GLP-1 Receptor Localization in Monkey and Human Tissue: Novel Distribution Revealed With Extensively Validated Monoclonal Antibody

Abstract

Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

“…A previous study reported T2D-related GLP-1R downregulation in human islets, 40 whereas in a recent study conducted by us there was little or no change in GLP-1R antibody immunoreactivity between normal islets and islets from a T2D patient. 33 As noted above, expression levels of the Glp-1r could be normalized following re-establishment of normoglycaemia in the pancreatectomized hyperglycaemic rat. 24 An interesting possibility is therefore that treatment with plasma glucose-lowering drugs over an extended period of time could restore the levels of the GLP-1R on b cells.…”

“…We recently developed a novel antibody against the primate GLP-1R, and predominant b cell labeling was observed within islets in humans and monkeys. 33 Targeting the same epitope we have developed and are currently validating an antibody against the rodent Glp-1r. Here, we tested the specificity of this antibody (7F38A2) in wt and Glp1r ¡/¡ mouse pancreata.…”

Risk of pancreatitis in patients treated with incretin-based therapies

“…Taken together with the observation of elevated lipase concentrations in patients treated with GLP-1 receptor agonists [9], it is conceivable that these drugs exert some effects on the exocrine pancreas, although a specific mechanism of action has not yet been identified, and the presence of GLP-1 receptors in pancreatic exocrine cells is still a matter of dispute [10]. However, because the absolute number of pancreatitis events was relatively small (2.1 events per 1,000 patient-years), the clinical relevance of such an increased risk of pancreatitis, if confirmed, is limited.…”

Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice

“…Generation of transgenic mice that overexpress GLP-1 receptor Since the expression of GLP1R is restricted to only a proportion of exocrine cells at much lower levels than that in beta cells [23], and Glp1r is expressed in pancreatic endocrine progenitors (Fig. 1a, b) and in newly generated beta cells in embryonic pancreases [24], we hypothesised that increased GLP-1 signalling may be able to induce the reprogramming of pancreatic exocrine cells into beta cells.…”

“…Based on the findings that GLP1R is detected in early endocrine progenitors of NEUROG3-Timer embryos (Fig. 1a, b), newly generated beta cells of Insulin-Timer embryos [24] and in acinar cells of the human adult pancreas [23], we hypothesised that GLP-1 may function in non-beta cells, including acinar and duct cells, and we activated the GLP-1 signalling pathway by the administration of exendin-4, a long-acting GLP1R agonist, and by overexpressing GLP1R in exocrine cells. Whereas in vitro studies have shown that GLP-1 and exendin-4 induce beta cell differentiation in the pancreatic tumour cell line AR42J [7,9], our present study revealed that exendin-4 itself fails to initiate beta cell neogenesis in SOX9-lineage exocrine cells in vivo, even after the overexpression of GLP1R (Fig.…”