Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

• Published in: PloS one 2009-09, Vol.4 (9), p.e7236-e7236
• Main Authors: Boesgaard, Trine Welløv, Gjesing, Anette Prior, Grarup, Niels, Rutanen, Jarno, Jansson, Per-Anders, Hribal, Marta Letizia, Sesti, Giorgio, Fritsche, Andreas, Stefan, Norbert, Staiger, Harald, Häring, Hans, Smith, Ulf, Laakso, Markku, Pedersen, Oluf, Hansen, Torben
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAMTS9 Protein; Adult; Alleles; Analysis; Beta cells; Caenorhabditis elegans; Clinical medicine; Clinical trials; Consortia; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetics; Endocrinology; Ethics; Fasting; Female; Genetic Variation; Genetics and Genomics; Genetics and Genomics/Complex Traits; Genetics and Genomics/Genetics of Disease; Genome-Wide Association Study; Genomes; Genomics; Glucose; Glucose metabolism; Glucose Tolerance Test; Health risks; Hospitals; Humans; Hypertension; Insulin; Insulin - metabolism; Insulin Resistance; Insulin-Secreting Cells - metabolism; Internal medicine; Intravenous administration; Laboratories; Male; MEDICAL AND HEALTH SCIENCES; Medical research; MEDICIN OCH HÄLSOVETENSKAP; Medicine; Meta-analysis; Middle Aged; Mutation; Nephrology; Offspring; Oral administration; Pancreas; Patients; Population genetics; Rodents; Science; Sensitivity; Sensitivity and Specificity; Smooth muscle; Studies; Tissues; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007236

A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.