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite a number of innovations in anti-diabetic drugs and substantial improvement in diabetes care, the number of people with diabetes continues to increase, suggesting further need to explore novel approaches to prevent diabetes. Type 2 diabetes (T2DM) is characterized by beta cell dysfunction and insulin resistance. However, insulin resistance, usually a consequence of obesity, is often emphasized and the role of beta cell dysfunction in T2DM is less appreciated. OBJECTIVE AND RESULTS This paper summarizes recent evidence showing the importance of beta cell dysfunction in T2DM and refines the "beta cell workload hypothesis", emphasizing the importance of beta cell preservation for the prevention and management of T2DM. CONCLUSION It is hoped that this novel concept will foster a better understanding of the pathophysiology of T2DM by not only medical staff and patients with diabetes, but also the general population, and encourage more people to adhere to a healthy lifestyle, eventually resulting in "stopping diabetes".
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Affiliation(s)
- Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Close AF, Dadheech N, Villela BS, Rouillard C, Buteau J. The orphan nuclear receptor Nor1/Nr4a3 is a negative regulator of β-cell mass. J Biol Chem 2019; 294:4889-4897. [PMID: 30696767 DOI: 10.1074/jbc.ra118.005135] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 01/15/2019] [Indexed: 12/14/2022] Open
Abstract
The Nr4a subfamily of nuclear receptor comprises three members in mammalian cells: Nur77/Nr4a1, Nurr1/Nr4a2, and Nor1/Nr4a3. Nr4a proteins play key roles in the regulation of glucose homeostasis in peripheral metabolic tissues. However, their biological functions in β-cells remain relatively uncharacterized. Here we sought to investigate the potential role of Nor1 in the regulation of β-cell mass and, in particular, β-cell survival/apoptosis. We used histological analysis to examine the consequences of genetic deletion of either Nur77 and Nor1 on β-cell mass, investigated the expression patterns of Nr4as in human islets and INS cells and performed gain- and loss-of-function experiments to further characterize the role of Nor1 in β-cell apoptosis. Surprisingly, Nor1 knockout mice displayed increased β-cell mass, whereas mice with genetic deletion of Nur77 did not exhibit any significant differences compared with their WT littermates. The increase in β-cell mass in Nor1 knockout mice was accompanied by improved glucose tolerance. A gene expression study performed in both human islets and INS cells revealed that Nor1 expression is significantly increased by pro-inflammatory cytokines and, to a lesser extent, by elevated concentrations of glucose. Nor1 overexpression in both INS and human islet cells caused apoptosis, whereas siRNA-mediated Nor1 knockdown prevented cytokine-induced β-cell death. Finally, Nor1 expression was up-regulated in islets of individuals with type 2 diabetes. Altogether, our results uncover that Nor1 negatively regulates β-cell mass. Nor1 represents a promising molecular target in diabetes treatment to prevent β-cell destruction.
