The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. Objective: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at incre...

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Published in:The journal of clinical endocrinology and metabolism 2006-06, Vol.91 (6), p.2334-2339
Main Authors: Sesti, Giorgio, Laratta, Emanuela, Cardellini, Marina, Andreozzi, Francesco, Del Guerra, Silvia, Irace, Concetta, Gnasso, Agostino, Grupillo, Maria, Lauro, Renato, Hribal, Marta Letizia, Perticone, Francesco, Marchetti, Piero
Format: Article
Language:English
Subjects:
Adult
Aged
Biological and medical sciences
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Female
Fundamental and applied biological sciences. Psychology
Genetic Variation
Humans
Hypoglycemic Agents - therapeutic use
Male
Medical sciences
Middle Aged
Potassium Channels, Inwardly Rectifying - genetics
Sulfonylurea Compounds - therapeutic use
Treatment Failure
Vertebrates: endocrinology
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Summary:Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. Objective: The objective of the study was 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 greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia. Setting: The study was conducted in an ambulatory care facility. Patients: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study. Intervention: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment. Main Outcome Measure: Secondary failure was the main outcome measure. Results: Of the diabetic patients enrolled in the study, 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 secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 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 (odds ratio, 1.69; 95% confidence interval, 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). After 24-h exposure to high (16.7 mmol/liter) 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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2005-2323