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 unrelatedCaucasian 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 Ϫ 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 Ͼ300 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 ϭ 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferatoractivated receptor-␥2 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 ϭ 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. Diabetes Care 27:1394 -1398, 2004T ype 2 diabetes is a progressive disorder, and maintenance of good metabolic control has been demonstrated to reduce the risk of its associated long-term vascular complications and a delay in their onset (1). It has been estimated that each year 5-7% of diabetic patients treated with sulfonylurea convert to insulin treatment progressively as sulfonylurea fails (2,3). This clinical phenomenon has been termed secondary failure to sulfonylurea. Secondary failure to sulfonylurea has been variably attributed to change in body weight, lack of adequate diet regimen, young age at diagnosis, deterioration of insulin sensitivity or presence of anti-islet cell and anti-GAD antibodies (3,4). However, the U.K. Prospective Diabetes Study has demonstrated that the progressive deterioration of glycemic control in type 2 diabetic patients was associated with declining of pancreatic ␤-cell function despite either conventional treatment with dietary modification or intensive monotherapy treatment (1,3). A progressive deterioration of insulin secretion has been confirmed in smaller studies, and ␤-cell homeostatic model assessment has been demonstrated to be a better predictor of the insulinrequiring stage in type 2 diabetes than clinical indexes such as duration of di...