Publications
Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes
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)alpha overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKCalpha 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.
Type | Journal |
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ISBN | 1939-327X (Electronic) |
Authors | Xu, G.;Kaneto, H.;Laybutt, D. R.;Duvivier-Kali, V. F.;Trivedi, N.;Suzuma, K.;King, G. L.;Weir, G. C.;Bonner-Weir, S. : |
Responsible Garvan Author | Associate Professor Ross Laybutt |
Publisher Name | DIABETES |
Published Date | 2007-01-01 |
Published Volume | 56 |
Published Issue | 6 |
Published Pages | 1551-8 |
Status | Published in-print |
URL link to publisher's version | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17360984 |
OpenAccess link to author's accepted manuscript version | https://publications.gimr.garvan.org.au/open-access/2306 |