【文摘发布】糖尿病患者高血糖引起的GLP-1 与 GIP受体表达下调可能造成其肠降血糖素分泌受损
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Title：Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia: Possible Contribution to Impaired Incretin Effects in Diabetes
Author：Gang Xu, Hideaki Kaneto, D. Ross Laybutt, Valerie F. Duvivier-Kali, Nitin Trivedi, Kiyoshi Suzuma, George L. King, Gordon C. Weir, and Susan Bonner-Weir
Resource: Diabetes 2007 56: 1551 -1558.
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.
PMID: 17360984
Author：Gang Xu, Hideaki Kaneto, D. Ross Laybutt, Valerie F. Duvivier-Kali, Nitin Trivedi, Kiyoshi Suzuma, George L. King, Gordon C. Weir, and Susan Bonner-Weir
Resource: Diabetes 2007 56: 1551 -1558.
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.
PMID: 17360984
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