Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Pancreatic Islet α-Cells and Promotes Insulin Secretion

Fujita, Yukihiro; Wideman, Rhonda D.; Asadi, Ali; Yang, Gary K.; Baker, Robert K.; Webber, Travis D.; Zhang, Tianjiao; Wang, Rennian; Ao, Ziliang; Warnock, Garth L.; Kwok, Yin Nam; Kieffer, Timothy J.

doi:10.1053/j.gastro.2010.01.049

Cited by 142 publications

(126 citation statements)

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“…8 Insulin release from non-diabetic islets exposed to unconditioned (black bars) or conditioned (light grey bars) (from islets previously incubated with 11.1 mmol/l glucose) medium without exendin (9-39) (an antagonist of GLP-1 receptors), or from islets exposed to unconditioned medium+exendin(9-39) (white bars) or to conditioned medium + exendin(9-39) (dark grey bars). Glucose-stimulated insulin release was higher than that at the basal (3.3 mmol/l glucose) condition, with a further significant potentiation by the conditioned medium, which was prevented by exendin other major incretin [35]. Therefore, although cell fractions from isolated islets usually show some degree of contamination, as shown here and by others [25,26], the available evidence suggests that alpha cells are the source of islet GLP-1.…”

Section: Discussionmentioning

confidence: 82%

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

et al. 2012

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Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. MethodsThe presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption-ionisation-time of flight (MALDI-TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. Diabetologia (2012) 55:3262-3272 DOI 10.1007/s00125-012-2716 Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2716-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Results Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from nondiabetic isolated islets. Conclusions/interpretation We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.

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Section: Discussionmentioning

confidence: 82%

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

et al. 2012

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“…In this case, a decrease in DPP-4 activity within the islet would result in more intact forms of SDF-1, which would in turn help drive further GLP-1 production from the islet. Other substrates of DPP-4 that have been shown to be expressed in islets include GIP, interferon γ inducible protein 10 (IP-10) and pituitary adenylate cyclase-activating polypeptide (PACAP) [31][32][33]. It remains to be determined what effect the decrease in DPP-4 activity seen in islets from type 2 diabetic patients has on the resulting action of these substrates.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

et al. 2014

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Aims/hypothesis Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves and inactivates glucagon-like peptide 1 (GLP-1), is a glucose-lowering strategy in type 2 diabetes. Since DPP-4 is a ubiquitously distributed enzyme, we examined whether it is expressed in islets and whether an islet effect to inhibit DPP-4 may result in stimulated insulin secretion. Methods We investigated DPP-4 expression and activity in the islets of mouse models of obesity as well as human islets from non-diabetic and type 2 diabetic donors. We further investigated whether inhibition with DPP-4 inhibitors could promote insulin secretion via islet GLP-1 in isolated islets.

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“…Of note, GLP2 and GLP2R expression might change following HFD, as reported in gut tissue (Rotondo et al 2011b, Baldassano et al 2013. Moreover, recent studies on glucose-dependent insulinotrophic polypeptide (GIP) and GLP1 have pointed out that both hormones are synthesized and secreted from islet α-cells under conditions of cellular stress imposed by β cytotoxic attack or increased insulin demand (Fujita et al 2010, Donath & Burcekin 2013, Moffett et al 2014. Increased expression of PC1/3 relative to PC2 in islet α-cells directs proglucagon processing away from glucagon towards GLP1 in these conditions (Wideman et al 2007, Marchetti et al 2012.…”

Section: Mechanistic Insightmentioning

confidence: 99%

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Amato¹,

Baldassano²,

Mulè³

2016

Journal of Endocrinology

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Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes.

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Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Pancreatic Islet α-Cells and Promotes Insulin Secretion

Cited by 142 publications

References 51 publications

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

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