Richard N Bergman

Cedars-Sinai Medical Center, Los Ángeles, California, United States

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Publications (411)3257.43 Total impact

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    ABSTRACT: Resistant starch (RS) is a type of dietary fiber that can improve glucose metabolism, but its effects may be modulated by sex or baseline insulin sensitivity. This study was designed to examine the effect of high-amylose maize resistant starch (HAM-RS2) on insulin sensitivity (S I ) in women, and to determine if S I status affects the response to RS. This was a randomized, placebo-controlled, double-blind, cross-over study. Participants were 40 healthy, non-diabetic women aged 22–67 years in the normal-weight to obese BMI range (20.6–47.4 kg/m 2 ). Two doses of HAM-RS2 were tested, 15 and 30 g per day, administered in the form of cookies. Participants were randomized to the order in which they received the experimental and placebo product. Each arm was 4 weeks, with a 4-week wash-out period in between. S I was assessed at the end of each 4-week arm of product consumption by frequently-sampled, insulin-modified, intravenous glucose tolerance test and minimal modeling. Participants were categorized as being insulin resistant (IR; S I < 7.8) or insulin sensitive (IS; S I ≥ 7.8) based on Gaussian analysis. The effect of treatment arm on S I was examined by mixed-model analysis within IR and IS sub-groups, using all available data. In addition, S I was examined by ANOVA among just those women who completed all three arms of the study with valid S I results. Among IR participants, S I was on average ~16 % higher after the 30 g arm when compared to the control arm by mixed-model analysis (n = 40, P < 0.05), and tended to be 23 % higher by ANOVA among women who completed all arms (n = 23, P = 0.06). HAM-RS2 did not affect S I in IS women. Consumption of HAM-RS2 at 30 g/day in the form of a snack food item was associated with improved insulin sensitivity in women with insulin resistance. Clinical trials registry number
    Full-text · Article · Jan 2016 · Nutrition & Metabolism
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    ABSTRACT: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
    Full-text · Article · Nov 2015 · Nature Genetics
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    ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
    Full-text · Article · Oct 2015 · PLoS Genetics
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    ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, men >50y, women 50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed signifi- cant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (!50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analy- sis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimor- phism of body shape.
    Full-text · Article · Oct 2015 · PLoS Genetics
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    ABSTRACT: Aims/hypothesis: The worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear. Methods: We performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6). Results: High-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function. Conclusions/interpretation: These data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.
    Full-text · Article · Sep 2015 · Diabetologia
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    ABSTRACT: The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism (s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in the skeletal muscle and the liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 weeks. Thereafter, while still maintained on a HFD, animals received either RIM (HFD+RIM; n=11) or placebo (HFD+PL; n=9) for an additional 16 weeks. HIC calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic hyperinsulinemic clamp. HFD+PL group showed a decrease in MCR. In contrast, HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM1 and IDE as well as gene expression of liver ADRs, were increased in HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM1 and IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs, RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway. Copyright © 2015, American Journal of Physiology - Endocrinology and Metabolism.
    No preview · Article · Aug 2015 · AJP Endocrinology and Metabolism
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    ABSTRACT: A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A1 adenosine receptor agonist. High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIRg). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIRg with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIRg. This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance.
    Full-text · Article · Aug 2015 · Diabetologia
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    ABSTRACT: Objective Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. Methods Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. Results Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus. Conclusions The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.
    Full-text · Article · Jun 2015 · Molecular Metabolism
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    ABSTRACT: Obesity has been associated with elevated plasma anandamide levels. In addition, anandamide has been shown to stimulate insulin secretion in vitro, suggesting that anandamide might be linked to hyperinsulinemia. To determine whether high-fat diet-induced insulin resistance increases anandamide levels and potentiates the insulinotropic effect of anandamide in isolated pancreatic islets. Dogs were fed a high-fat diet (n = 9) for 22 weeks. Abdominal fat depot was quantified by MRI. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Fasting plasma endocannabinoid levels were analyzed by liquid chromatography-mass spectrometry. All metabolic assessments were performed before and after fat diet regimen. At the end of the study, pancreatic islets were isolated prior to euthanasia to test the in vitro effect of anandamide on islet hormones. mRNA expression of cannabinoid receptors was determined in intact islets. The findings in vitro were compared with those from animals fed a control diet (n = 7). Prolonged fat feeding increased abdominal fat content by 81.3±21.6% (mean±S.E.M, P<0.01). In vivo insulin sensitivity decreased by 31.3±12.1% (P<0.05), concomitant with a decrease in plasma 2-arachidonoyl glycerol (from 39.1±5.2 to 15.7±2.0 nmol/L) but not anandamide, oleoyl ethanolamide, linoleoyl ethanolamide, or palmitoyl ethanolamide. In control-diet animals (body weight: 28.8±1.0 kg), islets incubated with anandamide had a higher basal and glucose-stimulated insulin secretion as compared with no treatment. Islets from fat-fed animals (34.5±1.3 kg; P<0.05 versus control) did not exhibit further potentiation of anandamide-induced insulin secretion as compared with control-diet animals. Glucagon but not somatostatin secretion in vitro was also increased in response to anandamide, but there was no difference between groups (P = 0.705). No differences in gene expression of CB1R or CB2R between groups were found. In canines, high-fat diet-induced insulin resistance does not alter plasma anandamide levels or further potentiate the insulinotropic effect of anandamide in vitro.
    Full-text · Article · Apr 2015 · PLoS ONE
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    ABSTRACT: Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. We have previously shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model, and measured the appearance of insulin in the muscle interstitium under hyperinsulinemic euglycemic clamp conditions. While lipid infusion lowered the glucose infusion rate, and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the interstitial fluid surrounding skeletal muscle tissue of the hindlimb. Interestingly, despite a significant ten-fold increase in plasma FFA, we detect little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid-infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. Copyright © 2015, American Journal of Physiology - Endocrinology and Metabolism.
    No preview · Article · Apr 2015 · AJP Endocrinology and Metabolism
  • Orison Woolcott · Marilyn Ader · Richard Bergman

