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The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1–based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1–based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

Objective: The natural course of diabetes of the exocrine pancreas (DEP) is not well established. We aimed to compare the risk of insulin initiation, diabetic complications, and mortality between DEP and type 2 diabetes.Research Design and Methods: Using the Korean National Health Insurance Service-Health Screening Cohort between 2012 and 2017, we divided patients with diabetes into those with diabetes without prior pancreatic disease (indicated type 2 diabetes, n = 153,894) and diabetes with a prior diagnosis of pancreatic disease (indicated DEP, n = 3,629). ICD-10 codes and pharmacy prescription information were used to define type 2 diabetes, DEP, and acute and chronic diabetes complications. Kaplan-Meier curves were produced to compare insulin use over time between groups. We created logistic regression models for odds of progression to diabetic complications and mortality.Results: DEP was associated with a higher risk of insulin use than type 2 diabetes (adjusted hazard ratio 1.38 at 5 years [95% CI 1.30-1.47], P < 0.0001). Individuals with DEP showed higher risks of hypoglycemia (odds ratio 1.85 [1.54-2.21], P < 0.0001), diabetic neuropathy (1.38 [1.28-1.49], P < 0.0001), nephropathy (1.38 [1.27-1.50], P < 0.0001), retinopathy (1.10 [1.01-1.20], P = 0.0347), coronary heart disease (1.59 [1.48-1.70], P < 0.0001), cerebrovascular disease (1.38 [1.28-1.49], P < 0.0001), and peripheral arterial disease (1.34 [1.25-1.44], P < 0.0001). All-cause mortality was higher in those with DEP (1.74 [1.57-1.93], P < 0.0001) than in those with type 2 diabetes.Conclusions: DEP is more likely to require insulin therapy than type 2 diabetes. Hypoglycemia, micro- and macrovascular complications, and all-cause mortality events are higher in DEP compared with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of sleep traits on glycated hemoglobin (HbA1c).Research Design and Methods: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female).Results: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect.Conclusions: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association of the cardiovascular risk factor lipoprotein (Lp)(a) and vascular complications in patients with type 1 diabetes.Research Design and Methods: Patients with type 1 diabetes receiving regular care were recruited in this observational cross-sectional study and divided into four groups according to their Lp(a) levels in nmol/L (very low <10, low 10-30, intermediate 30-120, high >120). Prevalence of vascular complications was compared between the groups. In addition, the association between metabolic control, measured as HbA1c, and Lp(a) was studied.Results: The patients (n = 1,860) had a median age of 48 years, diabetes duration of 25 years, and HbA1c of 7.8% (61 mmol/mol). The median Lp(a) was 19 (interquartile range 10-71) nmol/L. No significant differences between men and women were observed, but Lp(a) levels increased with increasing age. Patients in the high Lp(a) group had higher prevalence of complications than patients in the very low Lp(a) group. The age- and smoking-status-adjusted relative risk ratio of having any macrovascular disease was 1.51 (95% CI 1.01-2.28, P = 0.048); coronary heart disease, 1.70 (95% CI 0.97-3.00, P = 0.063); albuminuria, 1.68 (95% CI 1.12-2.50, P = 0.01); and calcified aortic valve disease, 2.03 (95% CI 1.03-4.03; P = 0.042). Patients with good metabolic control, HbA1c <6.9% (<52 mmol/mol), had significantly lower Lp(a) levels than patients with poorer metabolic control, HbA1c >6.9% (>52 mmol/mol).Conclusions: Lp(a) is a significant risk factor for macrovascular disease, albuminuria, and calcified aortic valve disease in patients with type 1 diabetes. Poor metabolic control in patients with type 1 diabetes is associated with increased Lp(a) levels. [ABSTRACT FROM AUTHOR]

