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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 [...]

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic β-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with non-carriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic [3-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed. Diabetes 53 (Suppl. 1):S103-S109, 2004, Diabetes a is collection of diseases characterized by the presence of chronic hyperglycemia. Maintenance of normal glucose homeostasis involves the action of a glucose sensor in the pancreatic β-cell that [...]

IGFs are important regulators of pancreatic β-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI., IGFs are regulators of processes like growth and metabolism (1-3). IGF-I and IGF-II also contribute to pancreatic β-cell growth and development by regulating β-cell replication, renewal, and apoptosis (4,5). Deregulation [...]

An association between type 2 diabetes and genetic variation in the KIR6.2 gene has been reported in several populations. Based on in vitro studies with cell lines expressing the [Glu.sup.23]Lys (E23K) mutation, it was recently suggested that this mutation might result in altered insulin secretion. We have examined glucose-stimulated insulin secretion in relation to this KIR6.2 gene variant in two independent Dutch cohorts. Subjects with normal (n = 65) or impaired (n = 94) glucose tolerance underwent 3-h hyperglycemic clamps at 10 mmol/l glucose. We did not observe significant differences in first- or second-phase insulin secretion between carriers and noncarriers of the gene variant in either of the study populations (all P > 0.45). Furthermore, we found no evidence for a significant interaction with disease-associated gene variants in the sulfonylurea receptor (SUR1) gene. We conclude that the E23K mutation in the KIR6.2 gene is not associated with detectable alterations in glucose-stimulated insulin secretion in two independent populations from the Netherlands., The ATP-sensitive [K.sup.+] channel in the β-cell is an important regulator of insulin secretion. The channel is composed of two subunits in a heterooctomeric complex of four sulfonylurea receptor (SUR1) [...]

Associations between type 2 diabetes (and/or parameters contributing to glucose homeostasis) and genetic variation in the genes encoding insulin receptor substrate (IRS)-1 and -2 have been reported in several populations. [...]

We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) [tRNA.sup.Leu(UUR)] gene in a large family with non-insulin-dependent diabetes mellitus (NIDDM). Characteristic [...]

Like insulin, exposure of 3T3-L1 adipocytes to arsenite leads to a time-and dose-dependent translocation of GLUT4 to the plasma-membrane, as well as a time- and dose-dependent stimulation of glucose uptake. [...]

The polypeptide growth factors insulin and EGF strongly stimulate c-jun transcription in the NIH3T3-derived cell line A14 via a process strictly dependent on the presence of two cJun/ATF2 binding sites [...]