    No preview · Article · Feb 2015 · Endocrine reviews
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Full-text · Article · Feb 2015 · Nature
  • Orison O Woolcott · Marilyn Ader · Richard N Bergman
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    ABSTRACT: Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may be more important in relation to human disease, as more than 400 million people worldwide reside above 1,500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and a better glucose tolerance compared with those who live near sea level. There is also emerging evidence of lower prevalences of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1,500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalences of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis.
    No preview · Article · Feb 2015 · Endocrine Reviews
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    ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
    Full-text · Article · Feb 2015 · Nature
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    ABSTRACT: 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<5x10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
    Full-text · Article · Jan 2015 · PLoS Genetics
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    ABSTRACT: Objectives To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance.Methods Sympathetic denervation of the omental fat was performed under general inhalant anesthesia by injecting 6-hydroxydopamine in the omental fat of lean mongrel dogs (n = 11). In the conscious animal, whole-body insulin sensitivity was assessed by the minimal model (SI) and the euglycemic hyperinsulinemic clamp (SICLAMP). Changes in abdominal fat were monitored by magnetic resonance. All assessments were determined before (Wk0) and 2 weeks (Wk2) after denervation. Data are medians (upper and lower interquartile).ResultsDenervation of omental fat resulted in increased percentage (and content) of visceral fat [Wk0: 10.2% (8.5-11.4); Wk2: 12.4% (10.4-13.6); P < 0.01]. Abdominal subcutaneous fat remained unchanged. However, no changes were found in SI [Wk0: 4.7 (mU/l)−1 min−1 (3.1-8.8); Wk2: 5.3 (mU/l)−1 min−1 (4.5-7.2); P = 0.59] or SICLAMP [Wk0: 42.0 × 10−4 dl kg−1 min−1 (mU/l)−1 (41.0-51.0); Wk2: 40.0 × 10−4 dl kg−1 min−1 (mU/l) −1 (34.0-52.0); P = 0.67].Conclusions Despite a selective increase in visceral adiposity in dogs, insulin sensitivity in vivo did not change, which argues against the concept that accumulation of visceral adipose tissue contributes to insulin resistance.
    Full-text · Article · Jan 2015 · Obesity

