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Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis

Published on Mar 1, 2017in Cell Reports7.815
· DOI :10.1016/j.celrep.2017.03.005
Shuyang Traub5
Estimated H-index: 5
(University of Basel),
Daniel T. Meier2
Estimated H-index: 2
(University of Basel)
+ 11 AuthorsMarc Y. Donath60
Estimated H-index: 60
(University of Basel)
Sources
Abstract
Summary Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.
  • References (46)
  • Citations (28)
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References46
Newest
#1Katharina Timper (University of Basel)H-Index: 12
#2Elise Dalmas (University of Basel)H-Index: 8
Last. Marc Y. Donath (University of Basel)H-Index: 60
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Background & Aims Glucose-dependent insulinotropic peptide (GIP) induces production of interleukin 6 (IL6) by adipocytes. IL6 increases production of glucagon-like peptide (GLP)-1 by L cells and α cells, leading to secretion of insulin from β cells. We investigated whether GIP regulates GLP1 and glycemia via IL6. Methods We obtained samples of human pancreatic islets and isolated islets from mice; human α cells and β cells were sorted by flow cytometry and incubated with GIP. Islets were analyze...
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#1Jonathan E. Campbell (U of T: University of Toronto)H-Index: 23
#2Daniel J. Drucker (U of T: University of Toronto)H-Index: 106
Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and e...
603 CitationsSource
#1Helga EllingsgaardH-Index: 13
#2Irina HauselmannH-Index: 1
Last. Marc Y. DonathH-Index: 60
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458 CitationsSource
#1Elena-Dana Baraboi (Canadian Institutes of Health Research)H-Index: 10
#2David H. St-Pierre (Canadian Institutes of Health Research)H-Index: 18
Last. Denis Richard (Canadian Institutes of Health Research)H-Index: 57
view all 5 authors...
The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of Exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155 - 15.5 μg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155; 0.775 μg/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH - parvocellular) nuclei a...
43 CitationsSource
#1Safina Ali (U of T: University of Toronto)H-Index: 7
#2Benjamin J. Lamont (U of T: University of Toronto)H-Index: 3
Last. Daniel J. Drucker (U of T: University of Toronto)H-Index: 106
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Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr–/– mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr–/– mice by generating Gcg...
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#1A. M. K. Hansen (Novo Nordisk)H-Index: 1
#2Thora B. Bodvarsdottir (Novo Nordisk)H-Index: 12
Last. Allan E. KarlsenH-Index: 27
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Aims/hypothesis The hormone glucagon-like peptide 1 (GLP-1) is released in response to a meal from the intestinal L-cells, where it is processed from proglucagon by the proconvertase (PC)1/3. In contrast, in the adult islets proglucagon is processed to glucagon by the PC2 enzyme. The aim of the study was to evaluate if, during the development of diabetes, alpha cells produce GLP-1 that, in turn, might trigger beta cell growth.
59 CitationsSource
#1M. A. NauckH-Index: 24
#2Irfan VardarliH-Index: 5
Last. Juris J. Meier (RUB: Ruhr University Bochum)H-Index: 58
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The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this appl...
305 CitationsSource
#1Martha C. Washington (Tuskegee University)H-Index: 12
#2Shannon J. Raboin (Tuskegee University)H-Index: 9
Last. Ayman I. Sayegh (Tuskegee University)H-Index: 16
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Abstract Exenatide is a synthetic agonist of the glucagon-like peptide-1 (GLP-1) receptor, which has also been shown to reduce food intake. The goal of this work is to test the hypothesis that exenatide reduces food intake and activates the enteric nervous system (ENS; myenteric and submucosal plexuses) of the gastrointestinal (GI) tract and the areas of the dorsal vagal complex (DVC) of the hindbrain that control food intake. Experiment 1 Five groups of overnight food-deprived male Sprague Dawl...
36 CitationsSource
#1Juris J. Meier (RUB: Ruhr University Bochum)H-Index: 58
#2Peter R. Ritter (RUB: Ruhr University Bochum)H-Index: 8
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Background: Postprandial secretion of glucagon-like peptide 1 (GLP-1) has been found diminished in some patients with type 2 diabetes mellitus (T2DM) and high glucagon concentrations. We examined the effects of exogenous glucagon on the release of incretin hormones. Patients and Methods: Ten patients with T2DM and 10 healthy controls were examined with a meal test during the iv administration of glucagon 0.65 ng/kg · min and placebo. Results: GLP-1 plasma concentration increased after meal inges...
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#1Fabrizio ThorelH-Index: 21
#2NépoteH-Index: 1
Last. Pedro Luis HerreraH-Index: 50
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Pancreatic insulin-producing beta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-cell) source. H...
541 CitationsSource
Cited By28
Newest
#1Ellen M. Davis (UM: University of Michigan)
#2Darleen A. Sandoval (UM: University of Michigan)H-Index: 34
GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the beta-cell to induce insulin secretion in a glucose-dependent manner. GLP-1 also inhibits alpha-cell secretion of glucagon. As few, if any, GLP-1r are expressed on alpha-cells, indirect regulation, via beta- or delta-cell products has been thought to be the primary...
Source
#1Patrick Gilon (UCL: Université catholique de Louvain)H-Index: 27
Abstract Pancreatic α-cells are the major source of glucagon, a hormone that counteracts the hypoglycemic action of insulin and strongly contributes to the correction of acute hypoglycemia. The mechanisms by which glucose controls glucagon secretion are hotly debated, and it is still unclear to what extent this control results from a direct action of glucose on α-cells or is indirectly mediated by β- and/or δ-cells. Besides its hyperglycemic action, glucagon has many other effects, in particular...
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#1Myriam Abarkan (University of Bordeaux)
#2Julien Gaitan (University of Bordeaux)H-Index: 5
Last. Jochen Lang (University of Bordeaux)H-Index: 24
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Abstract Objective Islets secrete neurotransmitters including glutamate which participate in fine regulation of islet function. The excitatory ionotropic glutamate receptor GluK2 of the kainate receptor family is widely expressed in brain and also found in islets, mainly in α and γ cells. α cells co-release glucagon and glutamate and the latter increases glucagon release via ionotropic glutamate receptors. However, neither the precise nature of the ionotropic glutamate receptor involved nor its ...
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#2Jacqueline A. Koehler (Lunenfeld-Tanenbaum Research Institute)H-Index: 4
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Summary The importance of pancreatic versus intestinal-derived GLP-1 for glucose homeostasis is controversial. We detected active GLP-1 in the mouse and human pancreas, albeit at extremely low levels relative to glucagon. Accordingly, to elucidate the metabolic importance of intestinal proglucagon-derived peptides (PGDPs), we generated mice with reduction of Gcg expression within the distal (GcgDistalGut−/−) or entire (GcgGut−/−) gut. Substantial reduction of gut Gcg expression markedly reduced ...
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Glucagon is historically described as the counterregulatory hormone to insulin, induced by fasting/hypoglycemia to raise blood glucose through action mediated in the liver. However, it is becoming clear that the biology of glucagon is much more complex and extends beyond hepatic actions to exert control on glucose metabolism. We discuss the inconsistencies with the canonical view that glucagon is primarily a hyperglycemic agent driven by fasting/hypoglycemia and highlight the recent advances tha...
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#2Marie Winther-Sørensen (UCPH: University of Copenhagen)H-Index: 4
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Glucagon and insulin are important regulators of blood glucose. The importance of insulin receptor signaling for alpha-cell secretion and of glucagon receptor signaling for beta-cell secretion is w...
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