G M Reaven’s research while affiliated with Stanford University and other places

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Publications (885)


Weight Loss in Insulin Resistant Obese Individuals: 60% Vs 40% Carbohydrate Diet
  • Article

May 2023

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12 Reads

Journal of Investigative Medicine

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Fahim Abbasi

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Cindy Lamendola

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[...]

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Gerald M Reaven



Statins Are Associated With Increased Insulin Resistance and Secretion

August 2021

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53 Reads

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73 Citations

Arteriosclerosis Thrombosis and Vascular Biology

Objective Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISR AUC ) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m ² ). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P <0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% ( P =0.01) and insulin secretion (ISR AUC ) by a median of 9% ( P <0.001). There were small increases in oral glucose tolerance test glucose AUC (median increase, 0.05%; P =0.03) and fasting insulin (median increase, 7%; P =0.01). Conclusions In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02437084.


Regulatory variants within the FAM13A locus are associated with several IR traits
Intronic non-coding variants in the FAM13A locus show associations with several IR-related and metabolic traits, including body fat percentage (a), and fasting insulin (b) and waist-hip ratio (c) (adjusted for BMI) across cohorts and studies. These GWAS association signals colocalize with FAM13A eQTL association signal in subcutaneous adipose tissue (from GTEx v7, d). However, this association is not robust in visceral adipose tissue (e). f The variants show evidence of enrichment in a regulatory active H3K27ac region in adipose nuclei. Annotations from pancreas and lung are shown as negative comparators.
PheWAS analysis of FAM13A variants
a Phenome-wide association analysis of the variant rs1377290 (used as a proxy for finemapping lead variant rs9991328, LD R2 1.0) performed in ~337 K individuals in the U.K. Biobank shows associations with metabolically related phenotypes, including body fat and trunk fat percentage. Associations significant at 10% FDR are labeled. b In male subjects in the METSIM cohort, normalized FAM13A expression in subcutaneous adipose tissue (adjusted for BMI) shows a positive correlation with fasting insulin and waist-hip-ratio, but a negative correlation with bioimpedance measured fat percentage. Two-sided t-tests were used in cis-eQTL mapping.
Effects of FAM13A knockdown in human adipocyte differentiation
aFAM13A mRNA expression during adipogenesis of human SGBS preadipocytes. b mRNA expression of FAM13A, measured 2 days after siRNA transfection and before initiation of adipogenesis. c mRNA expression of adipogenic markers (CEBPA, PPARG), measured 5 days after adipogenic induction in cells transfected with scrambled siRNA or siFAM13A. d mRNA expression of FAM13A, measured 8 days after lentiviral infection and before initiation of adipogenesis. e mRNA expression of adipogenic markers (CEBPA, PPARG), measured 5 days after adipogenic induction in cells transduced with scrambled sgRNA or three independent sgRNAs against FAM13A. f mRNA expression of FAM13A, measured on D10 of adipogenesis and 2 days after siRNA transfection. g Basal and insulin-stimulated [3H] glucose uptake, measured on D12 differentiated adipocytes and 4 days after siRNA transfection. Data are presented as mean ± SEM. n = 3 independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, unpaired t test (for b and f), one-way ANOVA followed by Turkey’s multiple comparison test (for a and d), 2-way ANOVA followed by Sidak’s multiple comparison test (for c). Source Data are provided as a Source Data file.
Metabolic profiling of male Fam13a KO mice
a Representative H&E images (×20 magnification) of VAT and SAT in 14 weeks old of male WT and Fam13a KO mice fed on chow. (n = 7 per group, ×20 magnification, scale bar = 25 μm). b, c Adipocyte number per SAT or VAT depot (b) and the average diameter of adipocytes in SAT or VAT (c), in 14-week-old male WT and Fam13a KO mice fed on chow. (n = 7 per group). d, e Adipocytes size distribution in SAT (d) or VAT (e) of 14 weeks old of male WT and Fam13a KO mice fed on chow. (n = 7 per group; 2000–2200 cells per animal were used for adipocyte diameter determination; statistical differences between WT and KO mice in adipocyte diameter distribution curve were estimated by Kolmogorov-Smirnov test, ns for both SAT and VAT). f Body weight of male WT and Fam13a KO mice fed on HFD from 8 weeks to 20 weeks old. (n = 6 per group). g Tissue mass of male WT and Fam13a KO mice after 14 weeks HFD. (n = 6 per group). h Ratio of VAT/SAT, based on tissue mass, in male WT and Fam13a KO mice after 14 weeks HFD. (n = 6 per group). All values are presented as mean ± SEM. *p < 0.05, unpaired t-test. Source Data are provided as a Source Data file.
Effect of Fam13a on adipocyte differentiation of mouse SVFs isolated from SAT
a, bFam13a (a) and Adipoq (b) mRNA expression, quantified by qRT-PCR, in freshly isolated SVF, primary mature adipocytes (floater), or during in vitro adipogenesis of cultured SVFs (D0, D4, and D10). (8-week-old male WT mice, n = 3 per group, n = 3 culture wells per animal) c mRNA expression of adipogenic markers (Pparg, Cebpa, Fabp4), measured by qRT-PCR during in vitro adipogenesis of cultured SVFs (D0, D4, D10). (8-week-old male WT or Fam13a KO mice when isolating SVFs, n = 6 per group, n = 3 culture wells per animal). d, e Oil-Red O staining of lipid droplets (d) and semi-quantification (e) in D10 differentiated adipocytes from SVFs. (n = 6 per group, pictures represent n = 6 independent experiments, n = 3 cultures/animal, ×10 magnification, scale bar=100 μm). f Intracellular triglyceride content in D10 differentiated adipocytes from SVFs. (n = 6 per group, n = 3 culture wells per animal). g Basal and insulin-stimulated [3H] glucose uptake in D10 differentiated adipocytes from SVFs. (n = 3 per group, n = 3 culture wells per animal). h Basal and insulin-stimulated [3H] glucose uptake in SAT explants. (8-week-old male mice, n = 3 per group, n = 3 ex vivo cultures per animal). Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, one-way ANOVA followed by Turkey’s multiple comparison test. Source Data are provided as a Source Data file.

