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This version published online on April 4, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2323
A more recent version of this article appeared on June 1, 2006
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Submitted on October 21, 2005
Accepted on March 29, 2006

The E23K variant of KCNJ11 encoding the pancreatic {beta}-cell KATP channel subunits Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes

Giorgio Sesti MD*, Emanuela Laratta BS, Marina Cardellini MD, Francesco Andreozzi MD, Silvia Del Guerra BS, Concetta Irace MD, PhD, Agostino Gnasso MD, Maria Grupillo BS, Renato Lauro MD, Marta Letizia Hribal PhD, Francesco Perticone MD, and Piero Marchetti MD

Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy (GS,EL,FA,CI,AG,MLH,FP); Department of Internal Medicine, University of Rome-Tor Vergata 00133 Rome, Italy (MC,MLH,RL); Department of Endocrinology and Metabolism, Metabolic Unit, Cisanello Hospital, Pisa, Italy (SDG,MG,PM)

* To whom correspondence should be addressed. E-mail: sesti{at}unicz.it.

Context Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy, however conclusive evidences are still lacking.

Objective To investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure.

Design Secondary sulfonylurea failure was defined as fasting plasma glucose >300 mg/dl despite sulfonylurea-metformin combined therapy, appropriate diet, in the absence of other conditions causing hyperglycemia.

Setting Ambulatory care

Patients 525 Caucasian type 2 diabetic patients.

Intervention Sulfonylurea treatment followed by sulfonylurea-metformin combined therapy and then insulin treatment.

Main outcome measure Secondary failure

Results Of the total diabetic patients, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58% and 66.8% among patients treated with oral therapy or with secondary sulfonylurea failure respectively (OR=1.45, 95% CI 1.01-2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (OR=1.69, 95% CI 1.02-2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). Following 24 h exposure to high (16.7 mmol/l) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant.

Conclusions These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas thus representing an example of pharmacogenetics in type 2 diabetes.
Key words: secondary failure • Kir6.2 variant • type 2 diabetes




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