Identification and Characterization of GLP-1 Receptor–Expressing Cells Using a New Transgenic Mouse Model

Abstract

GLP-1 is an intestinal hormone with widespread actions on metabolism. Therapies based on GLP-1 are highly effective because they increase glucosedependent insulin secretion in people with type 2 diabetes, but many reports suggest that GLP-1 has additional beneficial or, in some cases, potentially dangerous actions on other tissues, including the heart, vasculature, exocrine pancreas, liver, and central nervous system. Identifying which tissues express the GLP-1 receptor (GLP1R) is critical for the development of GLP-1-based therapies. Our objective was to use a method independent of GLP1R antibodies to identify and characterize the targets of GLP-1 in mice. Using newly generated glp1r-Cre mice crossed with fluorescent reporter strains, we show that major sites of glp1r expression include pancreatic b-and d-cells, vascular smooth muscle, cardiac atrium, gastric antrum/pylorus, enteric neurones, and vagal and dorsal root ganglia. In the central nervous system, glp1r-fluorescent cells were abundant in the area postrema, arcuate nucleus, paraventricular nucleus, and ventromedial hypothalamus. Sporadic glp1r-fluorescent cells were found in pancreatic ducts. No glp1r-fluorescence was observed in ventricular cardiomyocytes. Enteric and vagal neurons positive for glp1r were activated by GLP-1 and may contribute to intestinal and central responses to locally released GLP-1, such as regulation of intestinal secretomotor activity and appetite.

A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells

“…GLP1R is widely expressed in pancreatic islets, as well as in the brain, heart, kidney, and gastrointestinal tract (19 -21). Specifically in the pancreas, GLP1R expression was confirmed in beta and delta cells; however, it was 10-fold lower in delta cells when quantified by quantitative real time PCR (qPCR) (21). In the alpha cell population, very low expression of GLP1R was detected (21).…”

“…Specifically in the pancreas, GLP1R expression was confirmed in beta and delta cells; however, it was 10-fold lower in delta cells when quantified by quantitative real time PCR (qPCR) (21). In the alpha cell population, very low expression of GLP1R was detected (21). Like other B class GPCRs, GLP1R signals through the G s protein complex and activates adenylyl cyclase, which converts ATP into cAMP (22,23).…”

“…GLP1R was shown to be abundantly expressed in islet beta cells, less in delta cells, and very low in alpha cells (21). As such, we reasoned that isolated human and mouse islets would serve as reasonable models to study the GLP1R interactome in the setting of the pancreatic beta cell.…”

Impact of incretin-related agents on endothelial cell function

“…13 It was reported that native GLP-1 infusion for several hours to individuals with type 2 diabetes resulted in improvement in endothelial function. 27,28 Although both GLP-1 and cleaved GLP-1, such as GLP-1(9-36) and GLP-1 (28)(29)(30)(31)(32)(33)(34)(35)(36), may cause these effects, a study comparing the effect of native GLP-1 on vascular function with or without of sitagliptin to prevent an increase of the cleaved form of GLP-1 resulted in no detectable changes in both groups. 29 Although the existence of the GLP-1 receptor on the vascular endothelium has been suggested, recent accumulating evidence showed that the endothelium does not possess the GLP-1 receptor, 30,31 but there is currently no consensus.…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…The exact role of GLP-1 released from these neurons is still under investigation, but they seem to be involved in the mediation of reduced eating in response to aversive stimuli or in sickness anorexia. 12 Further, recent data indicate that locally released GLP-1 also contributes to the physiological control of eating and body weight (for example, Kanoski et al, 13 Hisadome et al 14 and Richards et al 15 ) because the knockdown of GLP-1 in the nucleus of the solitary tract leads to increased eating, body weight and adiposity. 16 …”