G M Reaven

Stanford Medicine, Stanford, California, United States

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Publications (474)3049.87 Total impact

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    ABSTRACT: Importance There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.Objective To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Design, Setting, and Participants Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Main Outcomes and Measures Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Results Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).Conclusions and Relevance These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.
    No preview · Article · Oct 2015
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    Ki-Chul Sung · Gerald Reaven
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    ABSTRACT: To evaluate the hypothesis that measurement of fasting plasma triglyceride concentration identifies individuals at enhanced risk of statin-induced type 2 diabetes mellitus. A retrospective analysis of data collected from routine health examinations in non-diabetic, East Asian individuals (n = 5790) with low-density lipoprotein cholesterol concentrations of ⩾3.4 mmol/L. Subjects were stratified into those with or without a triglyceride concentration of ⩾1.7 mmol/L, and comparisons made of risk factors for type 2 diabetes mellitus. Approximately 40% of men and 20% of women with elevations of both low-density lipoprotein cholesterol and triglyceride concentrations were more insulin resistant (homeostatic model assessment of insulin resistance), associated with higher plasma concentrations of HbA1c, glucose and insulin. Apparently, healthy, non-diabetic East Asian men and women with combined elevations of low-density lipoprotein cholesterol and triglyceride concentrations are glucose intolerant and insulin resistant, and thereby at enhanced risk of type 2 diabetes mellitus. Measurement of plasma triglyceride concentration can identify within a hypercholesterolemic population a subset of individuals at enhanced risk of statin-induced type 2 diabetes mellitus. © The Author(s) 2015.
    Preview · Article · May 2015 · Diabetes & Vascular Disease Research
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    ABSTRACT: Insulin resistance has been associated with higher plasma amino acid (AA) concentrations, but majority of studies have used indirect measures of insulin resistance. Our main objective was to define the relationship between plasma AA concentrations and a direct measure of insulin resistance in women and men. This was a cross-sectional study of 182 nondiabetic individuals (118 women and 64 men) who had measurement of 24 AAs and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. Fourteen out of 24 AA concentrations were significantly (P < 0.05) higher in men than women; only glycine was lower in men. Majority of these AAs were positively associated with SSPG; only glycine concentration was negatively associated. Glutamic acid, isoleucine, leucine, and tyrosine concentrations had the strongest correlation with SSPG (r ≥ 0.4, P < 0.001). The degree of association was similar in women and men, independent of obesity, and similar to traditional markers of insulin resistance (e.g., glucose, triglyceride, high-density lipoprotein cholesterol). Compared with women, men tended to have a more unfavorable AA profile with higher concentration of AAs associated with insulin resistance and less glycine. However, the strength of association between a direct measurement of insulin resistance and AA concentrations were similar between sexes and equivalent to several traditional markers of insulin resistance. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    Preview · Article · May 2015
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    ABSTRACT: Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
    Full-text · Article · Mar 2015 · The Journal of clinical investigation
  • J. Armato · R. Ruby · G. Reaven
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    ABSTRACT: Objective: To evaluate the ability of plasma triglyceride (TG) measurements to identify statin-treated persons at accentuated risk of statin-induced type 2 diabetes (T2DM). Methods: The experimental population consisted of nondiabetic, statin-treated patients (n = 469), classified as being at high risk for T2DM, subdivided on the basis of a plasma TG concentration of 1.7 mmol/L. Comparisons were made of demographic characteristics, concentrations of fasting glucose, insulin, HbA1c, and hs-CRP, oral glucose tolerance tests, estimates of insulin action and secretion, and lipid/lipoprotein profiles. Results: Despite similar fasting glucose and HbA1c concentrations, patients with elevated TG concentrations displayed markers of increased risk of T2DM (insulin resistance and compensatory hyperinsulinemia), more adverse lipid/lipoprotein profiles, and increased prevalence of abnormal hs-CRP values. Conclusion: These findings demonstrate that plasma TG concentrations ≥ 1.7 mmol/L identified a subset of individuals at enhanced risk of developing statin-induced diabetes within a population classified prior to statin treatment as being at high risk of T2DM.
