A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance.
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.
Tschritter
Otto
O
Medizinische Universitätsklinik, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
Machicao
Fausto
F
Stefan
Norbert
N
Schäfer
Silke
S
Weigert
Cora
C
Staiger
Harald
H
Spieth
Christian
C
Häring
Hans-Ulrich
HU
Fritsche
Andreas
A
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
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D001786:Blood Glucose; D051664:Kv1.3 Potassium Channel; D004247:DNA