Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function.
BACKGROUND
Type 2 diabetes arises when insulin resistance-induced compensatory insulin secretion exhausts. Insulin resistance and/or beta-cell dysfunction result from the interaction of environmental factors (high-caloric diet and reduced physical activity) with a predisposing polygenic background. Very recently, genetic variations within four novel genetic loci (SLC30A8, HHEX, EXT2, and LOC387761) were reported to be more frequent in subjects with type 2 diabetes than in healthy controls. However, associations of these variations with insulin resistance and/or beta-cell dysfunction were not assessed.


RESULTS
By genotyping of 921 metabolically characterized German subjects for the reported candidate single nucleotide polymorphisms (SNPs), we show that the major alleles of the SLC30A8 SNP rs13266634 and the HHEX SNP rs7923837 associate with reduced insulin secretion stimulated by orally or intravenously administered glucose, but not with insulin resistance. In contrast, the other reported type 2 diabetes candidate SNPs within the EXT2 and LOC387761 loci did not associate with insulin resistance or beta-cell dysfunction, respectively.


CONCLUSIONS
The HHEX and SLC30A8 genes encode for proteins that were shown to be required for organogenesis of the ventral pancreas and for insulin maturation/storage, respectively. Therefore, the major alleles of type 2 diabetes candidate SNPs within these genetic loci represent crucial alleles for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells towards adverse environmental factors.
Staiger
Harald
H
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Machicao
Fausto
F
Stefan
Norbert
N
Tschritter
Otto
O
Thamer
Claus
C
Kantartzis
Konstantinos
K
Schäfer
Silke A
SA
Kirchhoff
Kerstin
K
Fritsche
Andreas
A
Häring
Hans-Ulrich
HU
D000293:Adolescent; D000328:Adult; D000368:Aged; D001823:Body Composition; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D055815:Young Adult