Pleiotropic Effects of GIP on Islet Function Involve Osteopontin

Abstract

OBJECTIVEThe incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function.RESEARCH DESIGN AND METHODSAssociations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation.RESULTSThe A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells.CONCLUSIONSThese findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals

“…First, the associations of QPCTL with 2 h glucose and blood lipids are in agreement with other studies [27][28][29][30][31]. The QPCTL locus harbours the GIPR gene, identified in GWASs for 2 h glucose [27][28][29], which encodes a protein involved in insulin secretion and beta cell function [27][28][29].…”

Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

“…During perfusion with low levels of glucose (1.5 mmol/L), GIP had stimulatory and GLP-1 had inhibitory effects on glucagon secretion (16). The glucagonotropic effect of GIP is presumed to be mediated by activation of GIP receptors present on pancreatic a-cells (17,18). The glucagon inhibitory effects of GLP-1 have been attributed to paracrine inhibitory signaling (somatostatin) from neighboring d-cells (16) or-more controversially-direct effects via GLP-1 receptors present on a-cells (1,19).…”

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

“…Immunocytochemistry and microscopy Islets were treated as previously described [24] and incubated overnight at 4°C with anti-Ca v 1.3 (17 μg/ml, Cat. no.…”