Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion

Abstract

Aims/hypothesis G protein-coupled receptor 40 (GPR40) is abundantly expressed in pancreatic beta cells in rodents, where it facilitates glucose-induced insulin secretion in response to mid-to long-chain fatty acids in vitro. However, GPR40 gene expression in humans has not been fully investigated, and little is known about the physiological and pathophysiological roles of GPR40 in humans. The aim of this study, therefore, was to examine GPR40 expression and its clinical implications in humans. Methods: GPR40 mRNA expression in the human pancreas, pancreatic islets and islet cell tumours was analysed using TaqMan PCR. Results: GPR40 mRNA was detected in all human pancreases collected intraoperatively. It was enriched approximately 20-fold in isolated islets freshly prepared from the pancreases of the same individuals. The estimated mRNA copy number for the GPR40 gene in pancreatic islets was comparable to those for genes encoding sulfonylurea receptor 1, glucagon-like peptide 1 receptor and somatostatin receptors, all of which are known to be expressed abundantly in the human pancreatic islet. A large amount of GPR40 mRNA was detected in insulinoma tissues, whereas mRNA expression was undetectable in glucagonoma or gastrinoma. The GPR40 mRNA level in the pancreas correlated with the insulinogenic index, which reflects beta cell function (r=0.82, p=0.044), but not with glucose levels during the OGTT, the insulin area under the OGTT curve or the index for the homeostasis model assessment of insulin resistance (HOMA-IR). Conclusions/interpretation The present study provides evidence for GPR40 gene expression in pancreatic beta cells and implicates GPR40 in insulin secretion in humans.

Selective Small-Molecule Agonists of G Protein–Coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice

“…GPR40 is a G q -coupled family A GPCR specifically expressed in the pancreatic ␤-cell (46,47). The discovery of its activation by medium-and long-chain FFAs has sparked considerable interest in and experimentation on this receptor, from basic research to potential drug discovery efforts.…”

Fatty Acid Signaling in the β-Cell and Insulin Secretion

“…In one of the first reports, FFAR1 was shown to be highly expressed in rodent pancreatic ␤-cells (10), and its downregulation by RNAi caused impaired FA augmentation of insulin secretion (10). FFAR1 has also been documented to be highly expressed in human ␤-cells (90). Activation of FFAR1 by FFAs causes an increase in intracellular Ca 2ϩ levels, which is believed to be via activation of the G␣q-phospholipase C pathway with release of Ca 2ϩ from the endoplasmic reticulum (91).…”

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…GPR40 is highly expressed in mouse, rat and human pancreatic β cells, and thought to be involved in the regulation of FFA-potentiated glucose-stimulated insulin secretion (Itoh et al, 2003;Salehi et al, 2005;Tomita et al, 2006). In fact, GPR40 has been suggested to mediate the majority of the effects of fatty acids on β cells (Itoh et al, 2003;Salehi et al, 2005).…”