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Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p

Beneficial effects of statin treatment on cardiovascular morbidity and mortality has been not entirely explained by the reduction in LDL-cholesterol level. We hypothesised that antioxidant activity of statins may contribute to their salutary cardiovascular effects. The aim of the present study was to examine effect of simvastatin treatment on some parameters of LDL oxidation and antioxidant protection in patients with hypercholesterolemia and combined hyperlipidemia. Furthermore, we were interested, whether the effect of treatment is related to the type of hyperlipidemia.Fourty-two patients (12 males, 30 females, mean age 60+/-10 years) were included in the present study. Fourteen patients had hypercholesterolemia defined as total cholesterol5.0 mmol/l. Twenty-eight patients had combined hyperlipidemia defined by total cholesterol5.0 mmol/l and triglycerides1.7 mmol/l. Simvastatin was administered to patients during 8-week period in a daily dose of 20mg. Oxidation of LDL was measured by assessment of circulating conjugated diene (CD) and malondialdehyde (MDA) level. Antioxidant properties of blood were assessed based on measurement of total antioxidant status (TAS) and glutathione peroxidase (GPx) activity.Besides expected significant decrease in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels, simvastatin treatment also reduced significantly circulating CD by 41% (p0.0001) and MDA level non-significantly by 6% (p=0.078). Simvastatin treatment resulted in an increase of GPx activity by 38% (p0.0001), but did not have a significant effect on TAS. Patients with combined hyperlipidemia had significantly higher baseline CD (p0.01) and consequently significantly greater absolute and relative decrease (46% versus 23%) in circulating CD (DeltaCD), when compared with patients with hypercholesterolemia. The increase in GPx activity was significant only in patients with combined hyperlipidemia (p0.0001). In the multiple stepwise linear regression analysis, both baseline triglyceride (r(2)=0.32; p=0.004) and LDL cholesterol (r(2)=0.08; p=0.05) levels were significant independent predictors of DeltaCD after simvastatin treatment.Simvastatin treatment significantly reduced circulating conjugated diene level and led to an increase in glutathione peroxidase activity. These effects were more pronounced in patients with combined hyperlipidemia than in hypercholesterolemia. The results suggest that simvastatin possesses certain antioxidant properties, which may contribute to its beneficial cardiovascular effect.

Background Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin. Methods Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated. Results Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations. Conclusion Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.

Metabolic syndrome (MetS) is a cluster of metabolic traits associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Central obesity and insulin resistance are thought to play key roles in the pathogenesis of the MetS. The MetS has a significant genetic component, and therefore linkage analysis, candidate gene approach, and genome-wide association (GWA) studies have been applied in the search of gene variants for the MetS. A few variants have been identified, located mostly in or near genes regulating lipid metabolism. GWA studies for the individual components of the MetS have reported several loci having pleiotropic effects on multiple MetS-related traits. Genetic studies have provided so far only limited evidence for a common genetic background of the MetS. Epigenetic factors (DNA methylation and histone modification) are likely to play important roles in the pathogenesis of the MetS, and they might mediate the effects of environmental exposures on the risk of the MetS. Further research is needed to clarify the role of genetic variation and epigenetic mechanisms in the development of the MetS.

Recent studies have highlighted the role of height in complex diseases, but conflicting information has been reported on height as a predictor of changes in glycemia and risk of type 2 diabetes.Our aim was to investigate the association of height with insulin sensitivity, insulin secretion, glycemia, type 2 diabetes, and cardiovascular disease (CVD) in a large prospective population-based study.The study included 8746 Finnish men (mean ± standard deviation, age 57.2 ± 7.1 years, body mass index, 26.8 ± 3.8 kg/m2) selected from a population-based Metabolic Syndrome in Men (METSIM) study.The study was conducted at Kuopio University Hospital and University of Eastern Finland.The participants were nondiabetic at the recruitment, and 5401 subjects have participated in the follow-up study. During the follow-up, a total of 693 subjects converted to type 2 diabetes and 351 were diagnosed with a new CVD event during the follow-up.The main outcome measures were incidence of type 2 diabetes and CVD.Height measured at baseline was significantly associated with lower levels of 2-hour glucose in an oral glucose tolerance test, an increase in insulin secretion, a decrease in the risk of type 2 diabetes [hazard ratio (HR) = 0.83(confidence interval [CI] 0.77 to 0.90)] and CVD [HR = 0.75(CI 0.67 to 0.83)] during the follow-up.Short stature is associated with unfavorable changes in glucose metabolism and predicts an increase in the risk of type 2 diabetes and cardiovascular events.