  • No preview · Article · Jan 2015 · Diabetologia
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    ABSTRACT: Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components although few studies have examined their genetic architecture or their influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multi-cohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently-sampled intravenous glucose tolerance test (4 cohorts) or euglycemic clamp (3 cohorts) and random effects models were used to test association between loci and quantitative traits, adjusting for age, gender, and admixture proportions (Discovery). Analysis revealed significant (P<5.00x10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P<0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D cases and 9,232 controls of Mexican ancestry (Translation). Non-parametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive risk for T2D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Full-text · Article · Dec 2014 · Diabetes
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    ABSTRACT: Context: Metabolomic profiling of amino acids and acylcarnitines has revealed consistent patterns associated with metabolic disease. Objective: Use metabolomic profiling to identify analytes associated with insulin sensitivity (SI) and conversion to type 2 diabetes (T2D). Design: Insulin Resistance Atherosclerosis Study. Setting: Community-based. Patients: A total of 196 subjects (European American, Hispanic, and African American) were selected to represent extremes of the SI distribution and conversion to T2D between baseline and follow-up exams. Main Outcome: Mass spectrometry-based profiling of 69 metabolites. Subjects participated in a frequently sampled intravenous glucose tolerance test to measure SI and acute insulin response (AIR). T2D status was determined by a 2-hour oral glucose tolerance test. Results: Logistic regression analysis from 72 high and 75 low SI subjects, revealed significantly decreased glycine and increased valine, leucine, phenylalanine, and combined glutamine and glutamate (P=0.0079-7.7×10(-6)) in insulin resistant subjects. Ethnic-stratified results were strongest in European Americans. Comparing amino acid profiles between subjects that converted to T2D (76 converters; 70 non-converters) yielded a similar pattern of associations: decreased glycine and increased valine, leucine, and combined glutamine and glutamate (P=0.016-0.00010). Importantly, beta-cell function as a covariate revealed a similar pattern of association. Conclusions: A distinct pattern of differences in amino acids were observed when comparing subjects with high and low levels of SI. This pattern was associated with conversion to T2D, remaining significant when accounting for beta-cell function, emphasizing a link between this metabolic profile and insulin resistance. These results demonstrate a consistent metabolic signature associated with insulin resistance and conversion to T2D, providing potential insight into underlying mechanisms of disease pathogenesis.
    No preview · Article · Nov 2014 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: Background: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. Objective: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20%E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. Methods: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)), participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled iv. glucose tolerance tests were administered after each dietary period. Results: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference +/- SE: 0.47 +/- 0.14 mmol/L; P = 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (rho = -0.18, P = 0.03) and positively correlated with changes in the acute insulin response to glucose (rho = 0.15, P = 0.05). Conclusions: These findings suggest that short-term intake Of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937.
    No preview · Article · Nov 2014 · Journal of Nutrition

Publication Stats

39k Citations
3,257.43 Total Impact Points

Institutions

  • 2011-2015
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 1991-2015
    • University of California, Los Angeles
      • • Department of Medicine
      • • Department of Physiology
      Los Ángeles, California, United States
    • California Southern University
      Irvine, California, United States
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2014
    • The University of Warwick
      • Division of Metabolic and Vascular Health
      Coventry, England, United Kingdom
  • 1979-2014
    • University of Southern California
      • • Department of Physiology and Biophysics
      • • Keck School of Medicine
      • • Department of Biomedical Engineering
      Los Ángeles, California, United States
  • 2012
    • University of Pittsburgh
      • Division of Endocrinology and Metabolism
      Pittsburgh, Pennsylvania, United States
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 1999-2010
    • University of Michigan
      • Department of Biostatistics
      Ann Arbor, Michigan, United States
    • National Human Genome Research Institute
      Maryland, United States
  • 2004-2007
    • University of Helsinki
      • Department of Dental Public Health
      Helsinki, Uusimaa, Finland
  • 1981-2007
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 2006
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • Medical University of Graz
      Gratz, Styria, Austria
  • 2005
    • Laval University
      Quebec City, Quebec, Canada
  • 2004-2005
    • Wake Forest School of Medicine
      • • Division of Public Health Sciences
      • • Department of Biochemistry
      Winston-Salem, North Carolina, United States
  • 1992-2005
    • Pennington Biomedical Research Center
      • Human Genomics Laboratory
      Baton Rouge, Louisiana, United States
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 2003
    • University of Pennsylvania
      • School of Veterinary Medicine
      Philadelphia, PA, United States
  • 1987-2002
    • University of Toronto
      • Department of Physiology
      Toronto, Ontario, Canada
  • 2001
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1998
    • University of Cambridge
      Cambridge, England, United Kingdom
    • University of South Carolina
      • Department of Epidemiology & Biostatistics
      Columbia, SC, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1996
    • Wake Forest University
      • Department of Public Health Sciences
      Winston-Salem, North Carolina, United States
  • 1994
    • University of Turku
      Turku, Southwest Finland, Finland
    • Italian National Research Council
      Roma, Latium, Italy
  • 1990
    • University of Texas Health Science Center at San Antonio
      • Division of Hospital Medicine
      San Antonio, Texas, United States
  • 1986
    • University of Washington Seattle
      • Department of Medicine
      Seattle, Washington, United States
  • 1980
    • Northwest University
      Evanston, Illinois, United States