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Affiliation(s)
- Anne-Françoise Close
- From the Department of AFNS, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.,the Alberta Diabetes Institute, Edmonton, Alberta T6G 2E1, Canada
| | - Nidheesh Dadheech
- From the Department of AFNS, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.,the Alberta Diabetes Institute, Edmonton, Alberta T6G 2E1, Canada
| | - Bárbara Scoralick Villela
- From the Department of AFNS, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.,the Alberta Diabetes Institute, Edmonton, Alberta T6G 2E1, Canada
| | - Claude Rouillard
- the Département de Psychiatrie et Neurosciences, Université Laval, Québec, Québec G1V 4G2, Canada, and.,the Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada
| | - Jean Buteau
- From the Department of AFNS, University of Alberta, Edmonton, Alberta T6G 2E1, Canada, .,the Alberta Diabetes Institute, Edmonton, Alberta T6G 2E1, Canada
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Sun Y, Mao Q, Shen C, Wang C, Jia W. Exosomes from β-cells alleviated hyperglycemia and enhanced angiogenesis in islets of streptozotocin-induced diabetic mice. Diabetes Metab Syndr Obes 2019; 12:2053-2064. [PMID: 31632115 PMCID: PMC6790122 DOI: 10.2147/dmso.s213400] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/29/2019] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Exosomes are small nanoscale vesicles secreted from cells. Exosome-based therapeutic approaches have been evaluated in treating ischemic diseases. In the present study, we explored the effect of exosomes on streptozotozin (STZ)-induced diabetic mouse and its underlying mechanisms. METHODS Exosomes were isolated from MIN6 cells. Transmission electron microscopy, dynamic light scattering and Western blot were used to identify the exosomes. STZ was used to establish diabetic or abnormal glucose tolerance mouse model. Histology study and flow cytometry were applied to detect the changes in immune responses. RESULTS Transplantation of the exosomes into diabetic mice resulted in a longer median survival time compared with the untreated diabetic mice (P<0.01). Transplantation of the exosomes improved glucose tolerance, increased insulin content and preserved the architectures of islets in mice with abnormal glucose tolerance. Moreover, exosome treatment enhanced the expression of CD31, a marker of endothelial cells, and tended to reduce macrophage infiltration in islets of STZ-treated mice. CONCLUSION Exosomes derived from β-cells play a role in preserving pancreatic islet architecture and its function, and in inducing islet angiogenesis, which implicates that exosome treatment could be a novel therapeutic strategy for diabetes.
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Affiliation(s)
- Yun Sun
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai200233, People’s Republic of China
| | - Qianyun Mao
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai200233, People’s Republic of China
| | - Chao Shen
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai200233, People’s Republic of China
| | - Chen Wang
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai200233, People’s Republic of China
- Correspondence: Chen Wang Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Yishan Road, Shanghai200233, People’s Republic of ChinaTel +86 212 405 8657Fax +86 216 436 8031 Email
| | - Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai200233, People’s Republic of China
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Moonschi FH, Hughes CB, Mussman GM, Fowlkes JL, Richards CI, Popescu I. Advances in micro- and nanotechnologies for the GLP-1-based therapy and imaging of pancreatic beta-cells. Acta Diabetol 2018; 55:405-418. [PMID: 29264724 DOI: 10.1007/s00592-017-1086-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/03/2017] [Indexed: 12/20/2022]
Abstract
Therapies to prevent diabetes in particular the progressive loss of β-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the β-cells; it normalizes β-cell sensitivity to glucose, has an antiapoptotic role, stimulates β-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post-secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP-1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non-invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs.
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Affiliation(s)
- Faruk H Moonschi
- Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA
| | - Corey B Hughes
- Barnstable Brown Kentucky Diabetes Center, University of Kentucky, 900 S. Limestone, CTW 469, Lexington, KY, 40536, USA
| | - George M Mussman
- Barnstable Brown Kentucky Diabetes Center, University of Kentucky, 900 S. Limestone, CTW 469, Lexington, KY, 40536, USA
| | - John L Fowlkes
- Barnstable Brown Kentucky Diabetes Center, University of Kentucky, 900 S. Limestone, CTW 469, Lexington, KY, 40536, USA
| | - Chris I Richards
- Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA
| | - Iuliana Popescu
- Barnstable Brown Kentucky Diabetes Center, University of Kentucky, 900 S. Limestone, CTW 469, Lexington, KY, 40536, USA.
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Hart NJ, Aramandla R, Poffenberger G, Fayolle C, Thames AH, Bautista A, Spigelman AF, Babon JAB, DeNicola ME, Dadi PK, Bush WS, Balamurugan AN, Brissova M, Dai C, Prasad N, Bottino R, Jacobson DA, Drumm ML, Kent SC, MacDonald PE, Powers AC. Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight 2018; 3:98240. [PMID: 29669939 PMCID: PMC5931120 DOI: 10.1172/jci.insight.98240] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/14/2018] [Indexed: 12/20/2022] Open
Abstract
Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of β cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine β cells did not affect β cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of β cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by β cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.
