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1
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Rayas M, Pezzica S, Honka H, Carli F, Peterson R, DeFronzo R, Gastaldelli A, Salehi M. GLP-1 enhances β-cell response to protein ingestion and bariatric surgery amplifies it. Obesity (Silver Spring) 2025; 33:104-115. [PMID: 39635951 DOI: 10.1002/oby.24182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/23/2024] [Accepted: 09/25/2024] [Indexed: 12/07/2024]
Abstract
OBJECTIVE The glycemic-independent actions of glucagon-like peptide-1 (GLP-1) in the prandial state in humans are unknown. We examined the contribution of GLP-1 to β-cell secretory response (primary endpoint) and glucose metabolism during protein ingestion under basal glycemia, as well as whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG). METHODS Insulin secretion rate (ISR) and glucose fluxes during a 50-g oral protein load were compared among 10 nondiabetic individuals with GB, 9 with SG, and 7 non-operated controls (CN), with and without intravenous infusion of exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R) antagonist. RESULTS Blocking GLP-1R increased glucose before and after protein ingestion and decreased β-cell sensitivity to glucose in the first 30 min of protein ingestion in all three groups (p < 0.05). Reduction in the premeal ISR by Ex-9 infusion was only observed in CN, whereas diminished prandial ISR3h by GLP-1R blockade was only observed in GB and SG (p < 0.05 for interaction). GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN, and exaggerated endogenous glucose production only GB (p < 0.05 for interaction). CONCLUSIONS These findings are consistent with both pancreatic and extra-pancreatic roles for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery.
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Affiliation(s)
- Maria Rayas
- Department of Pediatrics, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy
| | - Henri Honka
- Division of Diabetes, Department of Medicine, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy
| | - Richard Peterson
- Department of Surgery, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Ralph DeFronzo
- Division of Diabetes, Department of Medicine, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy
- Division of Diabetes, Department of Medicine, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Marzieh Salehi
- Division of Diabetes, Department of Medicine, University of Texas Health at San Antonio, San Antonio, Texas, USA
- South Texas Veterans Health Care System, Audie Murphy Hospital, San Antonio, Texas, USA
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2
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Gharib SA, Vemireddy R, Castillo JJ, Fountaine BS, Bammler TK, MacDonald JW, Hull-Meichle RL, Zraika S. Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs. Sci Rep 2024; 14:25689. [PMID: 39463434 PMCID: PMC11514218 DOI: 10.1038/s41598-024-76722-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/16/2024] [Indexed: 10/29/2024] Open
Abstract
Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.
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Affiliation(s)
- Sina A Gharib
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
- Computational Medicine Core at Center for Lung Biology, University of Washington, Seattle, Washington, USA
| | - Rachna Vemireddy
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Joseph J Castillo
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
- Research and Development Service, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
| | - Brendy S Fountaine
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Theo K Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - James W MacDonald
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - Rebecca L Hull-Meichle
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
- Research and Development Service, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Alberta Diabetes Institute, Department of Cell Biology, University of Alberta, Edmonton, AB, Canada
| | - Sakeneh Zraika
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA.
- Research and Development Service, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
- Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA, 98108, USA.
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Sridhar A, Khan D, Babu G, Irwin N, Gault VA, Flatt PR, Moffett CR. Chronic exposure to incretin metabolites GLP-1(9-36) and GIP(3-42) affect islet morphology and beta cell health in high fat fed mice. Peptides 2024; 178:171254. [PMID: 38815655 DOI: 10.1016/j.peptides.2024.171254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/24/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to their major circulating metabolites GLP-1(9-36) and GIP(3-42). This study investigates the possible effects of these metabolites, and the equivalent exendin molecule Ex(9-39), on pancreatic islet morphology and constituent alpha and beta cells in high-fat diet (HFD) fed mice. Male Swiss TO-mice (6-8 weeks-old) were maintained on a HFD or normal diet (ND) for 4 months and then received twice-daily subcutaneous injections of GLP-1(9-36), GIP(3-42), Ex(9-39) (25 nmol/kg bw) or saline vehicle (0.9% (w/v) NaCl) over a 60-day period. Metabolic parameters were monitored and excised pancreatic tissues were used for immunohistochemical analysis. Body weight and assessed metabolic indices were not changed by peptide administration. GLP-1(9-36) significantly (p<0.001) increased islet density per mm2 tissue, that was decreased (p<0.05) by HFD. Islet, beta and alpha cell areas were increased (p<0.01) following HFD and subsequently reduced (p<0.01-p<0.001) by GIP(3-42) and Ex(9-39) treatment. While GLP-1(9-36) did not affect islet and beta cell areas in HFD mice, it significantly (p<0.01) decreased alpha cell area. Compared to ND and HFD mice, GIP(3-42) treatment significantly (p<0.05) increased beta cell proliferation. Whilst HFD increased (p<0.001) beta cell apoptosis, this was reduced (p<0.01-p<0.001) by both GLP-1(9-36) and GIP(3-42). These data indicate that the major circulating forms of GLP-1 and GIP, namely GLP-1(9-36) and GIP(3-42) previously considered largely inactive, may directly impact pancreatic morphology, with an important protective effect on beta cell health under conditions of beta cell stress.
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Affiliation(s)
- Ananyaa Sridhar
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
| | - Dawood Khan
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Gayathri Babu
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Victor A Gault
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Charlotte R Moffett
- Biomedical Sciences Research Institute, Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
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4
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Huang W, O'Hara SE, Xie C, Liu N, Rayner CK, Nicholas LM, Wu T. Effects of a bitter substance, denatonium benzoate, on pancreatic hormone secretion. Am J Physiol Endocrinol Metab 2024; 326:E537-E544. [PMID: 38477876 DOI: 10.1152/ajpendo.00046.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/14/2024]
Abstract
There is increasing evidence linking bitter taste receptor (BTR) signaling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterized. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1 mM) augmented insulin secretion at both 2.8 mM and 16.7 mM glucose. This effect was no longer present at 5 mM DB likely due to the greater levels of cellular apoptosis. DB-stimulated insulin secretion involved closure of the KATP channel, activation of T2R signaling in beta-cells, and intraislet glucagon-like peptide-1 (GLP-1) release. DB also enhanced glucagon and somatostatin secretion, but the underlying mechanism was less clear. Together, this study demonstrates that the bitter substance, DB, is a strong potentiator of islet hormone secretion independent of glucose. This observation highlights the potential for widespread off-target effects associated with the clinical use of bitter-tasting substances.NEW & NOTEWORTHY We show that the bitter substance, denatonium benzoate (DB), stimulates insulin, glucagon, somatostatin, and GLP-1 secretion from pancreatic islets, independent of glucose, and that DB augments insulin release via the KATP channel, bitter taste receptor signaling, and intraislet GLP-1 secretion. Exposure to a high dose of DB (5 mM) induces cellular apoptosis in pancreatic islets. Therefore, clinical use of bitter substances to improve glucose homeostasis may have unintended negative impacts beyond the gut.