    No preview · Article · Feb 2015 · Atherosclerosis
  • Danit Ariel · Gerald Reaven
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    ABSTRACT: Aims This study was based on the hypothesis that: (1) coronary heart disease (CHD) risk is accentuated in the insulin-resistant subset of persons with normal glucose tolerance (NGT) or prediabetes (PreDM); (2) the prevalence of insulin resistance, and associated abnormalities, is greater in subjects with PreDM; and (3) insulin resistance is the major contributor to increased CHD risk in these individuals. Methods A 75 g oral glucose challenge was used to classify volunteers as having NGT or PreDM. Steady-state plasma glucose (SSPG) concentrations during the insulin suppression test subdivided both groups into insulin sensitive (IS = SSPG
    No preview · Article · Oct 2014 · Acta Diabetologica
  • Ki-Chul Sung · Gerald Reaven · Sun Kim
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    ABSTRACT: Aim The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) has identified increased cardio-metabolic risk and outcome in European populations. The goal of this study was to see if this ratio would also have clinical utility in identifying cardio-metabolic risk in an East Asian population. Methods Measurements of various cardio-metabolic risk factors, including coronary calcium scores, were available on 12,166 apparently healthy Korean adults. Approximately 25% of men and women with the highest TG/HDL-C ratios were classified as being at high cardio-metabolic risk, and their risk factor profiles compared to the remainder of the population, as well as to individuals with the metabolic syndrome (MetS). Results High cardio-metabolic risk (upper 25%) was defined as a TG//HDL-C ratio ≥3.5 (men) or ≥2.0 (women), and all cardio-metabolic risk factors measured, including coronary calcium scores, were significantly more adverse when compared to individuals beneath these cut-points. Although cardio-metabolic risk profiles appeared reasonably comparable in subjects identified by either a high TG/HDL-C or a diagnosis of MetS, use of the TG/HDL-C increased the numbers at high risk. Conclusion Evidence that determination of the plasma TG/HDL-C concentration ratio provides a simple way to identify individuasl at increased cardio-metabolic risk has been extended to an East Asian population. The ability of an elevated TG/HDL-C ratio to accomplish this goal is comparable to that achieved using the more complicated MetS criteria.
    No preview · Article · Jul 2014 · Diabetes Research and Clinical Practice
  • D. Ariel · S.H. Kim · F. Abbasi · C.A. Lamendola · A. Liu · G.M. Reaven
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    ABSTRACT: Background and Aims To evaluate the effects of 14 weeks of liraglutide plus modest caloric restriction on lipid/lipoprotein metabolism in overweight/obese persons with prediabetes. Methods and Results Volunteers with prediabetes followed a calorie restricted diet (-500 Kcal/day) plus liraglutide (n=23) or placebo (n=27) for 14 weeks. The groups were similar in age (58±7 vs. 58±8 years) and body mass index (31.9±2.8 vs. 39.1±3.5 kg/m²). A comprehensive lipid/lipoprotein profile was obtained before and after intervention using Vertical Auto Profile (VAP). Weight loss was greater in the liraglutide group than in the placebo group (6.9 vs. 3.3 kg, p<0.001), as was the fall in fasting plasma glucose concentration (9.9 mg/dL vs. 0.3 mg/dL, p<0.001). VAP analysis revealed multiple improvements in lipid/lipoprotein metabolism in liraglutide-treated compared with placebo-treated volunteers, including decreases in concentrations of total cholesterol, low-density lipoprotein cholesterol and several of its sub-classes, triglyceride, and non-high-density cholesterol. The liraglutide-treated group also had a significant shift away from small, dense low-density lipoprotein-particles, as well as decreases in apolipoprotein B concentration and ratio of apolipoprotein B/apolipoprotein A-1. There were no significant changes in the lipoprotein profile in the placebo-treated group. Conclusion Treatment with liraglutide plus modest calorie restriction led to enhanced weight loss, a decrease in fasting plasma glucose concentration, and improvement in multiple aspects of lipid/lipoprotein metabolism associated with increased cardiovascular disease (CVD) risk. The significant clinical benefit associated with liraglutide-assisted weight loss in a group at high risk for CVD – obese/overweight individuals with prediabetes – as seen in our pilot study, suggests that this approach deserves further study.
    No preview · Article · Jun 2014 · Nutrition Metabolism and Cardiovascular Diseases
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    Joshua W Knowles · Gerald Reaven