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P, Author Summary Lipid traits are heritable, but many of the DNA variants that influence lipid levels remain unknown. In a genomic region, more than one variant may affect gene expression or function, and the frequencies of these variants can differ across populations. Genotyping densely spaced variants in individuals with different ancestries may increase the chance of identifying variants that affect gene expression or function. We analyzed high-density genotyped variants for association with TG, HDL-C, and LDL-C in African Americans, East Asians, and Europeans. At several genomic regions, we provide evidence that two or more variants can influence lipid traits; across loci, these additional signals increase the proportion of trait variation that can be explained by genes. At some association signals shared across populations, combining data from individuals of different ancestries narrowed the set of likely functional variants. At PCSK9 and APOA5, the data suggest that different variants influence trait levels in different populations. Variants previously reported to alter gene expression or function frequently exhibited the strongest association at those signals. The multiple signals and population-specific characteristics of the loci described here may be shared by genetic loci for other complex traits.

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.

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.

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.

This study investigates the role of serine/threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism. The effect of depleting STK25 in muscle cells was studied by reducing the mRNA and protein content of this target in the rat myoblast cell line L6 by small interfering (si)RNA. The changes in the mRNA and protein levels of several members of the fatty acid oxidative and glucose metabolic pathways were measured by quantitative real-time (qRT)-PCR and western blot. The rate of palmitate oxidation and glucose uptake was measured after transfection with siRNA for Stk25. Expression of STK25 was also evaluated in skeletal muscle biopsies from 41 white Europid men and women with normal and impaired glucose tolerance and type 2 diabetes using qRT-PCR. We demonstrate that partial depletion of STK25 increases the expression of uncoupling protein 3 (Ucp3), accompanied by increased lipid oxidation, in myoblasts. In addition, a reduced level of STK25 enhances the expression of Slc2a1 (also known as Glut1), Slc2a4 (also known as Glut4) and hexokinase 2, and correspondingly, improves insulin-stimulated glucose uptake in muscle cells. Consistent with these results, significantly higher STK25 levels were observed in the skeletal muscle of type 2 diabetic patients, compared with individuals with normal glucose tolerance. This is the first study indicating a possible role for STK25 in the regulation of glucose and lipid metabolism in L6 myoblasts. This kinase appears to be an interesting new mediator to be evaluated for therapeutic intervention in type 2 diabetes and related complications, as controlled increase in lipid oxidation and insulin-stimulated glucose uptake in skeletal muscle is favourable and can restore energy balance in metabolically compromised states.

BACKGROUND AND AIM: The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample.METHODS: For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses.RESULTS: The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([-41.3;-3.0], P = 0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (β = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (β = 1.76% [0.04; 3.49], P = 0.05).CONCLUSION: The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.

Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults., Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r 2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p interaction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary, Editors’ Summary Background Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods. Why Was This Study Done? The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies. What Did the Researchers Do and Find? The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen. What Do these Findings Mean? This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116. This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

OBJECTIVE The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation. RESULTS The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.

El pdf del artículo es el manuscrito de autor: PMC3262230.-- et al., Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10−6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10−26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10−11) and one near SPRY2 (P = 3 × 10−8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat–decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance., Funding was provided by Academy of Finland (10404, 124243, 129680, 129494, 141005 and 213506); Agency for Health Care Policy Research (HS06516); Althingi (the Icelandic Parliament); American Heart Association (10SDG269004); AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council (G20234); British Heart Foundation (PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671); CamStrad; Cancer Research UK; Cedars-Sinai Board of Governors’ Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport (196-1962766-2747, 216-1080315-0302 and 309-0061194-2023); Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII, FP7/2007-2013, FP7-KBBE-2010-4-266408, HEALTH-F2-2007-201681, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2003-503041, LSHM-CT-2004-512013, QLG1-CT-2001-01252 and QLG2-CT-2002-01254), Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhälsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bündesministerium für Forschung und Technology (01AK803A-H and 01IG07015G); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, Närpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Ludwig-Maximilians Universität München; Lundberg Foundation; Medical Research Council (UK); Men’s Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovación (Spain) (SAF-2009 and SAF-2008-02073); Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Närpes Health Care Foundation; National Institute for Health Research (UK); US National Institutes of Health (USA) (AG13196, DK063491, K23-DK080145, M01-RR00425, N01-AG12100, N01-AG62101, N01-AG62103, N01-AG62106, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55222, N01-HC75150, N01- HC85079 through N01-HC85086, P30-DK072488, R01-AG031890-01, R01-AG18728, R01-AG032098-01A1, R01-AR/AG41398, R01-AR046838, R01-DK06833603, R01-DK075787, R01-DK07568102, R01-HL036310-20A2, R01-HL087652, R01-HL08770003, R01-HL088119, U01-HL080295, U01-HL72515 and U01-HL84756); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (175.010.2005.011 and 911-03-012); Netherlands Organization for the Health Research and Development; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council (K2010-54X-09894-19-3, K2010-52X-20229-05-3 and 2006-3832); Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 310000-112552 and 33CSCO-122661); TEKES (1510/31/06); Torsten and Ragnar Söderberg’s Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; Västra Götaland Foundation; and Wellcome Trust (077016/Z/05/Z, 084723/Z/08/Z and 091746/Z/10/Z).

