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.


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.
Sesti
Giorgio
G
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia di Catanzaro-Via Tommaso Campanella, 115 88100 Catanzaro, Italy. sesti@unicz.it
Marini
Maria Alelaide
MA
Cardellini
Marina
M
Sciacqua
Angela
A
Frontoni
Simona
S
Andreozzi
Francesco
F
Irace
Concetta
C
Lauro
Davide
D
Gnasso
Agostino
A
Federici
Massimo
M
Perticone
Francesco
F
Lauro
Renato
R
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001120:Arginine; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D017211:Treatment Failure; D044465:White People
D005819:Genetic Markers; D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D013453:Sulfonylurea Compounds; D001120:Arginine