Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia

Possible Contribution to Impaired Incretin Effects in Diabetes

  1. Gang Xu1,
  2. Hideaki Kaneto1,
  3. D. Ross Laybutt12,
  4. Valerie F. Duvivier-Kali1,
  5. Nitin Trivedi1,
  6. Kiyoshi Suzuma3,
  7. George L. King3,
  8. Gordon C. Weir1 and
  9. Susan Bonner-Weir1
  1. 1Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
  2. 2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
  3. 3Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
  1. 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

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)α overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKCα 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db06-1033.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 19, 2007.
    • Received July 25, 2006.
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  1. Published online before print March 14, 2007, doi: 10.2337/db06-1033 Diabetes June 2007 vol. 56 no. 6 1551-1558
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