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Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

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.

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.

In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polymorphisms, of which 393 have not been reported previously. These 393 mutations are both very rare and estimated to be caused by very recent mutations but individuals with type 2 diabetes do not possess more of these variants. Population genetics analysis using Bayesian skyline plot shows a recent history of rapid population growth in the Danish population in accordance with the fact that >40% of variable sites are observed as singletons.

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

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.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by autoantibodies against insulin producing pancreatic beta cells and initial lack of need for insulin treatment. The aim of the present study was to investigate if individuals with LADA have an altered gut microbiota relative to non-diabetic control subjects, individuals with type 1 diabetes (T1D), and individuals with type 2 diabetes (T2D). Bacterial community profiling was performed with primers targeting the variable region 4 of the 16S rRNA gene and sequenced. Amplicon sequence variants (ASVs) were generated with DADA2 and annotated to the SILVA database. The gut virome was sequenced, using a viral particle enrichment and metagenomics approach, assembled, and quantified to describe the composition of the viral community. Comparison of the bacterial alpha- and beta-diversity measures revealed that the gut bacteriome of individuals with LADA resembled that of individuals with T2D. Yet, specific genera were found to differ in abundance in individuals with LADA compared with T1D and T2D, indicating that LADA has unique taxonomical features. The virome composition reflected the stability of the most dominant order Caudovirales and the families Siphoviridae, Podoviridae, and Inoviridae, and the dominant family Microviridae. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.

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.

Background: Based on the association of common GLIS3 variants with various forms of diabetes and the biological role of GLIS3 in beta-cells, we sequenced GLIS3 in non-diabetic and diabetic Danes to investigate the effect of rare missense variants on glucose metabolism. Methods: We sequenced 53 patients with maturity-onset diabetes of the young (MODY), 5,726 non-diabetic participants, 2,930 patients with newly diagnosed type 2 diabetes and 206 patients with glutamic acid decarboxylase antibody (GADA) -positive diabetes. Results: In total we identified 86 rare (minor allele frequency < 0.1%) missense variants. None was considered causal for the presence of MODY. Among patients with type 2 diabetes, we observed a higher prevalence of rare GLIS3 missense variants (2.5%) compared to non-diabetic individuals (1.8%) (odds ratio of 1.37 (interquartile range:1.01–1.88, p = 0.04)). A significantly increased HbA1c was found among patients with type 2 diabetes and with GADA-positive diabetes carrying rare GLIS3 variants compared to non-carriers of rare GLIS3 variants with diabetes (p = 0.02 and p = 0.004, respectively). One variant (p.I28V) was found to have a minor allele frequency of only 0.03% among patients with type 2 diabetes compared to 0.2% among non-diabetic individuals suggesting a protective function (odds ratio of 0.20 (interquartile range: 0.005–1.4, p = 0.1)), an effect which was supported by publically available data. This variant was also associated with a lower level of fasting plasma glucose among non-diabetic individuals (p = 0.046). Conclusion: Rare missense variants in GLIS3 associates nominally with increased level of HbA1c and increased risk of developing type 2 diabetes. In contrast, the rare p.I28V variant associate with reduced level of fasting plasma glucose and may be protective against type 2 diabetes. [ABSTRACT FROM AUTHOR]

Over the past decades, attention has been paid to understanding the impact of oxidative stress and related modifications of DNA and RNA on various human health risks. A recent meta-analysis comprising 1915 smokers and 3462 non-smokers found a significantly higher level of DNA oxidation measured as urinary 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG) excretion in smokers compared with non-smokers in a healthy population. We aimed to investigate if an increased urinary excretion of 8-oxodG in smokers versus never smokers and former smokers could be verified in a population with type 2 diabetes. Additionally, we measured RNA oxidation levels through urinary excretion of 8-oxo-7, 8-dihydroguanosine (8-oxoGuo). Our study included urinary samples from 2721 type 2 diabetic patients, analyzed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Logistic regression was used to examine the relationship between daily smokers (n = 462) versus former (n = 1341) and never smokers (n = 918) regarding the RNA and DNA oxidation, respectively. We did not find any significant effect of smoking on urinary excretion of 8-oxodG or 8-oxoGuo in our study. Due to a sparse study area, it is still too early to draw any conclusions on smoking and RNA-oxidation. Regarding DNA oxidation, our study suggests that the effect of smoking seen in healthy populations might be attenuated in patients with type 2 diabetes. [ABSTRACT FROM PUBLISHER]

