Polymorphisms within Novel Risk Loci for Type 2 Diabetes Determine β-Cell Function

• Published in: PloS one Vol. 2; no. 9; p. e832
• Main Authors: Staiger, Harald, Machicao, Fausto, Stefan, Norbert, Tschritter, Otto, Thamer, Claus, Kantartzis, Konstantinos, Schäfer, Silke A., Kirchhoff, Kerstin, Fritsche, Andreas, Häring, Hans-Ulrich
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.09.2007; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Alleles; Body Composition; Body fat; Cloning; Deoxyribonucleic acid; Diabetes; Diabetes and Endocrinology; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; DNA; Drug dosages; Endocrinology; Environmental factors; Exhausts; Genetic diversity; Genetic Predisposition to Disease; Genetic testing; Genetics and Genomics/Genetics of Disease; Genomes; Genotyping; Glucose; Glucose Tolerance Test; Health risks; Humans; Insulin; Insulin resistance; Insulin secretion; Internal medicine; Islets of Langerhans - physiopathology; Loci; Medicine; Middle Aged; Nephrology; Organogenesis; Pancreas; Physical activity; Plasma; Polymorphism, Genetic; Proteins; Secretion; Single-nucleotide polymorphism; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000832

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. 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. 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.