A New Variant in the Human Kv1.3 Gene Is Associated with Low Insulin Sensitivity and Impaired Glucose Tolerance

Autor: Norbert Stefan, Otto Tschritter, Fausto Machicao, Christian Spieth, Harald Staiger, Hans-Ulrich Häring, Andreas Fritsche, Cora Weigert, Silke A. Schäfer
Rok vydání: 2006
Předmět:
Zdroj: The Journal of Clinical Endocrinology & Metabolism. 91:654-658
ISSN: 1945-7197
0021-972X
DOI: 10.1210/jc.2005-0725
Popis: Context: The voltage-gated potassium channel Kv1.3 (KCNA3 )i s expressed in a variety of tissues including liver and skeletal muscle. In animal models, knockout of Kv1.3 has been found to improve insulin sensitivity and glucose tolerance. Objective: We examined whether mutations in the Kv1.3 gene exist in humans and whether they are associated with alterations of glucose homeostasis. Design and Setting: We conducted a genotype-phenotype association study at a university hospital. ParticipantsandMethods:In50nondiabeticsubjects,wescreened approximately4.5kbofchromosome1comprisingthesingleexon,the promoter/5-untranslated region, and the 3-untranslated region of the human Kv1.3 gene for mutations by direct sequencing. Subsequently, all identified single-nucleotide polymorphisms were analyzed in 552 nondiabetic subjects who underwent an oral glucose tolerance test (OGTT). Of these, 304 had undergone an additional hyperinsulinemic euglycemic clamp. Main Outcome Measures: We assessed postprandial blood glucose during OGTT and insulin sensitivity measured by hyperinsulinemic euglycemic clamp. Results: We identified five single-nucleotide polymorphisms in the promoter region (T-548C, G-697T, A-845G, T-1645C, and G-2069A) with allelic frequencies of the minor allele of 26, 23, 9, 41, and 16%, respectively. The 1645C allele was associated with higher plasma glucose concentrations in the 2-h OGTT (P 0.03) even after adjustment for sex, age, and body mass index (P0.002). In addition, it was associated with lower insulin sensitivity (P 0.01, adjusted for sex, age, and body mass index). Functional in vitro analysis using EMSA showed differential transcription factor binding to the T-1645C polymorphism. Conclusions: We show that a variant in the promoter of the Kv1.3 gene is associated with impaired glucose tolerance and lower insulin sensitivity. Therefore, the Kv1.3 channel represents a candidate gene for type 2 diabetes. (J Clin Endocrinol Metab 91: 654–658, 2006)
Databáze: OpenAIRE
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