Aims/hypothesis: To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors. Methods: Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM. Results: At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model’s intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort. Conclusions/interpretation: In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P ≤ 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake. [ABSTRACT FROM AUTHOR]

Aims: Carefully designed and established biobanks are considered one of the most essential resources to foster biomedical research as they provide cost-effective and rapid access to a vast variety of biological materials and related anthropometrics allowing for testing of various biomarkers as well as numerous original and pertinent bioclinical hypotheses related to human disease etiology and prognosis. The objective of the present study was to present the baseline data, design, and methods used for the establishment of the Vejle Diabetes Biobank. Further aims included assessment of the prevalence of diabetes and quality of diabetes treatment in a specified Danish region. Methods: The Vejle Diabetes Biobank was established from 2007 to 2010 as a regional Biobank containing blood, DNA, and urine samples from patients with diabetes and a gender- and age-matched control population aged 25-75 years. Anthropometrics were obtained by physical examination, questionnaires, and interviews at the time of inclusion into the Biobank. The cohort was linked to the Danish Civil Registration System, the Danish National Patient Registry, and the Danish National Prescription Registry. Results: In total, 4,255 nondiabetic individuals and 3,320 patients with diabetes were included. Type 2 diabetes (T2D) patients had a higher body mass index (30 kg/m ²) than type 1 diabetes (T1D) patients (25 and 26 kg/m² in women and men, respectively) and control subjects (25 and 27 kg/m² in women and men, respectively). Fasting levels of plasma triglycerides and blood pressure were higher in T2D patients (1.5 mmol/L and 148/85 mmHg, respectively) compared with T1D patients (0.9 mmol/L and 139/81 mmHg, respectively), whereas glycated hemoglobin (HbA1c), plasma high density lipoprotein, low density lipoprotein, and total cholesterol were lower in T2D patients (51 mmol/mol, 1.2 mmol/L, 2.2 mmol/L, and 4.2 mmol/L, respectively) compared with findings in T1D patients (61 mmol/mol, 1.6 mmol/L, 2.3 mmol/L, and 4.4 mmol/L, respectively). At the time of inclusion into the Biobank, 56% of the T2D patients and 25% of T1D patients had an HbA1c <7% (53 mmol/mol). Only 28% and 34% of the T2D patients, respectively, reached treatment target for blood pressure and lipids. Conclusion: The Vejle Diabetes Biobank represents one of the largest open diabetes case-control cohorts in Denmark. The Biobank invites collaborative investigations of diabetes and diabetes complication etiologies as well as studies of prognostic or predictive biomarkers. [ABSTRACT FROM AUTHOR]

Objective: Forty-nine known single nucleotide polymorphisms (SNPs) associating with body mass index (BMI)-adjusted waist-hip-ratio (WHR) (WHRadjBMI) were recently suggested to cluster into three groups with different associations to cardiometabolic traits. Genetic risk scores of the clusters on the risk of incident diabetes and associations with detailed cardiometabolic phenotypes were tested.Methods: In a prospective study of 6,121 Inter99 individuals, the risk of incident diabetes using Cox proportional hazards regression was evaluated. Using linear regession, the associations between genetic risk scores and anthropometry and blood samples at fasting and during an oral glucose tolerance test were tested. Analyses were adjusted for age, sex, and BMI.Results: Cluster 1 associated with an increased risk of diabetes (HR = 1.05, P = 2.74 × 10(-) (4) ) and with a poor metabolic profile, including fasting serum triglyceride (β = 0.98% mmol/L, P = 3.33 × 10(-) (8) ) and Matsuda index (β = -0.74%, P = 1.29 × 10(-) (4) ). No similar associations for Clusters 2 and 3 were found. The three clusters showed different patterns of association with waist circumference, hip circumference, and height.Conclusions: Our results suggest that the 49 WHRadjBMI-associated SNPs affect metabolic health differently depending on the cluster of SNPs. The clusters further associate differently with anthropometric measures. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of non-autoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and glucagon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms. [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.