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Affiliation(s)
- Weikun Huang
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Institute for Photonics and Advanced Sensing, School of Physics, Chemistry and Earth Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Stephanie E O'Hara
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- Adelaide Centre for Epigenetics, School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Cong Xie
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Ning Liu
- Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
| | - Christopher K Rayner
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Lisa M Nicholas
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- Adelaide Centre for Epigenetics, School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Tongzhi Wu
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
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5
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Welch AA, Farahani RA, Egan AM, Laurenti MC, Zeini M, Vella M, Bailey KR, Cobelli C, Dalla Man C, Matveyenko A, Vella A. Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans. J Clin Invest 2023; 133:e173495. [PMID: 37751301 PMCID: PMC10645389 DOI: 10.1172/jci173495] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/12/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.RESULTSExendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia.CONCLUSIONThese data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATIONThis study was registered at ClinicalTrials.gov NCT04466618.FUNDINGThe study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016).
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Affiliation(s)
- Andrew A. Welch
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Rahele A. Farahani
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Aoife M. Egan
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Marcello C. Laurenti
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Maya Zeini
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Max Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Kent R. Bailey
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Chiara Dalla Man
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Adrian Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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6
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Wang K, Cui X, Li F, Xia L, Wei T, Liu J, Fu W, Yang J, Hong T, Wei R. Glucagon receptor blockage inhibits β-cell dedifferentiation through FoxO1. Am J Physiol Endocrinol Metab 2023; 324:E97-E113. [PMID: 36383639 DOI: 10.1152/ajpendo.00101.2022] [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: 11/17/2022]
Abstract
Glucagon-secreting pancreatic α-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated β-cell-specific markers and inhibited insulin secretion in cultured β-cells. These results suggested that glucagon induced β-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced β-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated β-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited β-cell dedifferentiation. To investigate the possible mechanism, we found that glucagon decreased FoxO1 expression. FoxO1 inhibitor mimicked the effect of glucagon, whereas FoxO1 overexpression reversed the glucagon-induced β-cell dedifferentiation. In db/db mice and β-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased β-cell area, and inhibited β-cell dedifferentiation. In aged β-cell-specific FoxO1 knockout mice (with the blood glucose level elevated as a diabetic model), the glucose-lowering effect of GCGR mAb was attenuated and the plasma insulin level, β-cell area, and β-cell dedifferentiation were not affected by GCGR mAb. Our results proved that glucagon induced β-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between α- and β-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment.NEW & NOTEWORTHY Glucagon-secreting pancreatic α-cells can interact with β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells has remained elusive. Our new finding shows that long-term glucagon induces β-cell dedifferentiation in cultured β-cells. FoxO1 inhibitor mimicks whereas glucagon signaling blockage by GCGR mAb reverses the effect of glucagon. In type 2 diabetic mice, GCGR mAb increases β-cell area, improves β-cell function, and inhibits β-cell dedifferentiation, and the effect is partially mediated by FoxO1.
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Affiliation(s)
- Kangli Wang
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Xiaona Cui
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Fei Li
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Li Xia
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Tianjiao Wei
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Junling Liu
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Wei Fu
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
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7
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Chen YC, Klimek-Abercrombie AM, Potter KJ, Pallo LP, Soukhatcheva G, Dai L, Bellin MD, Verchere CB. Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients. Am J Transplant 2022; 22:1992-2005. [PMID: 35506189 DOI: 10.1111/ajt.17076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 01/25/2023]
Abstract
Pancreatic islet transplantation has therapeutic potential in type 1 diabetes and is also an established therapy in chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. We analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n = 28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In an immuno-deficient mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced proportional insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratios, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.
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Affiliation(s)
- Yi-Chun Chen
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Agnieszka M Klimek-Abercrombie
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Kathryn J Potter
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Montreal Clinical Research Institute, Montréal, Québec, Canada
| | - Lindsay P Pallo
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Galina Soukhatcheva
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Lei Dai
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Melena D Bellin
- Department of Pediatrics and Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - C Bruce Verchere
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
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8
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Holter MM, Phuong DJ, Lee I, Saikia M, Weikert L, Fountain S, Anderson ET, Fu Q, Zhang S, Sloop KW, Cummings BP. 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing. SCIENCE ADVANCES 2022; 8:eabn3773. [PMID: 35867787 PMCID: PMC9307243 DOI: 10.1126/sciadv.abn3773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 06/08/2022] [Indexed: 06/15/2023]
Abstract
Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β cell paracrine interactions in the effects of GLP-1R agonists is undefined. We previously found that increased β cell GLP-1R signaling activates α cell GLP-1 expression. Here, we characterized the bidirectional paracrine cross-talk by which α and β cells communicate to mediate the effects of the GLP-1R agonist, liraglutide. We find that the effect of liraglutide to enhance GSIS is blunted by α cell ablation in male mice. Furthermore, the effect of β cell GLP-1R signaling to activate α cell GLP-1 is mediated by a secreted protein factor that is regulated by the signaling protein, 14-3-3-zeta, in mouse and human islets. These data refine our understanding of GLP-1 pharmacology and identify 14-3-3-zeta as a potential target to enhance α cell GLP-1 production.
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Affiliation(s)
- Marlena M. Holter
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Daryl J. Phuong
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Isaac Lee
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Mridusmita Saikia
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, NY, USA
| | - Lisa Weikert
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Samantha Fountain
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Elizabeth T. Anderson
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Qin Fu
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Sheng Zhang
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Kyle W. Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Bethany P. Cummings
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
- Department of Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California, Davis, Sacramento, CA, USA
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9
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Khan D, Moffett RC, Flatt PR, Tarasov AI. Classical and non-classical islet peptides in the control of β-cell function. Peptides 2022; 150:170715. [PMID: 34958851 DOI: 10.1016/j.peptides.2021.170715] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/25/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022]
Abstract
The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes enzymes into the small intestine aiding digestion of sugars and fats, whereas the endocrine pancreas secretes a cocktail of hormones into the blood, which is responsible for blood glucose control and regulation of carbohydrate, protein and fat metabolism. Classical islet hormones, insulin, glucagon, pancreatic polypeptide and somatostatin, interact in an autocrine and paracrine manner, to fine-tube the islet function and insulin secretion to the needs of the body. Recently pancreatic islets have been reported to express a number of non-classical peptide hormones involved in metabolic signalling, whose major production site was believed to reside outside pancreas, e.g. in the small intestine. We highlight the key non-classical islet peptides, and consider their involvement, together with established islet hormones, in regulation of stimulus-secretion coupling as well as proliferation, survival and transdifferentiation of β-cells. We furthermore focus on the paracrine interaction between classical and non-classical islet hormones in the maintenance of β-cell function. Understanding the functional relationships between these islet peptides might help to develop novel, more efficient treatments for diabetes and related metabolic disorders.