The Finnish Diabetes Risk Score (FINDRISC) is a well established method to evaluate the risk of type 2 diabetes. However, it is unknown whether biochemical markers or confirmed type 2 diabetes risk genes improve the risk evaluation beyond the FINDRISC.We investigated the role of biochemical markers and type 2 diabetes risk loci in the identification of previously undiagnosed diabetic subjects beyond the FINDRISC in a cross-sectional study.A random sample of 7232 Finnish men aged 45-74 yr (including 518 men with new type 2 diabetes) participated in the study. Insulin sensitivity and insulin secretion were evaluated by oral glucose tolerance test-derived indices. Total triglycerides, high-density lipoprotein cholesterol, adiponectin, and alanine transaminase were measured. Nineteen type 2 diabetes risk single-nucleotide polymorphisms were genotyped.FINDRISC was the best single indicator of prevalent undiagnosed diabetes among all variables tested and strongly associated with insulin resistance. It was also more strongly associated with insulin secretion compared with the type 2 risk alleles. The receiver operating characteristics area under the curve based on logistic regression models for the identification of previously undiagnosed type 2 diabetic subjects with the FINDRISC alone was 0.727, and 0.772 after adding total triglycerides, high-density lipoprotein cholesterol, adiponectin, and alanine transaminase in the model. Adding type 2 risk alleles did not further improve the model (0.772).Biochemical markers, but not genetic markers, improve the identification of previously undiagnosed type 2 diabetes beyond the FINDRISC alone.

SummaryType 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.

Background and aim The common single nucleotide polymorphism (SNP) in the FTO (fat mass and obesity associated) gene has been consistently associated with an increased risk of obesity. We investigated whether the SNP rs9939609 (T/A) of the FTO is associated with risk factors of cardiovascular diseases (CVD), including serum levels of C – reactive protein (CRP), the chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and serum and lipoprotein lipids in the Finnish Diabetes Prevention Study (DPS). Furthermore, we examined whether the rs9939609 increased the CVD risk in the DPS and if these results could be replicated in a larger cross-sectional population-based random sample of Finnish men (the METSIM). Methods and results In the DPS, altogether 490 (BMI≥25kg/m 2 ) subjects with impaired glucose tolerance were genotyped for rs9939609. Cardiovascular morbidity and mortality data were collected during the median follow-up of 10.2 years. The replication study was a population-based cross-sectional study of 6214 men. In the DPS, the AA genotype of rs9939609 was associated, independently of BMI, with increased RANTES ( p =0.002) and decreased HDL cholesterol concentrations ( p =0.007) in men. During the follow-up, the AA genotype was associated with an adjusted 2.09-fold risk (95% CI 1.17–3.73, p =0.013) of CVD in men. In the METSIM Study, the association with a history of myocardial infarction was replicated in the subgroup of men with type 2 diabetes. Conclusion We suggest that the variation in the FTO gene may contribute to the development of CVD in men with an abnormal glucose metabolism.

Objective To investigate the changes in the levels of cytokines and adhesion molecules in response to acute hyperinsulinemia in the offspring of type 2 diabetic subjects. Methods Forty healthy offspring of type 2 diabetic subjects and 19 control offspring of healthy parents were included in the study. Twenty offspring had normal glucose tolerance (NGT) and twenty offspring impaired glucose tolerance (IGT). Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp and insulin secretion with the intravenous glucose tolerance test. The levels of cytokines and adhesion molecules were measured before and at the end of the clamp. Results Acute hyperinsulinemia induced by the euglycemic hyperinsulinemic clamp reduced the levels of TNF-α, IL-8, IL-10 and IL-18 in healthy controls but not in the offspring of type 2 diabetic subjects having NGT or IGT. In response to insulin, levels of hs-CRP decreased and levels of IL-6 increased significantly in all study groups. The levels of adhesion molecules (ICAM-1, VCAM-1, E-Selectin) remained unchanged in response to hyperinsulinemia. Conclusions The suppression of cytokine levels (particularly proinflammatory cytokines) during acute hyperinsulinemia observed in healthy controls was not present in offspring of type 2 diabetic patients. This emphasizes the crucial role of low-grade inflammation in insulin resistance in subjects with high risk of developing diabetes.