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of β-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and β-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose. [ABSTRACT FROM AUTHOR]

Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity--related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites--glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)--and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits. [ABSTRACT FROM AUTHOR]

Aim. GCK-MODY is an autosomal dominant form of diabetes caused by heterozygous mutations in the glucokinase gene leading to a lifelong mild hyperglycemia. The risk of macrovascular complications is considered low, but studies are limited. We, therefore, investigated the carotid intima-media thickness (CIMT) as an indicator of macrovascular complications in a group of patients with GCK-MODY. Methods. Twenty-seven GCK mutation carriers and 24 controls recruited among their first-degree relatives were compared, all aging over 35 years. The CIMT was tested using a high-resolution B-mode carotid ultrasonography. Medical history, anthropometry, and biochemical blood workup were obtained. Results. The mean CIMT was 0.707 ± 0.215mm (mean ± SD) in GCK mutation carriers and 0.690 ± 0.180mm in control individuals. When adjusted for age, gender, and family status, the estimated mean difference in CIMT between the two groups increased to 0.049mm (P = 0.19). No difference was detected for other characteristics, with the exception of fasting blood glucose (GCK-MODY 7.6mmol/L ± 1.2 (136.4mg/dL); controls 5.3mmol/L ± 0.3 (95.4mg/dL); P < 0.0001) and glycated hemoglobin HbA1c (GCK-MODY 6.9% ± 1.0%, 52mmol/mol ± 10; controls 5.7% ± 0.4%, 39mmol/mol ± 3; P < 0.0001). The frequency of myocardial infarction and ischemic stroke did not differ between groups. Conclusion. Our data indicate that the persistent hyperglycemia in GCK-MODY is associated with a low risk of developing diabetic macrovascular complications. [ABSTRACT FROM AUTHOR]

Aim: To assess the individual and combined effect of 46 type 2 diabetes related risk alleles on incidence of a composite CVD endpoint. Methods: Data from the first Danish MONICA study (N = 3523) and the Inter99 study (N = 6049) was used. Using Cox proportional hazard regression the individual effect of each risk allele on incident CVD was analyzed. Risk was presented as hazard ratios (HR) per risk allele. Results: During 80,859 person years 1441 incident cases of CVD (fatal and non-fatal) occurred in the MONICA study. In Inter99 942 incident cases were observed during 61,239 person years. In the Danish MONICA study four gene variants were significantly associated with incident CVD independently of known diabetes status at baseline; SLC2A2 rs11920090 (HR 1.147, 95% CI 1.027-1.283 , P = 0.0154), C2CD4A rs7172432 (1.112, 1.027-1.205 , P = 0.0089), GCKR rs780094 (1.094, 1.007-1.188 , P = 0.0335) and C2CD4B rs11071657 (1.092, 1.007-1.183 , P = 0.0323). The genetic score was significantly associated with increased risk of CVD (1.025, 1.010-1.041, P = 0.0016). In Inter99 two gene variants were associated with risk of CVD independently of diabetes; SLC2A2 (HR 1.180, 95% CI 1.038-1.341 P = 0.0116) and FTO (0.909, 0.827-0.998, P = 0.0463). Analysing the two populations together we found SLC2A2 rs11920090 (HR 1.164, 95% CI 1.070-1.267, P = 0.0004) meeting the Bonferroni corrected threshold for significance. GCKR rs780094 (1.076, 1.010-1.146, P = 0.0229), C2CD4B rs11071657 (1.067, 1.003-1.135, P = 0.0385) and NOTCH2 rs10923931 (1.104 (1.001 ; 1.217 , P = 0.0481) were found associated with CVD without meeting the corrected threshold. The genetic score was significantly associated with increased risk of CVD (1.018, 1.006-1.031, P = 0.0043). Conclusions: This study showed that out of the 46 genetic variants examined only the minor risk allele of SLC2A2 rs11920090 was significantly (P = 0.0005) associated with a composite endpoint of incident CVD below the threshold for statistical significance corrected for multiple testing. This potential pathway needs further exploration. [ABSTRACT FROM AUTHOR]