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Affiliation(s)
- Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
| | - R Charlotte Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Andrei I Tarasov
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
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10
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Cabrera O, Ficorilli J, Shaw J, Echeverri F, Schwede F, Chepurny OG, Leech CA, Holz GG. Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon. J Biol Chem 2022; 298:101484. [PMID: 34896391 PMCID: PMC8789663 DOI: 10.1016/j.jbc.2021.101484] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
We report that intra-islet glucagon secreted from α-cells signals through β-cell glucagon and GLP-1 receptors (GcgR and GLP-1R), thereby conferring to rat islets their competence to exhibit first-phase glucose-stimulated insulin secretion (GSIS). Thus, in islets not treated with exogenous glucagon or GLP-1, first-phase GSIS is abolished by a GcgR antagonist (LY2786890) or a GLP-1R antagonist (Ex[9-39]). Mechanistically, glucose competence in response to intra-islet glucagon is conditional on β-cell cAMP signaling because it is blocked by the cAMP antagonist prodrug Rp-8-Br-cAMPS-pAB. In its role as a paracrine hormone, intra-islet glucagon binds with high affinity to the GcgR, while also exerting a "spillover" effect to bind with low affinity to the GLP-1R. This produces a right shift of the concentration-response relationship for the potentiation of GSIS by exogenous glucagon. Thus, 0.3 nM glucagon fails to potentiate GSIS, as expected if similar concentrations of intra-islet glucagon already occupy the GcgR. However, 10 to 30 nM glucagon effectively engages the β-cell GLP-1R to potentiate GSIS, an action blocked by Ex[9-39] but not LY2786890. Finally, we report that the action of intra-islet glucagon to support insulin secretion requires a step-wise increase of glucose concentration to trigger first-phase GSIS. It is not measurable when GSIS is stimulated by a gradient of increasing glucose concentrations, as occurs during an oral glucose tolerance test in vivo. Collectively, such findings are understandable if defective intra-islet glucagon action contributes to the characteristic loss of first-phase GSIS in an intravenous glucose tolerance test that is diagnostic of type 2 diabetes in the clinical setting.
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Affiliation(s)
- Over Cabrera
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
| | - James Ficorilli
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Janice Shaw
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | - Frank Schwede
- Biolog Life Science Institute GmbH & Co KG, Bremen, Germany
| | - Oleg G Chepurny
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - Colin A Leech
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - George G Holz
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA; Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA.
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11
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Holter MM, Saikia M, Cummings BP. Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol (Lausanne) 2022; 13:934775. [PMID: 35957816 PMCID: PMC9360487 DOI: 10.3389/fendo.2022.934775] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/28/2022] [Indexed: 01/14/2023] Open
Abstract
As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics.
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Affiliation(s)
- Marlena M. Holter
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- *Correspondence: Marlena M. Holter,
| | - Mridusmita Saikia
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
| | - Bethany P. Cummings
- School of Medicine, Department of Surgery, Center for Alimentary and Metabolic Sciences, University of California, Davis, Sacramento, CA, United States
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12
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Asadi F, Dhanvantari S. Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia. Front Endocrinol (Lausanne) 2021; 12:726368. [PMID: 34659118 PMCID: PMC8511682 DOI: 10.3389/fendo.2021.726368] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/13/2021] [Indexed: 12/15/2022] Open
Abstract
Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus.
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Affiliation(s)
- Farzad Asadi
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Program in Metabolism and Diabetes, Lawson Health Research Institute, London, ON, Canada
| | - Savita Dhanvantari
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Program in Metabolism and Diabetes, Lawson Health Research Institute, London, ON, Canada
- Imaging Research Program, Lawson Health Research Institute, London, ON, Canada
- Department of Medical Biophysics, Western University, London, ON, Canada
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13
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Galvin SG, Kay RG, Foreman R, Larraufie P, Meek CL, Biggs E, Ravn P, Jermutus L, Reimann F, Gribble FM. The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1. J Proteome Res 2021; 20:4507-4517. [PMID: 34423991 PMCID: PMC8419866 DOI: 10.1021/acs.jproteome.1c00463] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Indexed: 02/07/2023]
Abstract
To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.
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Affiliation(s)
- Sam G. Galvin
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Richard G. Kay
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Rachel Foreman
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Pierre Larraufie
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Claire L. Meek
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Emma Biggs
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Peter Ravn
- Research
and Early Development Cardiovascular, Renal and Metabolism (CVRM),
BioPharmaceuticals R&D, AstraZeneca
Ltd., Cambridge, CB21 6GH, U.K.
| | - Lutz Jermutus
- Research
and Early Development Cardiovascular, Renal and Metabolism (CVRM),
BioPharmaceuticals R&D, AstraZeneca
Ltd., Cambridge, CB21 6GH, U.K.
| | - Frank Reimann
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
| | - Fiona M. Gribble
- University
of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 0QQ, U.K.
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14
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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15
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Abstract
Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.
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Affiliation(s)
- Scott A. Campbell
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal Diabetes Research Centre CRCHUM, Montréal, Canada
| | - Janyne Johnson
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Peter E. Light
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
- CONTACT Peter E. Light Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AlbertaT6G 2E1, Canada
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16
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Saikia M, Holter MM, Donahue LR, Lee IS, Zheng QC, Wise JL, Todero JE, Phuong DJ, Garibay D, Coch R, Sloop KW, Garcia-Ocana A, Danko CG, Cummings BP. GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells. JCI Insight 2021; 6:141851. [PMID: 33554958 PMCID: PMC7934853 DOI: 10.1172/jci.insight.141851] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which α cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a β cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide was translationally relevant in human islets through application of a new scRNA-seq technology, DART-Seq. We found that the effect of liraglutide to increase α cell PC1/3 mRNA expression occurred in a subcluster of α cells and was associated with increased expression of other β cell-like genes, which we confirmed by IHC. Finally, we found that the effect of liraglutide to increase bihormonal insulin+ glucagon+ cells was mediated by the β cell GLP-1R in mice. Together, our data validate a high-sensitivity method for scRNA-seq in human islets and identify a potentially novel GLP-1-mediated pathway regulating human α cell function.
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Affiliation(s)
- Mridusmita Saikia
- Department of Biomedical Sciences and
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
| | | | | | | | | | | | | | | | | | - Reilly Coch
- Cayuga Medical Center, Ithaca, New York, USA
| | - Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Lilly, Indianapolis, Indiana, USA
| | | | - Charles G Danko
- Department of Biomedical Sciences and
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
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17
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Xie H, Yepuri N, Meng Q, Dhawan R, Leech CA, Chepurny OG, Holz GG, Cooney RN. Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. Rev Endocr Metab Disord 2020; 21:431-447. [PMID: 32851581 PMCID: PMC7572644 DOI: 10.1007/s11154-020-09584-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.
