Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes.
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.
Xu
Gang
G
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Kaneto
Hideaki
H
Laybutt
D Ross
DR
Duvivier-Kali
Valerie F
VF
Trivedi
Nitin
N
Suzuma
Kiyoshi
K
King
George L
GL
Weir
Gordon C
GC
Bonner-Weir
Susan
S
D000818:Animals; D018929:Cell Culture Techniques; D015536:Down-Regulation; D000067757:Glucagon-Like Peptide-1 Receptor; D015309:Glucose Clamp Technique; D006943:Hyperglycemia / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D010180:Pancreatectomy; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*; D018027:Receptors, Glucagon / Q000235:genetics*
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007527:Isoenzymes; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C041086:gastric inhibitory polypeptide receptor; D011493:Protein Kinase C