Background Neuron-derived orphan receptor (Nor) 1, nuclear receptor (Nur) 77, and nuclear receptor-related protein (Nurr) 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the NR4A3 locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or β-cell dysfunction. Methods We genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms (SNPs) rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 (minor allele frequencies ≥ 0.05) covering 100% of genetic variation within the NR4A3 locus (with D' = 1.0, r2 ≥ 0.9) and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test (OGTT), and a hyperinsulinemic-euglycemic clamp (subgroup, N = 506). SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort (METSIM Study; Finland; N = 5265) for replication. Results All five SNPs were in Hardy-Weinberg equilibrium (p ≥ 0.7, all). The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 min(OGTT), AUCC-peptide-to-AUCGluc ratio and the AUCIns30-to-AUCGluc30 ratio with rs12686676 reaching the level of significance (p ≤ 0.03, all; additive model). The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p ≤ 0.03, additive model). There was no consistent association with glucose tolerance or insulin resistance in both study cohorts. Conclusion We conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3 represents a novel candidate gene for β-cell function which was not covered by the SNP arrays of recent genome-wide association studies for type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. METHODS: Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. RESULTS: Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. CONCLUSIONS/INTERPRETATION: The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.

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 AUC(C-Peptide)/AUC(Glc) ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMIxrs9402571 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< or =25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (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.

The transcription factor forkhead box protein (FOX) O1A plays a crucial role in regulation of beta-cell function and metabolic effects of insulin in the liver.The objective of the study was to investigate whether common genetic variation within the FOXO1 gene encoding FOXO1A contributes to prediabetic phenotypes, such as insulin resistance or beta-cell dysfunction, and to risk of type 2 diabetes.Study I was a study enrolling thoroughly phenotyped subjects from Germany at increased risk for type 2 diabetes. Study II was a population-based study of Finnish men for the assessment of the prevalence of type 2 diabetes and metabolic syndrome.Study I included 941 nondiabetic subjects (353 males, 588 females, aged 39 +/- 1 yr, body mass index 29.2 +/- 0.3 kg/m(2)). Study II included 5957 middle-aged men (870 type 2 diabetic and 5087 nondiabetic subjects).Genotyping for 10 single-nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequencyor=10%) within the FOXO1 gene (r(2)or= 0.8) based on HapMap data, oral glucose tolerance test, and in a subset additionally a hyperinsulinemic-euglycemic clamp.Parameters of insulin secretion, insulin resistance, and glucose tolerance status were measured.In the German subjects at increased risk for type 2 diabetes, SNPs rs2721068 and rs17446614 were significantly (P = 0.0045 and P = 0.0018, respectively) and SNPs rs17446593 and rs2297627 were nominally (P = 0.0091 and P = 0.0387, respectively) associated with beta-cell dysfunction. rs2721068, rs17446614, and rs2297627 were also nominally associated with impaired glucose tolerance (P = 0.0264, P = 0.0162, and P = 0.0221, respectively). Minor allele carriers showed reduced insulin secretion and elevated glucose levels during an oral glucose tolerance test. Investigating the relevance of our findings in a separate cohort, we found that SNP rs2721068 was significantly associated with type 2 diabetes in the additive (P = 0.002) and dominant model (P = 0.009) in Finnish men.Common genetic variation within the FOXO1 gene affects insulin secretion and glucose tolerance and associates with an increased risk of type 2 diabetes.

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal., Author Summary We undertook analyses in 111,421 adults of European descent to examine whether physical activity diminishes the genetic risk of obesity predisposed by 12 single nucleotide polymorphisms, as previously reported in a study of 20,000 UK adults (Li et al, PLoS Med. 2010). Although the study by Li et al is widely cited, the original report has not been replicated to our knowledge. Therefore, we sought to confirm or refute the original study's findings in a combined analysis of 111,421 adults. Our analyses yielded a statistically significant interaction effect (Pinteraction = 0.015), confirming the original study's results; we also identified an interaction between the FTO locus and physical activity (Pinteraction = 0.003), verifying previous analyses (Kilpelainen et al, PLoS Med., 2010), and we detected a novel interaction between the SEC16B locus and physical activity (Pinteraction = 0.025). We also examined the power constraints of interaction analyses, thereby demonstrating that sources of within- and between-study heterogeneity and the manner in which data are treated can inhibit the detection of interaction effects in meta-analyses that combine many cohorts with varying characteristics. This suggests that combining many small studies that have measured environmental exposures differently may be relatively inefficient for the detection of gene × environment interactions.

We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.

SummaryThe fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility., Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.