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Affiliation(s)
- Han Xie
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Natesh Yepuri
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Qinghe Meng
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Ravi Dhawan
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Colin A Leech
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Oleg G Chepurny
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - George G Holz
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - Robert N Cooney
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA.
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18
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Pereira de Arruda EH, Vieira da Silva GL, da Rosa-Santos CA, Arantes VC, de Barros Reis MA, Colodel EM, Gaspar de Moura E, Lisboa PC, Carneiro EM, Damazo AS, Latorraca MQ. Protein restriction during pregnancy impairs intra-islet GLP-1 and the expansion of β-cell mass. Mol Cell Endocrinol 2020; 518:110977. [PMID: 32791189 DOI: 10.1016/j.mce.2020.110977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 07/14/2020] [Accepted: 08/03/2020] [Indexed: 12/26/2022]
Abstract
We evaluated whether protein restriction during pregnancy alters the morphometry of pancreatic islets, the intra-islet glucagon-like peptide-1 (GLP-1) production, and the anti-apoptotic signalling pathway modulated by GLP-1. Control non-pregnant (CNP) and control pregnant (CP) rats were fed a 17% protein diet, and low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) groups were fed a 6% protein diet. The masses of islets and β-cells were similar in the LPNP group and the CNP group but were higher in the CP group than in the CNP group and were equal in the LPP group and the LPNP group. Both variables were lower in the LPP group than in the CP group. Prohormone convertase 2 and GLP-1 fluorescence in α-cells was lower in the low-protein groups than in the control groups. The least PC2/glucagon colocalization was observed in the LPP group, and the most was observed in the CP group. There was less prohormone convertase 1/3/glucagon colocalization in the LPP group than in the CP group. GLP-1/glucagon colocalization was similar in the LPP, CP and CNP groups, which showed less GLP-1/glucagon colocalization than the LPNP group. The mRNA Pka, Creb and Pdx-1 contents were higher in islets from pregnant rats than in islets from non-pregnant rats. Protein restriction during pregnancy impaired the mass of β-cells and the intra-islet GLP-1 production but did not interfere with the transcription of genes of the anti-apoptotic signalling pathway modulated by GLP-1.
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Affiliation(s)
| | | | - Chaiane Aline da Rosa-Santos
- Mestrado em Nutrição, Alimentos e Metabolismo, Faculdade de Nutrição, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Vanessa Cristina Arantes
- Departamento de Alimentos e Nutrição, Faculdade de Nutrição, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | | | - Edson Moleta Colodel
- Departamento de Clínica Médica Veterinária, Faculdade de Agronomia e Medicina Veterinária, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Egberto Gaspar de Moura
- Laboratório de Fisiologia Endócrina, Departamento de Ciências Fisiológicas, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Patrícia Cristina Lisboa
- Laboratório de Fisiologia Endócrina, Departamento de Ciências Fisiológicas, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Everardo Magalhães Carneiro
- Departamento de Anatomia, Biologia Cellular, Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Amílcar Sabino Damazo
- Departamento de Ciências Básicas da Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Márcia Queiroz Latorraca
- Departamento de Alimentos e Nutrição, Faculdade de Nutrição, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil.
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19
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Abstract
The islet of Langerhans is a complex endocrine micro-organ consisting of a multitude of endocrine and non-endocrine cell types. The two most abundant and prominent endocrine cell types, the beta and the alpha cells, are essential for the maintenance of blood glucose homeostasis. While the beta cell produces insulin, the only blood glucose-lowering hormone of the body, the alpha cell releases glucagon, which elevates blood glucose. Under physiological conditions, these two cell types affect each other in a paracrine manner. While the release products of the beta cell inhibit alpha cell function, the alpha cell releases factors that are stimulatory for beta cell function and increase glucose-stimulated insulin secretion. The aim of this review is to provide a comprehensive overview of recent research into the regulation of beta cell function by alpha cells, focusing on the effect of alpha cell-secreted factors, such as glucagon and acetylcholine. The consequences of differences in islet architecture between species on the interplay between alpha and beta cells is also discussed. Finally, we give a perspective on the possibility of using an in vivo imaging approach to study the interactions between human alpha and beta cells under in vivo conditions. Graphical abstract.
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Affiliation(s)
- Tilo Moede
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska Sjukhuset L1:03, 17176, Stockholm, Sweden.
| | - Ingo B Leibiger
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska Sjukhuset L1:03, 17176, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska Sjukhuset L1:03, 17176, Stockholm, Sweden
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20
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Ramzy A, Asadi A, Kieffer TJ. Revisiting Proinsulin Processing: Evidence That Human β-Cells Process Proinsulin With Prohormone Convertase (PC) 1/3 but Not PC2. Diabetes 2020; 69:1451-1462. [PMID: 32291281 DOI: 10.2337/db19-0276] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 04/03/2020] [Indexed: 11/13/2022]
Abstract
Insulin is first produced in pancreatic β-cells as the precursor prohormone proinsulin. Defective proinsulin processing has been implicated in the pathogenesis of both type 1 and type 2 diabetes. Though there is substantial evidence that mouse β-cells process proinsulin using prohormone convertase 1/3 (PC1/3) and then prohormone convertase 2 (PC2), this finding has not been verified in human β-cells. Immunofluorescence with validated antibodies revealed that there was no detectable PC2 immunoreactivity in human β-cells and little PCSK2 mRNA by in situ hybridization. Similarly, rat β-cells were not immunoreactive for PC2. In all histological experiments, PC2 immunoreactivity in neighboring α-cells acted as a positive control. In donors with type 2 diabetes, β-cells had elevated PC2 immunoreactivity, suggesting that aberrant PC2 expression may contribute to impaired proinsulin processing in β-cells of patients with diabetes. To support histological findings using a biochemical approach, human islets were used for pulse-chase experiments. Despite inhibition of PC2 function by temperature blockade, brefeldin A, chloroquine, and multiple inhibitors that blocked production of mature glucagon from proglucagon, β-cells retained the ability to produce mature insulin. Conversely, suppression of PC1/3 blocked processing of proinsulin but not proglucagon. By demonstrating that healthy human β-cells process proinsulin by PC1/3 but not PC2, we suggest that there is a need to revise the long-standing theory of proinsulin processing.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Ali Asadi
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada
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21
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Panaro BL, Yusta B, Matthews D, Koehler JA, Song Y, Sandoval DA, Drucker DJ. Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion. Mol Metab 2020; 37:100990. [PMID: 32278655 PMCID: PMC7200938 DOI: 10.1016/j.molmet.2020.100990] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/01/2020] [Accepted: 04/02/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. METHODS Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (GcgGut-/-) and (2) selective reduction of Gcg expression in the distal gut (GcgDistalGut-/-). RESULTS The acute GLP-1 response to olive oil or arginine administration was markedly diminished in GcgGut-/- but preserved in GcgDistalGut-/- mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the GcgDistalGut-/- mice. The GLP-1 response to LPS was also markedly attenuated in the GcgGut-/- mice and remained submaximal in the GcgDistalGut-/- mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the GcgGut+/+ mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the GcgGut-/- mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the GcgDistalGut-/- mice. CONCLUSION These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues.