Objective: To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach.Research Design and Methods: A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200).Results: Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P = 0.007 for difference).Conclusions: These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: We conducted a Mendelian randomization study to investigate the associations of genetically predicted serum 25-hydroxyvitamin D (S-25OHD), calcium (S-Ca), and parathyroid hormone (S-PTH) levels with type 2 diabetes (T2DM).Research Design and Methods: Seven, six, and five single nucleotide polymorphisms (SNPs) associated with S-25OHD, S-Ca, and S-PTH levels, respectively, were used as instrumental variables. Data on T2DM were available for 74,124 case subjects with T2DM and 824,006 control subjects. The inverse variance-weighted method was used for the primary analyses, and the weighted median and Mendelian randomization (MR)-Egger methods were used for supplementary analyses.Results: Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For 1 SD increment of S-25OHD levels, the odds ratio (OR) of T2DM was 0.94 (95% CI 0.88-0.99; P = 0.029) in an analysis based on all seven SNPs and 0.90 (95% CI 0.83-0.98; P = 0.011) in an analysis based on three SNPs within or near genes involved in vitamin D synthesis. Only the association based on the SNPs involved in vitamin D synthesis remained in the weighted median analysis, and no pleiotropy was detected (P = 0.153). Pleiotropy was detected in the analysis of S-Ca (P = 0.013). After correcting for this bias using MR-Egger regression, the OR of T2DM per 1 SD increment of S-Ca levels was 1.41 (95% CI 1.12-1.77; P = 0.003).Conclusions: Modest lifelong higher S-25OHD levels were associated with reduced odds of T2DM, but the association was only robust for SNPs in the vitamin D synthesis pathway. The possible role of S-Ca levels for T2DM development requires further research. [ABSTRACT FROM AUTHOR]

Objective: To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis.Research Design and Methods: We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia.Results: We found that a 1-SD increase in childhood BMI (kg/m2) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 × 10-7) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 × 10-8) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m2), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of ß-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance (P < 0.0026).Conclusions: A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study tested the hypothesis that genetically raised hyperglycemia increases coronary artery disease (CAD) risk separately from the risk conferred by type 2 diabetes as a whole.Research Design and Methods: We conducted a Mendelian randomization (MR) analysis using summary-level statistics from the largest published meta-analyses of genome-wide association studies (GWAS) for fasting glucose (FG) (n = 133,010 participants free of diabetes) and CAD (n = 63,746 case subjects and 130,681 control subjects) of predominantly European ancestry. FG-increasing variants associated with type 2 diabetes from the largest GWAS for type 2 diabetes were excluded. Variants with pleiotropic effects on other CAD risk factors (blood lipids, blood pressure, and obesity) were excluded using summary-level data from the largest published GWAS. Data from the Framingham Heart Study were used to validate the MR instrument and to build an FG genetic risk score (GRS).Results: In an instrumental variable analysis comprising 12 FG-raising variants, a 1 mmol/L increase in FG revealed an effect-size estimate of 1.43 CAD odds (95% CI 1.14-1.79). The association was preserved after excluding variants for heterogeneity and pleiotropic effects on other CAD risk factors (odds ratio [OR] 1.33 [95% CI 1.02-1.73]). The 12 FG-increasing variants did not significantly increase type 2 diabetes risk (OR 1.05 [95% CI 0.91-1.23]), and its prevalence was constant across FG GRS quintiles (P = 0.72).Conclusions: Our data support that genetic predisposition to hyperglycemia raises the odds of CAD separately from type 2 diabetes and other CAD risk factors. These findings suggest that modulating glycemia may provide cardiovascular benefit. [ABSTRACT FROM AUTHOR]

