The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans.
The Gly972Arg polymorphism in the insulin receptor substrate (IRS)-1 was found in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. In the present study, we compared insulin secretion in well-matched normal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of beta-cell function from the oral glucose tolerance test were significantly lower in X/Arg (n = 31) compared with Gly/Gly (n = 181) (P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clamp, insulin secretion rates were significantly lower in Gly/Arg (n = 8) compared with Gly/Gly (n = 36) during the first phase (1,711+/-142 vs. 3,014+/-328 pmol/min, P = 0.05) and after maximal stimulation with arginine (5,340+/-639 vs. 9,075+/-722 pmol/min, P = 0.03). In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. It is possible that this polymorphism causes insulin resistance at the level of the beta-cell and contributes to the polygenic etiology of type 2 diabetes.
Stumvoll
M
M
Medical Clinic, Department of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Germany. Michael.Stumvoll@med.uni-tuebingen.de
Fritsche
A
A
Volk
A
A
Stefan
N
N
Madaus
A
A
Maerker
E
E
Teigeler
A
A
Koch
M
M
Machicao
F
F
Häring
H
H
D001120:Arginine / Q000494:pharmacology; D014644:Genetic Variation / Q000502:physiology*; D005947:Glucose / Q000502:physiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D012016:Reference Values
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D001120:Arginine; D005947:Glucose