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Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

The article presents a study that aimed to identify factors that influenced postpartum oral glucose tolerance test (OGTT) rates. The study found that prepartum counselling and a diagnosis of polycystic ovarian syndrome were the strongest predictors of adherence to postpartum diabetes screening. It also revealed the importance of considering health care delivery when developing strategies to increase the screening rates of OGTT.

OBJECTIVE -- To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients. RESEARCH DESIGN AND METHODS -- After preliminary testing, 11 male patients d (24 ± 2 years, HbA1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg-1 BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg-1 BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucosemonitoring system. RESULTS -- All glycemic responses were similar across conditions up to 60 min postexercise. d After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50%(50%[10.4 ± 1.2] vs. Full [6.2±0.7] and 75% [7.6 ± 1.2 mmol ⋅ L ], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50%(blood glucose#3.9; Full, n =5 ;7 5%, n =2 ;5 0%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions. CONCLUSIONS -- A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia. [ABSTRACT FROM AUTHOR]

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

OBJECTIVE-- Type 2 diabetes is characterized by impaired pancreatic β-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of β-cell function and whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS-- A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of β-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/ phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center. RESULTS-- CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic β-cell glucose sensitivity (P = 9.86 x 10 -5 and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity. CONCLUSIONS-- CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic β-cell function, including decreased β-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity. Diabetes 56: 3101-3104, 2007 [ABSTRACT FROM AUTHOR]

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001). Diabetes 56:879-883, 2007 [ABSTRACT FROM AUTHOR]

A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (∼20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. Methods and Findings Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. Conclusions Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases. [ABSTRACT FROM AUTHOR]

Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10-11). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10-5) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is ∼16%. The overall evidence for association for these variants (P = 4.4 x 10-14 combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance. Diabetes 55:2640-2644, 2006 [ABSTRACT FROM AUTHOR]

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits. Diabetes 55:2541-2548, 2006 [ABSTRACT FROM AUTHOR]

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at -23HphI (odds ratio [OR] 0.42 [95% CI 0.31-0.58], P = 2.4 X 10-8), A allele at +1,404Fnu4HI (0.50 [0.36-0.70], P = 3.2 x 10-5), and C allele at +3,580MspI (0.55 [0.35-0.85], P = 0.0046). As with type 1 diabetes, the -23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA. [ABSTRACT FROM AUTHOR]

Background: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. Methods: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. Results: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. Conclusion: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study. [ABSTRACT FROM AUTHOR]

The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44]) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q. [ABSTRACT FROM AUTHOR]

Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes. [ABSTRACT FROM AUTHOR]

The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The A allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (<1%) AA homozygotes had a raised BMI in each cohort; this was significant when all cohorts were combined (Z score = 0.67 AA vs. -0.05 G/x, P = 0.02). There was no association with corrected birth weight in 382 normal babies, but the only AA baby was 4,069 g. Our study suggests that genetic variation in SHP is unlikely to be common in the predisposition to diabetes, obesity, or increased birth weight in U.K. Caucasians. [ABSTRACT FROM AUTHOR]

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles. [ABSTRACT FROM AUTHOR]

For any mitochondrial DNA (mtDNA) mutation, the ratio of mutant to wild-type mtDNA (% heteroplasmy) varies across tissues, with low levels in leukocytes and high levels in postmitotic tissues (e.g., skeletal muscle). Direct sequencing is the gold-standard method used to detect novel mutations, but can only reliably detect % heteroplasmy >25%, which is rare in leukocytes. Therefore, we investigated the role of mtDNA defects in maternally inherited diabetes by first screening for the A3243G tRNA(Leu(UUR)) mutation by restriction assay, followed by sequencing of the entire mitochondrial genome using skeletal muscle derived mtDNA. A total of 28 patients had maternally inherited diabetes either alone (group 1, n = 17) or with one or more additional features of mitochondrial disease, including bilateral sensori-neural deafness and neuromuscular disease (group 2, n = 11). Three patients (all from group 2) carried the A3243G mutation. Skeletal muscle mtDNA from eight group 1 patients and six more group 2 patients was sequenced. No pathogenic mutations were found in the group 1 patients, while two patients from group 2 had mutations at positions 12258 and 14709 in the tRNA serine and glutamic acid genes, respectively. We conclude, therefore, that screening for mtDNA mutations should be considered in patients with maternally inherited diabetes, but only when additional features of mitochondrial disease are present. [ABSTRACT FROM AUTHOR]

The article focuses on a study which assessed whether the m.3243A>G mitochondrial DNA mutation is a suitable screening strategy for patients with deafness and diabetes. Definition of diabetes according to the World Health Organization criteria and the clinical definition of deafness are given. It recommends that patients with the combination of deafness and diabetes be screened for the m.3243A>G mutation. Urine screening is preferred compared to buccal mucosa or blood screening.

Provides information on a study which investigated the relation between the imbalances of maternal and paternal transmission of type 2 diabetes varies by ethnic group. Family history of maternal and paternal diabetes by ethnic group among Europeans and South Asians; Possible explanations for excess maternal diabetes.

The BAIR consortium has been formed to provide insight into the biological processes underlying insulin resistance through multidisciplinary research combining various genomic/proteomic/metabolomic approaches in animal models, followed by haman genetic analysis. Based on previously described associations, function and on BAIR biological data, we selected 11 candidate genes (ARNT; RBP4; HIF1a; EIF2S1; AKT1; ONECUT1; RPS6KB1; TRB3; FOXA2; PCK1; FOXO3A) for investigation. Pairwise tags (r²>0.8) spanning these genes were selected based on HapMap phase II CEU data to exhaustively capture common variation (MAF>0.05). 103 SNPs were genotyped in 5,602 samples (935 UKT2D, 1927 UK-controls, 926 French T2D, 934 French obese and 880 French controls) by iPLEX & SNPlex methods. Single-point analyses on 92 SNPs were carried out after stringent quality control. Coverage of common variation remained high (74%-100% per gene). There was no significant association with T2D or obesity (at the p=0.01 level) in 9 of the strong candidate genes examined. In the UK population, rs11908628 of PCK1 (encoding phosphoenolpyruvate carboxykinase 1, the main control point for the regulation of gluconeogenesis) was found to be protective against diabetes (MAFs 2.7% v 4.3%, OR(95%CIs): 0.62 (0.44-0.86); p=0.003 additive). Mantel-Haenszel meta-analysis of rs11908628 across the UK and French T2D samples provided additional support for this finding (p=0.002), although further investigation, given low MAFs, is warranted. When comparing genotypes between T2D cases and controls in the French population, 2 independent associations were seen in RPS6KB1: rs180535 (MAFs 18% v 15%; OR 1.29 (1.07 -1.55); p=0.006) and rs180531 (24% v 28%; OR 0.81 (0.69-0.95) p=0.008) (r²=0.06 in controls). RPS6KB1 codes for ribosomal protein S6 kinase 70KD 1, which negatively regulates insulin signalling. Interestingly, rs180531 (23% v 28%; OR 0.80 (0.69-0.94) p=0.005) was also associated with protection against obesity in the French. In conclusion, our genetic data suggest modest effects of the BAIR insulin resistance candidates PEPCK and S6K1 gene variation in UK (T2D) and French (T2D and obese) samples, results that require replication in additional populations. [ABSTRACT FROM AUTHOR]