Objective: We examined whether the addition of novel genetic risk variant data to conventional childhood risk factors improves risk assessment of impaired fasting glucose (IFG) and type 2 diabetes in adulthood.Research Design and Methods: An association of a weighted genetic risk score (wGRS) based on 73 risk variants with IFG and type 2 diabetes was analyzed in 2,298 participants of the Cardiovascular Risk in Young Finns Study who were followed for 24-31 years from childhood to adulthood. In addition, the value of the wGRS in pediatric prediction of type 2 diabetes was examined.Results: Of the 2,298 participants, 484 (21.8%) and 79 (3.4%) had IFG or type 2 diabetes in adulthood, respectively. Adjusting for age, sex, baseline BMI, parental diabetes, mother's BMI, fasting insulin concentration, systolic blood pressure, and smoking status, wGRS was associated with an increased risk of IFG (odds ratio 1.64 [95% CI 1.33-2.01] per unit increase in the wGRS) and type 2 diabetes (2.22 [1.43-3.44]). Incorporating wGRS into pediatric risk models improved model discrimination and reclassification properties. Area under the receiver operating curve improved for IFG (from 0.678 to 0.691, P = 0.015), combined IFG and type 2 diabetes outcome (from 0.678 to 0.692, P = 0.007), and type 2 diabetes (from 0.728 to 0.749, P = 0.158). The net reclassification improvement and integrated discrimination improvement were significant for all outcomes.Conclusions: A multifactorial approach combining genetic and clinical risk factors may be useful in identifying children at high risk for adult IFG and type 2 diabetes. [ABSTRACT FROM AUTHOR]

As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors' Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. RESEARCH DESIGN AND METHODS We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. RESULTS We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m² higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9h). CONCLUSIONS Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet--specifically higher carbohydrate and lower fat composition--and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants. [ABSTRACT FROM AUTHOR]

OBJECTIVE Abdominal obesity is a major risk factor for type 2 diabetes (T2D). We aimed to examine the association between the genetic predisposition to central obesity, assessed by the waist-to-hip ratio (WHR) genetic score, and T2D risk. RESEARCH DESIGN AND METHODS The current study included 2,591 participants with T2D and 3,052 participants without T2D of European ancestry from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Genetic predisposition to central obesity was estimated using a genetic score based on 14 established loci for the WHR. RESULTS We found that the central obesity genetic score was linearly related to higher T2D risk. Results were similar in the NHS (women) and HPFS (men). In combined results, each point of the central obesity genetic score was associated with an odds ratio (OR) of 1.04 (95% CI 1.01-1.07) for developing T2D, and the OR was 1.24 (1.03-1.45) when comparing extreme quartiles of the genetic score after multivariate adjustment. CONCLUSIONS The data indicate that genetic predisposition to central obesity is associated with higher T2D risk. This association is mediated by central obesity. [ABSTRACT FROM AUTHOR]

OBJECTIVE A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) And metabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits. RESEARCH DESIGN AND METHODS Diabetes risk was modelled with a 62-SNP GRS, nine metabolites, and clinical traits. We fit age- and sex-adjusted logistic regression models to test the association of these sources of information, separately and jointly, with incident type 2 diabetes among 1,622 initially nondiabetic participants from the Framingham Offspring Study. The predictive capacity of each model was assessed by area under the curve (AUC). RESULTS Two hundred and six new diabetes cases were observed during 13.5 years of follow-up. The AUC was greater for the model containing the GRS and metabolite measurements together versus GRS or metabolites alone (0.820 vs. 0.641, P < 0.0001, or 0.820 vs. 0.803, P = 0.01, respectively). Odds ratios for association of GRS or metabolites with type 2 diabetes were not attenuated in the combined model. The AUC was greater for the model containing the GRS, metabolites, and clinical traits versus clinical traits only (0.880 vs. 0.856, P = 0.002). CONCLUSIONS Metabolite and genetic traits provide complementary information to each other for the prediction of future type 2 diabetes. These novel markers of diabetes risk modestly improve the predictive accuracy of incident type 2 diabetes based only on traditional clinical risk factors. [ABSTRACT FROM AUTHOR]

