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Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia

Possible Contribution to Impaired Incretin Effects in Diabetes

¹ Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
² Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
³ Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Susan Bonner-Weir, PhD, Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215. E-mail: susan.bonner-weir{at}joslin.harvard.edu

Abbreviations: Ad-GFP, adenovirus-expressing green fluorescent protein; cAMP, cyclic AMP; DN-PKC, dominant-negative PKC; dNTP, deoxynucleotide triphosphate; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GSIS, glucose-stimulated insulin secretion; TPA, 12-O-tetradecanoylphorbol-13-acetate

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.

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