Background. Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood. Objectives. 1) To investigate the influence of parental history of type 2 diabetes (T2DM) on offspring birthweight and adult offspring glucose tolerance status in non-diabetic offspring of patients with T2DM and 2) to study the associations of birthweight with measures of pancreatic beta-cell function and insulin sensitivity. Design. Family cohort study. Population. Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes. Methods. Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in non-diabetic offspring. Birthweight and length obtained from birth records. Results. Among 122 offspring with maternal history of T2DM, 14.8% had diabetes compared to 8.0% in 137 offspring with paternal history of diabetes, p=0.09. Offspring with maternal history of T2DM had a mean birthweight 196g higher than offspring with paternal T2DM (3 651±640g (mean±SD) vs. 3 456±472g ( p=0.01)). Non-diabetic offspring with birthweights in the lowest tertile had significantly higher plasma glucose levels after an oral glucose tolerance test (OGTT) [Area under the curveglucOGTT, mean (95%CI), 1 795 (1 725-1 866) vs. 1 683 (1 613-1 753) mmol/L/min, p=0.02], and lower insulin sensitivity index calculated from a frequently sampled intravenous glucose tolerance test - Si 9.60 [10-5(min*pmol/L)-1] (8.23-10.97) vs. 11.79 (10.41-13.18), p=0.02 - in adulthood compared to offspring with birthweights in the upper tertile. Conclusions. Offspring with a family history of maternal T2DM have higher birthweights than those with paternal T2DM. Low birthweight associates with elevated plasma glucose levels after an oral glucose load and decreased insulin sensitivity in adulthood. [ABSTRACT FROM AUTHOR]

Gonsorcikova L, Vaxillaire M, Pruhova S, Dechaume A, Dusatkova P, Cinek O, Pedersen O, Froguel P, Hansen T, Lebl J. Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations. We present a unique case of a 19-year-old man with a positive family history of persistent mild hyperglycemia and a novel V84I mutation in ABCC8. The proband was initially detected to have fasting hyperglycemia (ranging 6.1-6.4 mmol/L) at the age of 12 years. Increased fasting blood glucose was also subsequently detected in five additional family members (in his twin brother, sister, mother, maternal aunt, and grandfather). The grandfather has been known to have mild diabetes since 30 years and has never been treated. After having excluded a causative mutation in five maturity-onset diabetes of the young genes (MODY1-4 and 6), we identified a novel ABCC8 V84I mutation, which segregated with autosomal dominant transmission of mild hyperglycemia within three generations. This mutation that is located in a conserved area of transmembrane domain TMD0 seems to be a rare cause of clinical phenotype resembling glucokinase-deficient diabetes. [ABSTRACT FROM AUTHOR]

Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, Cinek O, Lebl J. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Background: Glucokinase diabetes, also called GCK-MODY or maturity-onset diabetes of the young type 2 (MODY2), is caused by heterozygous mutations in the gene encoding glucokinase ( GCK). Objective: The aim of study was to investigate the current prevalence of GCK mutations in a large cohort of Czech patients with typical clinical appearance of GCK-MODY. In addition, we reanalyzed the negative results obtained previously by screening using the denaturing high-performance liquid chromatography (dHPLC). Methods: We studied 140 unrelated Czech probands with clinical picture of GCK-MODY who were referred to our center from the whole of the Czech Republic between the years 1999-2009 by direct sequencing of GCK gene. Results: A mutation in GCK was identified in 103 of 140 probands (74%). We identified 46 different GCK mutations of which 13 were novel. Several mutations were detected in multiple families: p.Glu40Lys (20 families), p.Gly318Arg (12), p.Leu315His (7) and p.Val33Ala (six families). Direct sequencing detected a GCK mutations in 9 of 20 previously dHPLC-negative samples; the sensitivity of the dHPLC screening was calculated as 84%. Conclusions: The study shows a relatively high proportion of GCK mutations among individuals with GCK-like phenotype, confirming the effectiveness of carefully applied clinical criteria prior to genetic testing. In the Czech MODY registry, GCK-MODY represents the biggest subgroup of MODY (35%). We report several prevalent GCK mutations with a likely founder effect in the Czech population. Furthermore, our results provide ground for a possible recommendation to reinspect all negative results previously obtained by screening using dHPLC. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits. RESEARCH DESIGN AND METHODS--MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells. RESULTS--No mutations m MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10-4) and increased BMI (β = 0.5 kg/m²; P = 1.2 x 10-5) and waist circumference (β = 1.2 cm; P = 9 x 10[sup -6]) in combined Danish and French study samples. 24E also associated with decreased FPG (β = -0.08 mmol/l; P = 9.2 x 10[sup -4]) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively. CONCLUSIONS--Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes. Diabetes 59: 1539-1548, 2010 [ABSTRACT FROM AUTHOR]

