Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1.
We previously discovered two aminoacid polymorphisms in codons 513 and 972 of the protein insulin receptor substrate-1 (IRS-1), which is important in cellular insulin action. We have investigated whether these polymorphisms are associated with changes in insulin sensitivity in a random sample of young healthy adults. Insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test in 380 unrelated white subjects aged 18-32. IRS-1 polymorphisms were examined by single-strand conformation polymorphism and verified by restriction-enzyme digestion. No homozygous carrier of the codon-513 variant was identified, but one non-obese man had the codon-972 mutation on both alleles. He had low fasting-serum insulin and C-peptide concentrations and low insulin sensitivity and glucose effectiveness. During a 24 h dexamethasone test, he developed transient diabetes. In their heterozygous forms the codon-513 and codon-972 variants of IRS-1 were found in 3% and 9% of the subjects. Non-obese carriers of either polymorphism had similar insulin sensitivity and pancreatic beta-cell function to non-obese wild-type subjects (no known variants of IRS-1). Analysis of variance showed, however, a significant interaction between obesity (body-mass index > or = 25 kg/m2) and the heterozygous form of the codon-972 variant (p < 0.003); obese polymorphism carriers had lower insulin sensitivity than obese non-carriers (mean 6.0 [SD 3.3] vs 12.3 [9.5] x 10(-5) L min-1 pmol-1). The obese carriers of the codon-972 variant were also characterised by a clustering of metabolic cardiovascular risk factors, with raised fasting concentrations of plasma glucose, serum triglyceride, and plasma tissue-plasminogen-activator and its fast-acting inhibitor. With adjustment for known modulators of insulin sensitivity, multivariate analyses showed that the combination of obesity and the codon-972 variant was associated with a 50% reduction in insulin sensitivity (p = 0.0008). Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders.
Clausen
J O
JO
Steno Diabetes Center, Gentofte, Denmark.
Hansen
T
T
Bjørbaek
C
C
Echwald
S M
SM
Urhammer
S A
SA
Rasmussen
S
S
Andersen
C B
CB
Hansen
L
L
Almind
K
K
Winther
K
K
D000293:Adolescent; D000328:Adult; D003062:Codon / Q000235:genetics; D003907:Dexamethasone; D005260:Female; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008297:Male; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D014044:Tolbutamide
D003062:Codon; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D003907:Dexamethasone; D014044:Tolbutamide