OBJECTIVE-Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.RESULTS-In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06 -1.20], P ϭ 9 ϫ 10 Ϫ5 ). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P ϭ 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P ϭ 1 ϫ 10 Ϫ12 ) and obesity (1.27 [1.20 -1.34], P ϭ 2 ϫ 10 Ϫ16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P ϭ 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 Ϯ 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.CONCLUSIONS-We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation. Diabetes 57:95-101, 2008 W orldwide incidence of obesity has increased dramatically and is today one of the leading causes of lifestyle-related disorders such as type 2 diabetes and premature cardiovascular disease. Association between common forms of obesity and genes such as GAD2 (1), ENPP1 (2), and INSIG2 (3) have been reported but difficult to validate (4 -6). Recently, variation in the fat mass and obesity-associated (FTO) gene was reported to associate with type 2 diabetes and increased fat mass. As a part of the Wellcome Trust Case Control Consortium genome-wide association study, which included 1,924 U.K. type 2 diabetic patients and 2,938 U.K. normoglycemic control subjects, an FTO variant (rs9939609) was found to associate with type 2 diabetes; however, this association abolished following adjustment for BMI (7). Subsequently, an association with overweight and obesity was demonstrated in seven population-based study samples comprising a total of 19,424 white European adults and two birth cohorts including 10,172 white European children. Moreover, evidence was presented that the increase in BMI resulted from an overall increase in body fat, evaluated by waist circumference and fat mass estimates, including skinfold measures (7).In another independent study, the effect of 48 neutral single-nucleotide polymorphisms (SNPs) on obesity was tested in 2,900 obese and 5,100 control subjects of European ancestry, and the FTO rs1121980 polymorphism, also ...

Aims/hypothesis We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. Methods We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. Results Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p<0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p<0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p=0.03) and GIP (p=0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele Diabetologia (2009) 52:1298-1307 DOI 10.1007/s00125-009-1307-x Electronic supplementary

OBJECTIVE Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS We examined European-descent participants in the Inter99 study ( n = 5,553), in a sample of young healthy Danes ( n = 372), in Danish twins ( n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients ( n = 1,626) and control subjects ( n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study ( n = 4,656), in the North Finland Birth Cohort 86 ( n = 5,258), and in the Haguenau study ( n = 1,461). RESULTS The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 × 10 −31 ) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 × 10 −11 ) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges ( P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance ( P = 0.017). CONCLUSIONS The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of β-cell dysfunction and hepatic insulin resistance.

The rs7903146 T-allele associates with hepatic insulin resistance and diminished glucose-stimulated plasma insulin secretion. Our study does not provide evidence of a role of TCF7L2 gene expression in sc fat tissue and muscle tissue in the regulation of glucose homeostasis. This suggests that the primary defect of rs7903146 T-allele carriers is impairment of insulin secretion rather than a defect in insulin action in peripheral tissues.

Our data indicate that the minor G-allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.