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Affiliation(s)
- Nathaniel J. Hart
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Radhika Aramandla
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Gregory Poffenberger
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Cody Fayolle
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ariel H. Thames
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Austin Bautista
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Aliya F. Spigelman
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Jenny Aurielle B. Babon
- Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Megan E. DeNicola
- Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Prasanna K. Dadi
- School of Medicine, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - William S. Bush
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Appakalai N. Balamurugan
- Center for Cellular Transplantation, Department of Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
| | - Marcela Brissova
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Chunhua Dai
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nripesh Prasad
- Hudson Alpha Institute of Biotechnology, Huntsville, Alabama, USA
| | - Rita Bottino
- Allegheny Singer Research Institute, Pittsburgh, Pennsylvania, USA
| | - David A. Jacobson
- School of Medicine, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Mitchell L. Drumm
- School of Medicine, Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Sally C. Kent
- Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Patrick E. MacDonald
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Alvin C. Powers
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- School of Medicine, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare, Nashville, Tennessee, USA
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Marchetti P, Suleiman M, Marselli L. Organ donor pancreases for the study of human islet cell histology and pathophysiology: a precious and valuable resource. Diabetologia 2018; 61:770-774. [PMID: 29354869 PMCID: PMC6449064 DOI: 10.1007/s00125-018-4546-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/06/2017] [Indexed: 12/15/2022]
Abstract
Direct in vivo assessment of pancreatic islet-cells for the study of the pathophysiology of diabetes in humans is hampered by anatomical and technological hurdles. To date, most of the information that has been generated is derived from histological studies performed on pancreatic tissue from autopsy, surgery, in vivo biopsy or organ donation. Each approach has its advantages and disadvantages (as summarised in this commentary); however, in this edition of Diabetologia, Kusmartseva et al ( https://doi.org/10.1007/s00125-017-4494-x ) provide further evidence to support the use of organ donor pancreases for the study of human diabetes. They show that length of terminal hospitalisation of organ donors prior to death does not seem to influence the frequency of inflammatory cells infiltrating the pancreas and the replication of beta cells. These findings are reassuring, demonstrating the reliability of this precious and valuable resource for human islet cells research.
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Affiliation(s)
- Piero Marchetti
- Department of Clinical and Experimental Medicine and University Hospital, University of Pisa, via Paradisa 2, 56121, Pisa, Italy.
| | - Mara Suleiman
- Department of Clinical and Experimental Medicine and University Hospital, University of Pisa, via Paradisa 2, 56121, Pisa, Italy
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine and University Hospital, University of Pisa, via Paradisa 2, 56121, Pisa, Italy
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Fex M, Nicholas LM, Vishnu N, Medina A, Sharoyko VV, Nicholls DG, Spégel P, Mulder H. The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol 2018; 236:R145-R159. [PMID: 29431147 DOI: 10.1530/joe-17-0367] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Affiliation(s)
- Malin Fex
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Lisa M Nicholas
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Neelanjan Vishnu
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Anya Medina
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Vladimir V Sharoyko
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - David G Nicholls
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Peter Spégel
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
- Department of ChemistryCenter for Analysis and Synthesis, Lund University, Sweden
| | - Hindrik Mulder
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
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Microbial Regulation of Glucose Metabolism and Insulin Resistance. Genes (Basel) 2017; 9:genes9010010. [PMID: 29286343 PMCID: PMC5793163 DOI: 10.3390/genes9010010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/21/2017] [Accepted: 12/21/2017] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients show a microbial dysbiosis, with reduced butyrate-producing bacteria and elevated potential pathogens compared to metabolically healthy individuals. Furthermore, probiotics are a known tool to modulate the microbiota, having a therapeutic potential. Current literature will be discussed to elucidate the complex interaction of gut microbiota, intestinal permeability and inflammation leading to peripheral and hepatic insulin resistance. Therefore, this review aims to generate a deeper understanding of the underlying mechanism of potential microbial strains, which can be used as probiotics.
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