Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia

Abstract

Stimulation of insulin secretion by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) has been found to be diminished in type 2 diabetes. We hypothesized that this impairment is due to a defect at the receptor level induced by the diabetic state, particularly hyperglycemia. Gene expression of incretin receptors, GLP-1R and GIPR, were significantly decreased in islets of 90% pancreatectomized (Px) hyperglycemic rats, with recovery when glucose levels were normalized by phlorizin. Perifused islets isolated from hyperglycemic Px rats showed reduced insulin responses to GLP-1 and GIP. To examine the acute effect of hyperglycemia on incretin receptor expression, a hyperglycemic clamp study was performed for 96 h with reduction of GLP-1 receptor expression but increase in GIP receptor expression. Similar findings were found when islets were cultured at high glucose concentrations for 48 h. The reduction of GLP-1 receptor expression by high glucose was prevented by dominant-negative protein kinase C (PKC)␣ overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKC␣ overexpression. Taken together, GLP-1 and GIP receptor expression is decreased with chronic hyperglycemia, and this decrease likely contributes to the impaired incretin effects found in diabetes. Diabetes

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…Finally, our mRNA expression studies suggest altered incretin signalling in ZF-Px islets, since the expression of Glp1r, Gipr and Ffral1 (also known as Gpr40) was reduced. Reduced mRNA expression and protein content of the GLP-1 receptor has been observed in islets of ZDF and 90% pancreatectomised diabetic rats [44]. Altered incretin signalling is thought to contribute to beta cell dysfunction and the current data are consistent with this view, at least with respect to the in vivo situation.…”

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

“…One possible explanation for the decrease in exenatide-induced insulin release during 7-day culture with elevated glucose is downregulation of the GLP-1 receptors on beta cells [45]. Furthermore, 7-day exenatide-treated islets had comparable basal insulin release but a greater insulin response to elevated glucose following incubation in exenatide-free buffer and had a higher insulin content.…”

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

“…It has been demonstrated that the effect of GIP in stimulating insulin secretion is impaired in type 2 diabetes (Vilsboll et al, 2002). The reason for this has recently been suggested to be secondary to hyperglycemia as demonstrated experimentally both in vivo (Xu et al, 2007) and in vitro (Zhou et al, 2007).…”