We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase ( CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7–23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient’s family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes. [ABSTRACT FROM AUTHOR]

Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes mellitus (T2DM) using a two-stage design. In the first stage, we analyzed 62 tagging single nucleotide polymorphisms (SNPs) in the Hoorn study (n=999 participants) covering all common variation in 13 biological candidate genes. These 13 candidate genes were selected from four clusters regarded essential for correct mitochondrial protein synthesis and biogenesis: aminoacyl tRNA synthetases, translation initiation factors, tRNA modifying enzymes and mitochondrial DNA transcription and replication. SNPs showing evidence for association with T2DM were measured in second stage genotyping (n=10164 participants). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85–1.00), P=0.06. Moreover, in a large meta-analysis of three genome-wide association studies, this SNP was also not associated with T2DM (P=0.72). In conclusion, we did not find evidence for association of common variants in 13 nuclear-encoded mitochondrial proteins with T2DM.European Journal of Human Genetics (2009) 17, 1056–1062; doi:10.1038/ejhg.2009.4; published online 11 February 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to develop a model for assessing the 5-year risk of developing type 2 diabetes from a panel of 64 circulating candidate biomarkers. RESEARCH DESIGN AND METHODS-- Subjects were selected from the Inter99 cohort, a longitudinal population-based study of ∼6,600 Danes in a nested case-control design with the primary outcome of 5-year conversion to type 2 diabetes. Nondiabetic subjects, aged ≤39 years, with BMI ≤25 kg/m² at baseline were selected. Baseline fasting serum samples from 160 individuals who developed type 2 diabetes and from 472 who did not were tested. An ultrasensitive immunoassay was used to measure of 58 candidate biomarkers in multiple diabetes-associated pathways, along with six routine clinical variables. Statistical learning methods and permutation testing were used to select the most informative biomarkers. Risk model performance was estimated using a validated bootstrap bias-correction procedure. RESULTS- A model using six biomarkers (adiponectin, C-reactive protein, ferritin, interleukin-2 receptor A, glucose, and insulin) was developed for assessing an individual's 5-year risk of developing type 2 diabetes. This model has a bootstrap-estimated area under the curve of 0.76, which is greater than that for A1C, fasting plasma glucose, fasting serum insulin, BMI, sex-adjusted waist circumference, a model using fasting glucose and insulin, and a noninvasive clinical model. CONCLUSIONS-- A model incorporating six circulating biomarkers provides an objective and quantitative estimate of the 5-year risk of developing type 2 diabetes, performs better than single risk indicators and a noninvasive clinical model, and provides better stratification than fasting plasma glucose alone. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to estimate the progression rates to impaired glucose regulation (impaired fasting glucose or impaired glucose tolerance) and diabetes in the Danish population-based Inter99 study and in a high-risk subpopulation, separately. RESEARCH DESIGN AND METHODS-- From a population-based primary prevention study, the Inter99 study, 4,615 individuals without diabetes at baseline and with relevant follow-up data were divided into a low- and a high-risk group based on a risk estimate of ischemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolemia, obesity, or impaired glucose tolerance). High-risk individuals (57.1%) were examined with an oral glucose tolerance test at 1 and 3 years, and all of the participants were reexamined at the 5-year follow-up. Person-years at risk were calculated. Progression rates to impaired glucose regulation and diabetes were estimated directly from baseline to the 5year follow-up for all the participants and from baseline through the 1- and 3- to 5-year follow-up examinations for the high-risk individuals, separately. RESULTS -- In the combined low- and high-risk group, 2.1 individuals per 100 person-years progressed from normal glucose tolerance (NGT) to impaired glucose regulation or diabetes. Among high-risk individuals, 5.8 per 100 person-years with NGT progressed to impaired glucose regulation or diabetes, and 4.9 per 100 person-years progressed from impaired glucose regulation to diabetes. CONCLUSIONS -- Progression rates to impaired glucose regulation using the current World Health Organization classification criteria were calculated for the first time in a large European population-based study. The progression rates to diabetes show the same pattern as seen in the few similar European studies. [ABSTRACT FROM AUTHOR]