Sugar-sweetened drinks have been associated with several health problems. In the point narrative as presented below, we provide our opinion and review of the data to date that we need to reconsider consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative following our contribution, Drs. Kahn and Sievenpiper provide a defense and suggest that dietary sugar is not the culprit. Data from the National Health and Nutrition Examination Survey and U.S. Department of Agriculture dietary surveys along with commercial Homescan data on household purchases were used to understand changes in sugar and fructose consumption. Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. About 75% of all foods and beverages contain added sugar in a large array of forms. Consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages (SSBs) is related to the risk of diabetes, the metabolic syndrome, and cardiovascular disease. Drinking two 16-ounce SSBs per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized controlled trials in children and adults lasting 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Recent studies suggest a gene-SSB potential relationship. Consumption of calorie-sweetened beverages has continued to increase and plays a role in the epidemic of obesity, the metabolic syndrome, and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain. [ABSTRACT FROM AUTHOR]

OBJECTIVE Despite its anti-inflammatory and antiatherogenic effects, adiponectin is potentially associated with adverse clinical outcomes, such as all-cause mortality. As plasma adiponectin levels are strongly influenced by single nucleotide polymorphisms in the gene encoding T-cadherin (CDH13), we conducted a longitudinal study to investigate the possible link between the CDH13 genotype, plasma adiponectin levels, and all-cause mortality. RESEARCH DESIGN AND METHODS This longitudinal study evaluated 2,020 Japanese subjects. Baseline clinical parameters were obtained from subjects' personal health records as evaluated at annual medical check-ups. Plasma high--molecular weight adiponectin (HMWA) levels were measured by an ELISA assay, and genotyping was performed by a TaqMan probe assay. RESULTS Mean follow-up duration was 6.5 years. Kaplan-Meier analysis showed that HMWA levels were positively associated with mortality (P < 0.001). HMWA levels were associated with older age, lower body weight, lower plasma triglyceride and glucose levels, and higher plasma HDL cholesterol. However, the Cox regression analysis showed that the positive association between HMWA and all-cause mortality was independent of these covariates (hazard ratio [HR] 1.92, P =0.006). The CDH13 rs4783244 genotype was strongly associated with baseline HMWA levels (per-allele effect size 1.65 µg/L, P < 0.001). In a separate analysis by the CDH13 genotype, the HR for all-cause mortality was linearly increased with the number of G alleles (P value for HMWA--CDH13 genotype interaction = 0.023). CONCLUSIONS Higher plasma HMWA level was an independent prognostic factor for all-cause mortality in a general population. The CDH13 genotype may be a factor that affects not only the plasma level of HMWA but also the prognostic significance of HMWA. [ABSTRACT FROM AUTHOR]

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome. RESEARCH DESIGN AND METHODS--The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits. RESULTS--During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 - 4.5]; P = 0.001), T2DM (2.4 [1.2-4.7]; P = 0.01), and progression to impaired glucosemetabolism (2.2 [1.3 - 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21. CONCLUSIONS--FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM. [ABSTRACT FROM AUTHOR]

OBJECTIVE-Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATPbinding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1).Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. RESEARCH DESIGN AND METHOD-We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). RESULT-Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively). CONCLUSION-Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1 [ABSTRACT FROM AUTHOR]