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Affiliation(s)
- Brandon L Panaro
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
| | - Bernardo Yusta
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Dianne Matthews
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Jacqueline A Koehler
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Youngmi Song
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | - Daniel J Drucker
- Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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22
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Adams JD, Dalla Man C, Laurenti MC, Andrade MDH, Cobelli C, Rizza RA, Bailey KR, Vella A. Fasting glucagon concentrations are associated with longitudinal decline of β-cell function in non-diabetic humans. Metabolism 2020; 105:154175. [PMID: 32045582 PMCID: PMC7093233 DOI: 10.1016/j.metabol.2020.154175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 02/05/2020] [Accepted: 02/07/2020] [Indexed: 01/31/2023]
Abstract
PURPOSE Abnormal glucagon concentrations are a feature of prediabetes but it is uncertain if α-cell dysfunction contributes to a longitudinal decline in β-cell function. We therefore sought to determine if a decline in β-cell function is associated with a higher nadir glucagon in the postprandial period or with higher fasting glucagon. METHODS This was a longitudinal study in which 73 non-diabetic subjects were studied on 2 occasions 6.6 ± 0.3 years apart using a 2-hour, 7-sample oral glucose tolerance test. Disposition Index (DI) was calculated using the oral minimal model applied to the measurements of glucose, insulin, C-peptide concentrations during the studies. We subsequently examined the relationship of glucagon concentrations at baseline with change in DI (used as a measure of β-cell function) after adjusting for changes in weight and the baseline value of DI. RESULTS After adjusting for covariates, nadir postprandial glucagon concentrations were not associated with changes in β-cell function as quantified by DI. On the other hand, fasting glucagon concentrations during the baseline study were inversely correlated with longitudinal changes in DI. CONCLUSIONS Defects in α-cell function, manifest as elevated fasting glucagon, are associated with a subsequent decline in β-cell function. It remains to be ascertained if abnormal α-cell function contributes directly to loss of β-cell secretory capacity in the pathogenesis of type 2 diabetes.
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Affiliation(s)
- Jon D Adams
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Marcello C Laurenti
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - M Daniela Hurtado Andrade
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Claudio Cobelli
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Robert A Rizza
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Kent R Bailey
- Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Adrian Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA.
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23
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Composite probiotics alleviate type 2 diabetes by regulating intestinal microbiota and inducing GLP-1 secretion in db/db mice. Biomed Pharmacother 2020; 125:109914. [PMID: 32035395 DOI: 10.1016/j.biopha.2020.109914] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 01/10/2020] [Accepted: 01/12/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUD/AIM Previous studies have found that probiotic fermented camel milk has anti-diabetic effect by inducing (glucagon-like peptide-1) GLP-1 secretion. Probiotics are valuable in prevention and treatment of diabetes. As a result, our team islolated 14 probiotics from fermented camel milk. These probiotics have beneficial characteristics, but the possible anti-diabetic mechanisms remains unclear. The present study aimed to explore the possoble anti-diabetic mechanisms of 14 probiotics. METHODS C57BL/Ks mice were normal group. The db/db mice were randomized into five groups: model group, metformin group, liraglutide group, low-dose and high-dose probiotic group. Biochemical parameters were determined by the respective assay kits. The levels of the short-chain fatty acids (SCFAs) and microbiota were respectively determined by gas chromatography and qRT-PCR. HE staining and immunofluorescence were used for histomorphological observation. Quantitative PCR and western-blot were determined the gene and protein expression of Bax, Bcl-2, Caspase-3 and PI3K/AKT. RESULTS Probiotics significantly improved blood glucose and blood lipid parameters, as well as the morphological changes of pancreas, liver and kidney. Probiotics improved the gut barrier function through increasing the levels of SCFA-producing bacteria and SCFAs as well as the expression of claudin-1 and mucin-2, and decreasing Escherichia coli and LPS level. In additon, probiotics enhanced insulin secretion through glucose-triggered GLP-1 secretion by upregulating G protein-coupled receptor 43/41 (GPR43/41), proglucagon and proconvertase 1/3 activity. Forthermore, probiotics protected pancreas against apoptosis, which may be dependent on the upregulation of PI3K/AKT pathway. CONCLUSIONS The anti-diabetic effect of 14 probiotics in db/db mice seem to be related to an increase of SCFA-producing bacteria, the improvement of intestinal barrier function and the upregulation of GLP-1 production, and indicate these probiotics might be a good candidate to prevent and treat diabetes.
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24
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Kanasaki K, Kawakita E, Koya D. Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon. Front Pharmacol 2019; 10:476. [PMID: 31156426 PMCID: PMC6531852 DOI: 10.3389/fphar.2019.00476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/16/2019] [Indexed: 12/13/2022] Open
Abstract
The biology of autophagy in health and disease conditions has been intensively analyzed for decades. Several potential interventions can induce autophagy in preclinical research; however, none of these interventions are ready for translation to clinical practice yet. The topic of the current review is the molecular regulation of autophagy by glucagon, glucagon-like peptide (GLP)-1 and the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP-4). Glucagon is a well-known polypeptide that induces autophagy. In contrast, GLP-1 has been shown to inhibit glucagon secretion; GLP-1 also has been related to the induction of autophagy. DPP-4 inhibitors can induce autophagy in a GLP-1-dependent manner, but other diverse effects could be relevant. Here, we analyze the distinct molecular regulation of autophagy by glucagon, GLP-1, and DPP-4 inhibitors. Additionally, the potential contribution to autophagy by glucagon and GLP-1 after bariatric surgery is discussed.
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Affiliation(s)
- Keizo Kanasaki
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan.,Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
| | - Emi Kawakita
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan.,Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
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25
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Chepurny OG, Matsoukas MT, Liapakis G, Leech CA, Milliken BT, Doyle RP, Holz GG. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP. J Biol Chem 2019; 294:3514-3531. [PMID: 30622136 DOI: 10.1074/jbc.ra118.005682] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 01/05/2019] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled receptors (GPCRs) for glucagon (GluR) and glucagon-like peptide-1 (GLP-1R) are normally considered to be highly selective for glucagon and GLP-1, respectively. However, glucagon secreted from pancreatic α-cells may accumulate at high concentrations to exert promiscuous effects at the β-cell GLP-1R, as may occur in the volume-restricted microenvironment of the islets of Langerhans. Furthermore, systemic administration of GluR or GLP-1R agonists and antagonists at high doses may lead to off-target effects at other receptors. Here, we used molecular modeling to evaluate data derived from FRET assays that detect cAMP as a read-out for GluR and GLP-1R activation. This analysis established that glucagon is a nonconventional GLP-1R agonist, an effect inhibited by the GLP-1R orthosteric antagonist exendin(9-39) (Ex(9-39)). The GluR allosteric inhibitors LY2409021 and MK 0893 antagonized glucagon and GLP-1 action at the GLP-1R, whereas des-His1-[Glu9]glucagon antagonized glucagon action at the GluR, while having minimal inhibitory action versus glucagon or GLP-1 at the GLP-1R. When testing Ex(9-39) in combination with des-His1-[Glu9]glucagon in INS-1 832/13 cells, we validated a dual agonist action of glucagon at the GluR and GLP-1R. Hybrid peptide GGP817 containing glucagon fused to a fragment of peptide YY (PYY) acted as a triagonist at the GluR, GLP-1R, and neuropeptide Y2 receptor (NPY2R). Collectively, these findings provide a new triagonist strategy with which to target the GluR, GLP-1R, and NPY2R. They also provide an impetus to reevaluate prior studies in which GluR and GLP-1R agonists and antagonists were assumed not to exert promiscuous actions at other GPCRs.
