The Arg972 variant in insulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes

OBJECTIVE: The aim of this study was to investigate whether diabetic patients carrying the Arg(972) insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS: A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD(-) antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose >300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia. RESULTS: Of the total patients, 53 (11.1%) were heterozygous for the Arg(972) IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18-3.70], P = 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38-3.86], P = 0.038). CONCLUSIONS: These data demonstrate that the Arg(972) IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes.