title: A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance.
abstract: BACKGROUND
  The voltage-gated potassium channel Kv1.3 (KCNA3) is 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.
  
  
  METHODS
  We conducted a genotype-phenotype association study at a university hospital.
  
  
  METHODS
  In 50 nondiabetic subjects, we screened approximately 4.5 kb of chromosome 1 comprising the single exon, 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.
  
  
  METHODS
  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 (P = 0.002). 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.
authors.affiliation: Medizinische Universitätsklinik, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Tschritter
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Silke
authors.initials: S
authors.lastname: Schäfer
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Christian
authors.initials: C
authors.lastname: Spieth
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D020413:3' Untranslated Regions / Q000737:chemistry / Q000235:genetics; D020121:5' Untranslated Regions / Q000737:chemistry / Q000235:genetics; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000235:genetics* / Q000502:physiology; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D017422:Sequence Analysis, DNA
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D001786:Blood Glucose; D051664:Kv1.3 Potassium Channel; D004247:DNA