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Affiliation(s)
| | | | - George Liapakis
- the Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece, and
| | | | - Brandon T Milliken
- the Department of Chemistry, Syracuse University, Syracuse, New York 13244
| | - Robert P Doyle
- From the Departments of Medicine, .,the Department of Chemistry, Syracuse University, Syracuse, New York 13244
| | - George G Holz
- From the Departments of Medicine, .,Pharmacology, State University of New York (SUNY), Upstate Medical University, Syracuse, New York 13210
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26
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Garibay D, Lou J, Lee SA, Zaborska KE, Weissman MH, Sloma E, Donahue L, Miller AD, White AC, Michael MD, Sloop KW, Cummings BP. β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice. Cell Rep 2018; 23:967-973. [PMID: 29694904 PMCID: PMC5983903 DOI: 10.1016/j.celrep.2018.03.120] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 03/05/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022] Open
Abstract
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible β cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the β cell GLP-1R in islet function. Our data show that loss of β cell GLP-1R signaling decreases α cell GLP-1 expression after VSG. Furthermore, we find a β cell GLP-1R-dependent increase in α cell expression of the prohormone convertase required for the production of GLP-1 after VSG. Together, the findings herein reveal two concepts. First, our data support a paracrine role for α cell-derived GLP-1 in the metabolic benefits observed after VSG. Second, we have identified a role for the β cell GLP-1R as a regulator of α cell proglucagon processing.
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Affiliation(s)
- Darline Garibay
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Jon Lou
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Seon A Lee
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Karolina E Zaborska
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Margot H Weissman
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Erica Sloma
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Leanne Donahue
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Andrew D Miller
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Andrew C White
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - M Dodson Michael
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
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Mulvihill EE. Dipeptidyl peptidase inhibitor therapy in type 2 diabetes: Control of the incretin axis and regulation of postprandial glucose and lipid metabolism. Peptides 2018; 100:158-164. [PMID: 29412815 DOI: 10.1016/j.peptides.2017.11.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 11/30/2017] [Accepted: 11/30/2017] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) is a widely expressed, serine protease which regulates the bioactivity of many peptides through cleavage and inactivation including the incretin hormones, glucagon like peptide -1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Inhibitors of DPP4 are used therapeutically to treat patients with Type 2 Diabetes Mellitus (T2DM) as they potentiate incretin action to regulate islet hormone secretion and improve glycemia and post-prandial lipid excursions. The widespread clinical use of DPP4 inhibitors has increased interest in the molecular mechanisms by which these drugs mediate their beneficial effects. Traditionally, focus has remained on inhibiting the catalytic activity of DPP4 within the plasma compartment, however evidence is emerging on the importance of inactivation of membrane-bound DPP4 in selective tissue beds to potentiate local hormone gradients. Here we review the recent advances in identifying the cellular sources of both circulating and membrane-bound DPP4 important for cleavage of the incretin hormones and regulation of glucose and lipoprotein metabolism.
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Affiliation(s)
- Erin E Mulvihill
- University of Ottawa Heart Institute, University of Ottawa, Department of Biochemistry, Microbiology and Immunology, 40 Ruskin Street, Ottawa, ON, K1Y4W7, Canada.
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28
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Sancho V, Daniele G, Lucchesi D, Lupi R, Ciccarone A, Penno G, Bianchi C, Dardano A, Miccoli R, Del Prato S. Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line. PLoS One 2017; 12:e0187836. [PMID: 29121068 PMCID: PMC5679617 DOI: 10.1371/journal.pone.0187836] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/26/2017] [Indexed: 12/15/2022] Open
Abstract
Background and aims An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. Materials and methods AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. Results Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. Conclusion These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions.
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Affiliation(s)
- Veronica Sancho
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Giuseppe Daniele
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Daniela Lucchesi
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Roberto Lupi
- Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero–Universitaria Pisana, Cisanello Hospital, Pisa, Italy
| | - Annamaria Ciccarone
- Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero–Universitaria Pisana, Cisanello Hospital, Pisa, Italy
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Cristina Bianchi
- Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero–Universitaria Pisana, Cisanello Hospital, Pisa, Italy
| | - Angela Dardano
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Roberto Miccoli
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa – Cisanello Hospital, Pisa, Italy
- * E-mail:
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29
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Zhang Y, Fava GE, Wu M, Htun W, Klein T, Fonseca VA, Wu H. Effects of Linagliptin on Pancreatic α Cells of Type 1 Diabetic Mice. J Endocr Soc 2017; 1:1224-1234. [PMID: 29264448 PMCID: PMC5686619 DOI: 10.1210/js.2017-00253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/28/2017] [Indexed: 11/19/2022] Open
Abstract
The dipeptidyl peptidase-4 inhibitor linagliptin promotes β-cell survival and insulin secretion by prolonging endogenous glucagon-like peptide 1 (GLP-1) action and therefore helps to maintain normoglycemia in diabetic patients. The effect of linagliptin on glucagon-producing α cells, however, was not clear. In this study, we investigated whether linagliptin had any effects on α cells with regard to their proliferation and hormonal production using type 1 diabetes mouse models, including streptozotocin-induced and nonobese diabetes mice. After diabetes development, the mice were either untreated or treated with linagliptin or insulin for up to 6 weeks. Our results showed that linagliptin significantly increased circulating GLP-1 levels in both type 1 diabetes models, but therapeutic benefit was detected in nonobese diabetes mice only. Circulating C-peptide and glucagon levels (nonfasting) were not significantly altered by linagliptin treatment in either model. In addition, we found that linagliptin did not increase α-cell proliferation compared with the untreated or insulin-treated controls as assessed by in vivo 5-bromo-2'-deoxyuridine labeling assay. Finally, we examined whether linagliptin treatment altered GLP-1 vs glucagon expression in pancreatic α cells. Immunohistochemistry assays showed that linagliptin treatment resulted in detection of GLP-1 in more α cells than in control groups, suggesting linagliptin was able to increase intraislet GLP-1 presence, presumably by inhibiting GLP-1 degradation. In summary, this study indicates that linagliptin would not confer adverse effect on α cells, such as causing α cell hyperplasia, and instead may facilitate a blood glucose-lowering effect by increasing GLP-1 presence in α cells.