Hypothesis: Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans. Methods: Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals. Results: Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUCC-Peptide/AUCGlc ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMI6rs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI#25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUCIns/AUCGlc (TT: 226±7, XG: 246±9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers. Conclusions: The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS--We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS--The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R² = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS--We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The role of intrauterine hyperglycemia and future risk of type 2 diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. RESEARCH DESIGN AND METHODS -- The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) was evaluated in 597 subjects, primarily Caucasians, aged 18-27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4) offspring of women from the background population (O-BP). RESULTS -- The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58-23.39) in O-GDM and 4.02 (1.31-12.33) in O-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was significantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04-1.91) per mmol/l. CONCLUSIONS--A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either diet-treated GDM or type 1 diabetes during pregnancy. [ABSTRACT FROM AUTHOR]

Mutations in LMNA encoding lamin A and C proteins cause monogenic syndromes characterized by muscular dystrophy and familial partial lipodystrophy. Eight tag single nucleotide polymorphisms in the LMNA locus were genotyped in 7,495 Danish whites and related to metabolic and anthropometric traits. The minor T-allele of rs4641 was nominally associated with type 2 diabetes (odds ratio 1.14 [95% CI 1.03-1.26], P = 0.01) in a study of 1,324 type 2 diabetic patients and 4,386 glucose-tolerant subjects and with elevated fasting plasma glucose levels in a population-based study of 5,395 middle-aged individuals (P = 0.008). The minor T-allele of rs955383 showed nominal association with obesity in a study of 5,693 treatment-naive subjects (1.25 [1.07-1.64], P = 0.01), and after dichotomization of waist circumference, the minor alleles of rs955383 and rs11578696 were nominally associated with increased waist circumference (1.14 [1.04-1.23], P = 0.003; 1.12 [1.00-1.25], P = 0.04). The minor G-allele of rs577492 was associated with elevated fasting serum cholesterol and short stature (P = 3.0 ⋅ 10-5 and P ⋅ 7.0 ⋅ 10-4). The findings are not corrected for multiple comparisons and are by nature exploratory. However, if replicated, these findings suggest that less severe variation in a gene locus known to harbor severe mutations causing monogenic syndromes may modestly increase susceptibility to common metabolic and anthropometrical phenotypes of polygenic origin. Diabetes 56:694-698, 2007 [ABSTRACT FROM AUTHOR]

The short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) protein is involved in the penultimate step of mitochondrial fatty acid oxidation. Previously, it has been shown that mutations in the corresponding gene (HADHSC) are associated with hyperinsulinism in infancy. The presumed function of the SCHAD enzyme in glucose-stimulated insulin secretion led us to the hypothesis that common variants in HADHSC on chromosome 4q22-26 might be associated with development of type 2 diabetes. In this study, we have performed a large-scale association study in four different cohorts from the Netherlands and Denmark (n = 7,365). Direct sequencing of HADHSC cDNA and databank analysis identified four tagging single nucleotide polymorphisms (SNPs) including one missense variant (P86L). Neither the SNPs nor haplotypes investigated were associated with the disease, enzyme function, or any relevant quantitative measure (all P > 0.1). The present study provides no evidence that the specific HADHSC variants or haplotypes examined do influence susceptibility to develop type 2 diabetes. We conclude that it is unlikely that variation in HADHSC plays a major role in the pathogenesis of type 2 diabetes in the examined cohorts. Diabetes 55:3193-3196, 2006 [ABSTRACT FROM AUTHOR]

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding. Diabetes 55:2915-2921, 2006 [ABSTRACT FROM AUTHOR]