OBJECTIVE-Both stressful intrauterine milieus and genetic susceptibility have been linked to later-life diabetes risk. The current study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterinemilieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS-The analysis included two independent, nested case-control studies of 2,591 type 2 diabetic case subjects and 3,052 healthy control subjects. We developed two genotype scores: an obesity genotype score based on 32 BMI predisposing variants and a diabetes genotype score based on 35 diabetes-predisposing variants. RESULTS-Obesity genotype scores showed a stronger association with type 2 diabetes risk in individuals with low birth weight. In low-birth weight individuals, the multivariable-adjusted odds ratio (OR) was 2.55 (95% CI 1.34-4.84) by comparing extreme quartiles of the obesity genotype score, while the OR was 1.27 (1.04-1.55) among individuals with birth weight >2.5 kg (P for interaction = 0.017). We did not observe significant interaction between diabetes genotype scores and birth weight with regard to risk of type 2 diabetes. In a comparison of extreme quartiles of the diabetes gene score, the multivariable-adjusted OR was 3.80 (1.76-8.24) among individuals with low birth weight and 2.27 (1.82-2.83) among those with high birth weight (P for interaction = 0.16). CONCLUSIONS-Our data suggest that low birth weight and genetic susceptibility to obesity may synergistically affect adulthood risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes. RESEARCH DESIGN AND METHODS--We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11,IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1,IRS-1,GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features. RESULTS--Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 x 10-21). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = 20.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = 20.032, SE = 0.0140, P = 0.022), and C-peptide index (β = 20.031, SE = 0.012, P = 0.0125). CONCLUSIONS--Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell-preserving therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic β-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a "gatekeeper", determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism. RESEARCH DESIGN AND METHODS--Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (KGK), glycolysis (K12), and whole body fractional lactate clearance (K01). RESULTS--To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland--United States Investigation of NIDDM Genetics study cohort. Parameters KGK, K12, and K01 were precisely estimated. Median model parameter estimates were consistent with previously published values. CONCLUSIONS--This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To test if knowledge of type 2 diabetes genetic variants improves disease prediction. RESEARCH DESIGN AND METHODS -- We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age (<50 years, diabetes cases = 144; or ≥50 years, diabetes cases = 302). Models included clinical risk factors and a 40-SNP weighted genetic risk score. RESULTS -- In people <50 years of age, the clinical risk factors model C-statistic was 0.908; the 40-SNP score increased it to 0.911 (P = 0.3; net reclassification improvement (NRI): 10.2%, P = 0.001). In people ≥50 years of age, the C-statistics without and with the score were 0.883 and 0.884 (P = 0.2; NRI: 0.4%). The risk per risk allele was higher in people <50 than ≥50 years of age (24 vs. 11%; P value for age interaction = 0.02). CONCLUSIONS -- Knowledge of common genetic variation appropriately reclassifies younger people for type 2 diabetes risk beyond clinical risk factors but not older people. [ABSTRACT FROM AUTHOR]

In the book Epidemiology of Diabetes and Its Vascular Lesions (1978), Kelly West summarized extant knowledge of the distribution and causes of diabetes. The 30 years of epidemiological research that followed have seen remarkable advances in the understanding of obesity as a risk factor for type 2 diabetes, and diabetes and pre-diabetes as risk factors for cardiovascular disease. Increasingly detailed understanding of these relationships has, unfortunately, been accompanied by an alarming increase in the prevalence of obesity, diabetes, and cardiovascular disease. West recognized that pre-diabetes is recognizable as what we now call metabolic syndrome. He predicted that novel insight into diabetes pathogenesis would come from biochemical and genetic epidemiology studies. He predicted that type 2 diabetes could be prevented by healthy lifestyle change. The challenge now is for us to translate these insights into effective strategies for the prevention of the modern epidemic of diabetes and vascular disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE-An elevated insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) is more commonly seen in the Mexican American population than in European populations. We report quantitative ancestral effects within a Mexican American population, and we correlate ancestral components with HOMA-IR. RESEARCH DESIGN AND METHOD-We performed ancestral analysis in 1,551 participants of the Cameron County Hispanic Cohort by genotyping 103 ancestry-informative markers (AIMs). These AIMs allow determination of the percentage (0-100%) ancestry from three major continental populations, i.e., European, African, and Amerindian. RESULT-We observed that predominantly Amerindian ancestral components were associated with increased HOMA-IR (β = 0.124, P = 1.64 × 10-7). The correlation was more significant in males (Amerindian β = 0.165, P = 5.08×10-7) than in females (Amerindian β = 0.079, P = 0.019). CONCLUSION-This unique study design demonstrates how genomic markers for quantitative ancestral information can be used in admixed populations to predict phenotypic traits such as insulin resistance. [ABSTRACT FROM AUTHOR]