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Affiliation(s)
- Yanqing Zhang
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Genevieve E. Fava
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Meifen Wu
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Wynn Htun
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Thomas Klein
- Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach 88597, Germany
| | - Vivian A. Fonseca
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Hongju Wu
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
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Zhang Y, Wu M, Htun W, Dong EW, Mauvais-Jarvis F, Fonseca VA, Wu H. Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors. Sci Rep 2017; 7:7964. [PMID: 28801559 PMCID: PMC5554162 DOI: 10.1038/s41598-017-08271-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/06/2017] [Indexed: 12/19/2022] Open
Abstract
Linagliptin is a dipeptidyl Peptidase-4 (DPP-4) inhibitor that inhibits the degradation of glucagon-like peptide 1 (GLP-1), and has been approved for the treatment of type 2 diabetes (T2D) in clinic. Previous studies have shown linagliptin improves β cell function using animal models and isolated islets from normal subjects. Since β cell dysfunction occurs during diabetes development, it was not clear how human islets of T2D patients would respond to linagliptin treatment. Therefore, in this study we employed human islets isolated from donors with and without T2D and evaluated how they responded to linagliptin treatment. Our data showed that linagliptin significantly improved glucose-stimulated insulin secretion for both non-diabetic and diabetic human islets, but its effectiveness on T2D islets was lower than on normal islets. The differential effects were attributed to reduced GLP-1 receptor expression in diabetic islets. In addition, linagliptin treatment increased the relative GLP-1 vs glucagon production in both non-diabetic and diabetic islets, suggesting a positive role of linagliptin in modulating α cell function to restore normoglycemia. Our study indicated that, from the standpoint of islet cell function, linagliptin would be more effective in treating early-stage diabetic patients before they develop severe β cell dysfunction.
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Affiliation(s)
- Yanqing Zhang
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Meifen Wu
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Medicine, Guangdong Medical University, Zhanjiang, Guangdong Province, China
| | - Wynn Htun
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Emily W Dong
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Franck Mauvais-Jarvis
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Vivian A Fonseca
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Hongju Wu
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Fava GE, Dong EW, Wu H. Intra-islet glucagon-like peptide 1. J Diabetes Complications 2016; 30:1651-1658. [PMID: 27267264 PMCID: PMC5050074 DOI: 10.1016/j.jdiacomp.2016.05.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/14/2016] [Accepted: 05/17/2016] [Indexed: 02/06/2023]
Abstract
PURPOSE Glucagon-like peptide-1 (GLP-1) is originally identified in the gut as an incretin hormone, and it is potent in stimulating insulin secretion in the pancreas. However, increasing evidence suggests that GLP-1 is also produced locally within pancreatic islets. This review focuses on the past and current discoveries regarding intra-islet GLP-1 production and its functions. MAIN FINDINGS There has been a long-standing debate with regard to whether GLP-1 is produced in the pancreatic α cells. Early controversies lead to the widely accepted conclusion that the vast majority of proglucagon is processed to form glucagon in the pancreas, whereas an insignificant amount is cleaved to produce GLP-1. With technological advancements, recent studies have shown that bioactive GLP-1 is produced locally in the pancreas, and the expression and secretion of GLP-1 within islets are regulated by various factors such as cytokines, hyperglycemia, and β cell injury. CONCLUSIONS GLP-1 is produced by the pancreatic α cells, and it is fully functional as an incretin. Therefore, intra-islet GLP-1 may exert insulinotropic and glucagonostatic effects locally via paracrine and/or autocrine actions, under both normal and diabetic conditions.
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Affiliation(s)
- Genevieve E Fava
- Endocrinology Section, Department of Medicine, Tulane University Health Science Center, New Orleans, LA, United States
| | - Emily W Dong
- Endocrinology Section, Department of Medicine, Tulane University Health Science Center, New Orleans, LA, United States
| | - Hongju Wu
- Endocrinology Section, Department of Medicine, Tulane University Health Science Center, New Orleans, LA, United States.
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PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 2015; 24:251-260. [PMID: 26435408 DOI: 10.1038/mt.2015.181] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 09/25/2015] [Indexed: 12/19/2022] Open
Abstract
The transcription factor Pax4 plays a critical role in the determination of α- versus β-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into α-cells could convert them into functional β-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.Pax4, induced insulin expression and reduced glucagon expression in αTC1.9 cells. More importantly, these cells exhibited glucose-stimulated insulin secretion, a key feature of functional β-cells. When injected into streptozotocin-induced diabetic mice, Pax4-treated αTC1.9 cells significantly reduced blood glucose, and the mice showed better glucose tolerance, supporting that Pax4 gene transfer into αTC1.9 cells resulted in the formation of functional β-cells. Furthermore, treatment of primary human islets with Ad5.Pax4 resulted in significantly improved β-cell function. Detection of glucagon(+)/Pax4(+)/Insulin(+) cells argued for Pax4-induced α-to-β cell transitioning. This was further supported by quantification of glucagon and insulin bi-hormonal cells, which was significantly higher in Pax4-treated islets than in controls. Finally, direct administration of Ad5.Pax4 into the pancreas of insulin-deficient mice ameliorated hyperglycemia. Taken together, our data demonstrate that manipulating Pax4 gene expression represents a viable therapeutic strategy for the treatment of insulin deficient diabetes.
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Huang C, Yuan L, Cao S. Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets. Int J Mol Med 2015; 36:173-85. [PMID: 25976560 PMCID: PMC4494597 DOI: 10.3892/ijmm.2015.2207] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 05/07/2015] [Indexed: 01/15/2023] Open
Abstract
The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.
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Affiliation(s)
- Chenghu Huang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shuyi Cao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Moffett RC, Patterson S, Irwin N, Flatt PR. Positive effects of GLP-1 receptor activation with liraglutide on pancreatic islet morphology and metabolic control in C57BL/KsJ db/db mice with degenerative diabetes. Diabetes Metab Res Rev 2015; 31:248-55. [PMID: 25256010 DOI: 10.1002/dmrr.2608] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 09/11/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Stable glucagon-like peptide-1 (GLP-1) mimetics, such as the GLP-1 analogue liraglutide, are approved for treatment of type 2 diabetes. GLP-1 has a spectrum of anti-diabetic effects that are of possible utility in the treatment of more severe forms of diabetes. METHODS The present study has evaluated the effect of once daily liraglutide injection (25 nmol/kg bw) for 15 days on metabolic control, islet architecture, and islet morphology in C57BL/KsJ db/db mice. RESULTS Liraglutide had no appreciable effects on body weight, food intake, and non-fasting glucose and insulin concentrations. However, HbA1c was significantly (p < 0.001) decreased, and oral glucose tolerance improved in liraglutide treated db/db mice. Pancreatic insulin content was increased (p < 0.05) compared with saline controls, and the ratio of pancreatic insulin to glucagon in liraglutide mice was similar to lean mice. Although liraglutide did not alter islet number or area, the proportion of beta cells per islet was significantly increased (p < 0.05) and alpha cells decreased (p < 0.05), with normalization of islet architecture. In harmony with this, cell proliferation was significantly (p < 0.001) augmented and apoptosis reduced (p < 0.001) in liraglutide treated mice. Expression of pancreatic islet glucose-dependent insulinotropic polypeptide immunoreactivity was observed in lean control and, particularly, liraglutide treated db/db mice, whereas control db/db mice exhibited little glucose-dependent insulinotropic polypeptide staining. CONCLUSION These data reveal that stable GLP-1 analogues exert important beneficial effects on pancreatic islet architecture and beta-cell turnover, indicating that they may be useful in the treatment of severe forms of diabetes with islet degeneration.
