A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance

J Clin Endocrinol Metab. 2006 Feb;91(2):654-8. doi: 10.1210/jc.2005-0725. Epub 2005 Nov 29.


Context: 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.

Design and setting: We conducted a genotype-phenotype association study at a university hospital.

Participants and 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.

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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / chemistry
  • 3' Untranslated Regions / genetics
  • 5' Untranslated Regions / chemistry
  • 5' Untranslated Regions / genetics
  • Adult
  • Blood Glucose / metabolism
  • DNA / chemistry
  • DNA / genetics
  • Electrophoretic Mobility Shift Assay
  • Female
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / physiopathology
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance / genetics*
  • Insulin Resistance / physiology
  • Kv1.3 Potassium Channel / genetics*
  • Kv1.3 Potassium Channel / physiology
  • Male
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology
  • Sequence Analysis, DNA


  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • Blood Glucose
  • Kv1.3 Potassium Channel
  • DNA