    Preview · Article · Mar 2014 · American journal of epidemiology
  • G. Reaven

    No preview · Article · Mar 2014 · Journal of Internal Medicine
  • Joshua W Knowles · Gerald Reaven
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    ABSTRACT: The thoughtful discussion by Wang, et al [1] of their finding that serum urate concentration "predicts subclinical atherosclerosis independently of BMI" emphasizes an unresolved question-is hyperuricemia a mechanism promoting atherogenesis, or simply a marker of other metabolic abnormalities that are the culprits. Although we tend to favor the second alternative, we also believe that it is difficult to come to a clear-cut answer concerning this quandary based solely on associations of serum uric acid levels with atherosclerosis. Moreover, there are data not discussed by Wang, et al that we believe are relevant to this issue. Insulin- mediated glucose uptake varies widely in nondiabetic individuals, and the more insulin resistant, the greater the degree of compensatory hyperinsulinemia [2-4]. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2014 · Journal of Internal Medicine
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    ABSTRACT: Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone. This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals. Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea. A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss. ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.
    No preview · Article · Dec 2013 · Diabetologia
  • Sun H Kim · Gerald Reaven
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    ABSTRACT: Context:The possibility that differences in insulin sensitivity explain why women, especially younger women, have a lower cardiovascular disease (CVD) risk than men remains an unsettled issue.Objective:The objective of this study was to evaluate whether sex disparities in CVD risk are associated with differences in insulin resistance.Design/Setting/Participants:This was a cross-sectional study of women (n = 468) and men (n = 354) who had the measurement of CVD risk factors and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. The population was also divided by median age (51 y) to evaluate the effect of age on sex differences.Main Outcome Measures/Results:In general, the SSPG concentration was similar between sexes. At higher BMI (≥30 kg/m(2)), women had significantly lower SSPG concentration than men (sexBMI interaction, P = .001). However, sex differences in CVD risk factors were not due to differences in SSPG but accentuated by a higher degree of insulin resistance in younger (age < 51 y) but not older (≥ 51 y) individuals. In younger individuals, women had significantly (P ≤ .007) lower diastolic blood pressure and fasting glucose and triglyceride concentration compared with men in SSPG tertile 3 (most insulin resistant) but not in tertile 1 (least insulin resistant). Older women had lower diastolic blood pressure compared with men, regardless of SSPG. High-density lipoprotein cholesterol remained higher in women, regardless of age or SSPG.Conclusions:The female advantage is not due to a difference in insulin action but results from an attenuation of the relationship between insulin resistance and CVD risk, especially in younger individuals.
    No preview · Article · Sep 2013 · The Journal of Clinical Endocrinology and Metabolism
  • Gerald Reaven

    No preview · Article · Jul 2013 · The Lancet
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    ABSTRACT: OBJECTIVE The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.RESEARCH DESIGN AND METHODS We randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.RESULTSEleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P = 0.001).CONCLUSIONS The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.
    Full-text · Article · Jul 2013 · Diabetes care
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    G M Reaven

    Preview · Article · May 2013 · Diabetologia
  • A Liu · G M Reaven
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    ABSTRACT: Background and aims: The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. Methods and results: Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥ 4.14 and ≥ 4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥ 4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. Conclusion: While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.
    No preview · Article · Jan 2013 · Nutrition, metabolism, and cardiovascular diseases: NMCD
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    Gerald Reaven
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    ABSTRACT: The goal of this review was to summarize evidence supporting the view that insulin resistance/compensatory hyperinsulinemia play an important role in the pathogenesis of coronary heart disease (CHD) in nondiabetic individuals. Results of case-control and epidemiological studies in nondiabetic individuals will be reviewed to examine the link between insulin resistance/compensatory hyperinsulinemia, associated abnormalities, and CHD. The primary focus of the review will be on the central role that dyslipidemia plays in the link between insulin resistance/compensatory hyperinsulinemia and CHD. Additional issues to be addressed include the following: (1) the relationship among obesity, insulin resistance, and CHD; (2) a listing of other abnormalities that contribute to risk of CHD in insulin-resistant individuals; and (3) discussion of the importance of differential tissue insulin sensitivity in the development of abnormalities that increase CHD risk in insulin-resistant, nondiabetic individuals. The information will reflect the author's decision as to what issues are believed to be of particular relevance or less well appreciated concerning the complex relationship between insulin resistance and CHD. Resistance to insulin-mediated glucose disposal and hyperinsulinemia is a common finding in apparently healthy individuals and is associated with a number of abnormalities that greatly increase risk of CHD.
    Preview · Article · Aug 2012 · Arteriosclerosis Thrombosis and Vascular Biology
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    Full-text · Article · Mar 2012 · Journal of the American College of Cardiology
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    G Reaven

    Preview · Article · Sep 2011 · Journal of Internal Medicine

Publication Stats

33k Citations
3,049.87 Total Impact Points


  • 1976-2015
    • Stanford Medicine
      • • Division of Cardiovascular Medicine
      • • Department of Medicine
      Stanford, California, United States
  • 1965-2015
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Department of Medicine
      • • Division of Endocrinology, Gerontology and Metabolism
      Stanford, California, United States
  • 1984-2010
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Maryland, United States
  • 1982-2007
    • Palo Alto University
      Palo Alto, California, United States
  • 2000
    • Fakultní nemocnice Plzeň
      Pilsen, Plzeňský, Czech Republic
  • 1991-2000
    • Università degli studi di Parma
      • Department of Clinical and Experimental Medicine
      Parma, Emilia-Romagna, Italy
    • University of California, San Francisco
      San Francisco, California, United States
    • Università degli Studi di Genova
      Genova, Liguria, Italy
  • 1979-1997
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 1996
    • University of Geneva
      Genève, Geneva, Switzerland
  • 1987-1996
    • Tri-Service General Hospital
      T’ai-pei, Taipei, Taiwan
  • 1994
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1990
    • National Defense Medical Center
      • Tri-Service General Hospital
      Taipei, Taipei, Taiwan
  • 1989-1990
    • Taipei Veterans General Hospital
      • Department of Medicine
      T’ai-pei, Taipei, Taiwan
  • 1986
    • University of California, Davis
      • Department of Nutrition
      Davis, California, United States