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 |
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Rok vydání: | 2006 |
Předmět: |
Adult
Blood Glucose Male medicine.medical_specialty Candidate gene Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry Electrophoretic Mobility Shift Assay Type 2 diabetes Biology Polymerase Chain Reaction Polymorphism Single Nucleotide Biochemistry Impaired glucose tolerance Endocrinology Insulin resistance Internal medicine Glucose Intolerance medicine Humans Glucose homeostasis Promoter Regions Genetic 3' Untranslated Regions Glucose tolerance test Kv1.3 Potassium Channel medicine.diagnostic_test Insulin Biochemistry (medical) DNA Sequence Analysis DNA Glucose Tolerance Test medicine.disease Postprandial Female Insulin Resistance 5' Untranslated Regions |
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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