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36
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Moffett RC, Vasu S, Flatt PR. Functional GIP receptors play a major role in islet compensatory response to high fat feeding in mice. Biochim Biophys Acta Gen Subj 2015; 1850:1206-14. [PMID: 25688757 DOI: 10.1016/j.bbagen.2015.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 01/30/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Consumption of high fat diet and insulin resistance induce significant changes in pancreatic islet morphology and function essential for maintenance of normal glucose homeostasis. We have used incretin receptor null mice to evaluate the role of gastric inhibitory polypeptide (GIP) in this adaptive response. METHODS C57BL/6 and GIPRKO mice were fed high fat diet for 45 weeks from weaning. Changes of pancreatic islet morphology were assessed by immunohistochemistry. Body fat, glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1) and GIP were assessed by routine assays. RESULTS Compared with normal diet controls, high fat fed C57BL/6 mice exhibited increased body fat, hyperinsulinaemia and insulin resistance, associated with decreased pancreatic glucagon, unchanged pancreatic GLP-1 and marked increases of insulin, islet number, islet size and both beta- and alpha-cell areas. Beta cell proliferation and apoptosis were increased under high fat feeding, but the overall effect favoured enhanced beta cell mass. A broadly similar pattern of change was observed in high fat fed GIPRKO mice but islet compensation was severely impaired in every respect. The inability to enhance beta cell proliferation was associated with the depletion of pancreatic GLP-1 and lack of hyperinsulinaemic response, resulting in non-fasting hyperglycaemia. GIP and GLP-1 were expressed in islets of all groups of mice but high fat fed GIPRKO mice displayed decreased numbers of GLP-1 containing alpha cells plus non-functional enhancement of pancreatic GIP content. GENERAL SIGNIFICANCE These data suggest that GIP released from islet alpha-cells and intestinal K-cells plays an important role in islet adaptations to high fat feeding.
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Affiliation(s)
- R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK.
| | - Srividya Vasu
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK
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Liu L, Omar B, Marchetti P, Ahrén B. Dipeptidyl peptidase-4 (DPP-4): Localization and activity in human and rodent islets. Biochem Biophys Res Commun 2014; 453:398-404. [PMID: 25268763 DOI: 10.1016/j.bbrc.2014.09.096] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 09/22/2014] [Indexed: 01/26/2023]
Abstract
Dipeptidyl peptidase 4 (DPP-4) was recently found to be expressed in human and mouse islets with different expression patterns. However, whether species-dependent expression pattern is a generalized phenomenon and whether islet DPP-4 activity is regulated are not known. This study was conducted to investigate DPP-4 localization in several different species, and to examine the impact of glucose, incretin hormones, and insulin on islet DPP-4 activity. It was shown by immuofluorescent staining that there were two distinct species-specific expression patterns of islet DPP-4. The enzyme was expressed exclusively in α-cells in human and pig islets, but primarily in β-cells in mouse and rat islets. INS-1 832/13 cells also expressed DPP-4, and inhibition of DPP-4 enhanced insulin secretion in the presence of glucagon-like peptide-1 (GLP-1) in the cells. DPP-4 activity was remarkably robust when cultured with high glucose, incretin hormones, and insulin in mouse and human islets as well as INS-1 832/13 cells and islet DPP-4 activity and expression pattern was not altered in double incretin receptor knockout mice, compared to wild type mice. We conclude that islet DPP-4 is species-specifically expressed in α-cell and β-cell dominant patterns in several species and both patterns remained robust in enzyme activity during short-term metabolic challenge.
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Affiliation(s)
- Liehua Liu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Clinical Sciences, Lund, Medicine, Lund University, SE22184 Lund, Sweden
| | - Bilal Omar
- Department of Clinical Sciences, Lund, Medicine, Lund University, SE22184 Lund, Sweden
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Medicine, Lund University, SE22184 Lund, Sweden.
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Guizzetti L, McGirr R, Dhanvantari S. Two dipolar α-helices within hormone-encoding regions of proglucagon are sorting signals to the regulated secretory pathway. J Biol Chem 2014; 289:14968-80. [PMID: 24727476 DOI: 10.1074/jbc.m114.563684] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Proglucagon is expressed in pancreatic α cells, intestinal L cells, and some hypothalamic and brainstem neurons. Tissue-specific processing of proglucagon yields three major peptide hormones as follows: glucagon in the α cells and glucagon-like peptides (GLP)-1 and -2 in the L cells and neurons. Efficient sorting and packaging into the secretory granules of the regulated secretory pathway in each cell type are required for nutrient-regulated secretion of these proglucagon-derived peptides. Our previous work suggested that proglucagon is directed into granules by intrinsic sorting signals after initial processing to glicentin and major proglucagon fragment (McGirr, R., Guizzetti, L., and Dhanvantari, S. (2013) J. Endocrinol. 217, 229-240), leading to the hypothesis that sorting signals may be present in multiple domains. In the present study, we show that the α-helices within glucagon and GLP-1, but not GLP-2, act as sorting signals by efficiently directing a heterologous secretory protein to the regulated secretory pathway. Biophysical characterization of these peptides revealed that glucagon and GLP-1 each encode a nonamphipathic, dipolar α-helix, whereas the helix in GLP-2 is not dipolar. Surprisingly, glicentin and major proglucagon fragment were sorted with different efficiencies, thus providing evidence that proglucagon is first sorted to granules prior to processing. In contrast to many other prohormones in which sorting is directed by ordered prodomains, the sorting determinants of proglucagon lie within the ordered hormone domains of glucagon and GLP-1, illustrating that each prohormone has its own sorting "signature."
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Affiliation(s)
| | - Rebecca McGirr
- the Metabolism/Diabetes and Imaging Programs, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada
| | - Savita Dhanvantari
- From the Departments of Medical Biophysics, the Metabolism/Diabetes and Imaging Programs, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada Pathology, and Medicine, University of Western Ontario, London, Ontario N6A 3K7 and
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