Search

OBJECTIVE--Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of [beta]-cell function. RESEARCH DESIGN AND METHODS--For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/ CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B. RESULTS--Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 x [10.sup.-3]). The THADA gene variant was associated with lower [beta]-cell response to GLP-1 and arginine (both P < 1.6 x [10.sup.-3]), suggesting lower [beta]-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNRIB (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with [beta]-cell function. CONCLUSIONS--Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of [beta]-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic [beta]-cells., Genome-wide association (GWA) studies have revealed a large number of novel type 2 diabetes susceptibility loci (1-4). Most of the genes identified during the first wave of GWA study results [...]

OBJECTIVE--At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS--A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS--The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x [10.sup.-6]). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x [10.sup.-3]). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different. CONCLUSIONS--A combined risk allele score for eight known β-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci., Type 2 diabetes is a polygenic disease in which the contribution of a number of detrimental gene variants in combination with environmental factors is thought to be necessary for the [...]

Previously, we have shown that a mutation in the mitochondrial DNA--encoded tRN[A.sup.Leu(UUR)] gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRN[A.sup.Leu(UUR)] In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRN[A.sup.Leu(UUR)], associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis., Previously, we have shown that an A3243G mutation in the mitochondrial DNA-encoded tRN[A.sup.Leu(UUR)] gene is associated with maternally inherited diabetes and deafness (1,2). Carriers of the 3243 mutation have a [...]

Background: Gene-nutrient interactions affecting hepatic lipase (HL) activity may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Objective: We determined the associations of dietary fat intake with postheparin HL activity and the possible modifying effect of the HL -480C [right arrow] T polymorphism on these associations. Design: Subjects were recruited from participants in the 2000-2001 follow-up examination of the Hoorn Study. HL activity was determined in postheparin plasma in a sample of 211 men and 218 women aged 60-87 y. Information about dietary intake of the participants was obtained with a validated food-frequency questionnaire. Linear regression was performed, adjusted for age. Results: Total dietary fat was positively associated with HL activity (standardized [beta]: 0.11; 95% CI: 0.02, 0.21), and this association was also seen for saturated fat (0.10; 0.01, 0.20) and monounsaturated fatty acid (0.10; 0.01, 0.19). We observed a significant interaction of the HL polymorphism with the relation between total fat intake and HL activity. The association of total fat with HL activity was stronger in subjects with CT (0.27; 0.11, 0.43) and TT (0.39; -0.22, 1.00) genotypes than in subjects with the CC genotype (0.06; -0.06, 0.18; P for interaction < 0.10). The interaction remained statistically significant in models that included age, sex, carbohydrate and protein intakes, and insulin or body mass index. Conclusions: Higher intakes of total and saturated fat were positively associated with higher HL activity. In addition, the observed association of total fat with HL activity was modified by the HL-480C [right arrow] T polymorphism, after adjustment for age, sex, carbohydrate and protein intakes, and insulin or body mass index. KEY WORDS Hepatic lipase, gene-nutrient interaction, fat intake