Format

Send to

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2006 Feb;91(2):654-8. Epub 2005 Nov 29.

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

Author information

  • 1Medizinische Universitätsklinik, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.

Abstract

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.

[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon
    Loading ...
    Write to the Help Desk