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4α gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P = 0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to assess agreement between glomerular filtration rate (GFR) and the decline in GFR estimated with the Modification of Diet in Renal Disease (MDRD) Study Group equation or the Cockcroft-Gault formula and measured by the plasma clearance of 51Cr-EDTA. RESEARCH DESIGN AND METHODS -- We followed a cohort of 156 microalbuminuric type 2 diabetic patients for 8 years with four measurements of GFR and another cohort of 227 type 2 diabetic patients with overt diabetic nephropathy for 6.5 (range 3-17) years with seven (3-22) measurements of GFR. RESULTS -- For patients with microalbuminuria, mean ± SD baseline GFR was 117 ± 24 measured, 92 ± 20 estimated (MDRD equation), or 103 ± 24 ml ⋅ min-1 per 1.73 m² estimated (Cockcroft-Gault formula) (both P < 0.001); 95% limits of agreement were -66.1 to 20.3 (MDRD equation) and -58.7 to 30.7 (Cockcroft-Gault formula). The rate of decline in GFR was 4.1 ± 4.2 measured, 2.9 ± 2.8 estimated (MDRD equation), or 3.4 ± 3.2 ml ⋅ min-1 per 1.73 m² estimated (Cockcroft-Gault formula) (both P < 0.001). For patients with overt nephropathy, baseline GFR was 84 ± 30 measured, 73 ± 24 estimated (MDRD equation), or 81 ± 28 ml ⋅ min-1 per 1.73 m² estimated (Cockcroft-Gault formula) (both P < 0.001) with 95% limits of agreement -47 to 25 (MDRD equation) and -39 to 33 (Cockcroft-Gault formula). The rate of decline in GFR was 5.2 ± 4.1 measured, 4.2 ± 3.8 estimated (MDRD equation), and 4.6 ± 4.1 ml ⋅ min-1 per 1.73 m² estimated (Cockcroft-Gault formula) (both P < 0.001). CONCLUSIONS -- Particularly in microalbuminuric (hyperfiltering) patients, GFR is significantly underestimated with wide limits of agreement by the MDRD equation as well as by the Cockcroft-Gault formula. The rate of decline in GFR is also significantly underestimated with both equations. This makes GFR estimations based upon these equations unacceptable for monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Among Europeans, mutations in the hepatocyte nuclear factor-1α (HNF1α) gene are associated with the most common form of maturity-onset diabetes of the young (MODY)3. In Asian Indians, type 2 diabetes occurs earlier and often overlaps with MODY, but the genetics of the latter are unknown. The aim of this study was to estimate the prevalence of Ala98Val polymorphism of the: HNF1α gene in different types of diabetes in Asian Indians. RESEARCH DESIGN AND METHODS -- Genotyping of Ala98Val was done by the PCR-restriction fragment-length polymorphism method in the following groups: 1) MODY, defined as non-insulin-dependent diabetes (age at onset <25 years) and vertical transmission of diabetes through at least three generations (n = 122); 2) very-early-onset type 2 diabetes (age at onset <25 years) without family history (n = 23); 3) early-onset type 2 diabetes (age at onset between 26 and 40 years, n = 171); 4) late-onset type 2 diabetes (age at onset >40 years, n = 133); 5) type 1 diabetes (n = 130); and 6) normal glucose tolerance (n = 130). The frequency of the Val genotypes was compared in the diabetic and control groups. RESULTS -- The frequency of the Val allele was significantly higher in MODY patients (P = 0.0013) compared with control groups. Furthermore, in the total group of patients with type 2-like diabetes (groups 1-4), the Val allele was associated with an earlier diagnosis of diabetes (P = 0.0002). CONCLUSIONS -- Among Asian Indians, the Ala98Val polymorphism of HNF1α gene is associated with MODY and with earlier age at onset of type 2 diabetes. [ABSTRACT FROM AUTHOR]

A graded relationship has been reported between fasting and postprandial plasma glucose levels and the subsequent risk of cardiovascular morbidity and mortality. We hypothesized that the GCK -30G>A promoter polymorphism is associated with elevated glycemia in the middle-aged general population of whites, as well as with features of the World Health Organization (WHO)-defined metabolic syndrome. The GCK -30G>A polymorphism was genotyped in the population-based Inter99 study cohort (5,965 subjects) and in 332 nondiabetic subjects and 1,063 patients with type 2 diabetes. In the Inter99 cohort, the GCK -30A allele was associated with increased fasting (P < 0.001) and post-oral glucose tolerance test (OGTT) plasma glucose levels (P < 0.001), and in the same cohort, the GCK -30A allele was more frequent among 1,325 subjects with the metabolic syndrome than among 1,679 subjects without any components of the metabolic syndrome (P = 0.002). Moreover, the GCK -30A allele frequency was higher among 2,587 subjects with impaired glucose regulation (IGR) than among 4,773 glucose-tolerant subjects (17.3% [95% CI 16.2-18.3] vs. 15.0% [14.3-15.7], P < 0.001, odds ratio GG vs. GA 1.21 [1.08-1.36], GG vs. AA 1.62 [1.17-2.24]). In conclusion, the GCK -30G>A polymorphism associates with elevated fasting and post-OGTT glycemia in the middle-aged general population of whites, as well as with IGR and other features of the WHO-defined metabolic syndrome. Diabetes 54:3026-3031, 2005 [ABSTRACT FROM AUTHOR]