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FAM13A affects body fat distribution and adipocyte function
  • Article
  • Full-text available

March 2020

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361 Reads

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44 Citations

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution. Genetic variants in the FAM13A locus have been associated with anthropometric and glycemic traits. Here, using fine-mapping, in vitro knockdown studies in pre-adipocytes and in vivo knockout in mice, the authors show that FAM13A is involved in regulating fat distribution and metabolic traits.

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Cardiorespiratory Fitness, Body-Mass Index, and Markers of Insulin Resistance in Apparently Healthy Women and Men

January 2020

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28 Reads

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19 Citations

The American Journal of Medicine

Background: Insulin resistance may be present in healthy adults and is associated poor health outcomes. Obesity is a risk factor for insulin resistance, but most obese adults do not have insulin resistance. Fitness may be protective, but the association between fitness, weight, and insulin resistance has not been studied in a large population of healthy adults. Methods: A cross-sectional analysis of cardiorespiratory fitness, body-mass index, and markers of insulin resistance was performed. Study participants were enrolled at the Cooper Clinic (Dallas, Texas). The analysis included 19,263 women and 48,433 men with no history of diabetes or cardiovascular disease. Cardiorespiratory fitness was measured using exercise treadmill testing. Impaired fasting glucose (100-125 mg/dL) and elevated fasting triglycerides (≥150 mg/dL) were used as a markers of insulin resistance. Results: Among normal weight individuals, poor fitness was associated with a 2.2 (1.4-3.6; p=0.001) fold higher odds of insulin resistance in women and a 2.8 (2.1-3.6; p<0.001) fold higher odds in men. The impact of fitness remained significant for overweight and obese individuals, with the highest risk group being the unfit obese. Among obese women, the odds ratio for insulin resistance was 11.0 (8.7-13.9; p<0.001) for fit and 20.3 (15.5-26.5; p<0.001) for unfit women. Among obese men, the odds ratio for insulin resistance was 7.4 (6.7-8.2; p<0.001) for fit and 12.9 (11.4-14.6; p<0.001) for unfit men. Conclusion: Independent of weight, poor fitness is associated with risk of insulin resistance. Obese individuals, particularly women, may benefit from the greatest absolute risk reduction by achieving moderate fitness.


Plasma glucose concentration 60 min post oral glucose load and risk of type 2 diabetes and cardiovascular disease: Pathophysiological implications

July 2019

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44 Reads

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3 Citations

Diabetes and Vascular Disease Research

Aim: The aim of this study was to gain insight into the pathophysiological significance of elevated plasma glucose concentrations (mmol/L) 60 min post oral glucose load in apparently healthy individuals. Methods: Comparison of resistance to insulin action and associated cardio-metabolic risk factors in 490 apparently healthy persons, subdivided into those with a plasma glucose concentration 60 min following a 75-g oral glucose challenge of <8.6 versus ⩾8.6. Results: Insulin resistance was significantly greater in persons with normal glucose tolerance whose 60-min glucose concentration was ⩾8.6, associated with higher blood pressure, plasma concentrations of glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol concentrations. Similar differences were seen in persons with impaired fasting glucose, but not in those with impaired glucose tolerance or both impaired fasting glucose and impaired glucose tolerance. The group whose 60-min glucose was <8.6 (n = 318) contained primarily persons with normal glucose tolerance (88%), whereas the majority of those whose 60-min value was ⩾8.6 (n = 172) had prediabetes (59%) and in particular combined impaired fasting glucose and impaired glucose tolerance. Conclusion: Plasma glucose concentration of ⩾8.6 mmol/L 60 min post oral glucose identifies higher proportions of combined impaired fasting glucose and impaired glucose tolerance individuals as well as normal glucose tolerance and impaired fasting glucose individuals with a more adverse cardio-metabolic profile, contributing to observed increased overall risk of type 2 diabetes and other metabolic diseases.


Relationship among obesity, insulin resistance, and hyperinsulinemia in the polycystic ovary syndrome

June 2019

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38 Reads

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58 Citations

Endocrine

Purpose To evaluate the relationship between obesity and insulin resistance among women with polycystic ovary syndrome (PCOS) using a gold standard test. Methods A retrospective database analysis of 75 women with PCOS and 118 normal controls who underwent a modification of the insulin suppression test. The relationships between body mass index (BMI) and steady-state plasma glucose (SSPG) levels were investigated. Results Mean SSPG score for PCOS subjects was statistically similar than that of the controls at all BMI groupings. Only when PCOS subjects reached a BMI of ≥30 kg/m² that the PCOS subjects had higher mean SSPG score than the control subjects, although not significantly so (p = 0.07). The distribution of PCOS and control subjects in each SSPG quartile grouping was investigated. When comparing all PCOS and control subjects, PCOS subjects were more likely to be in the higher quartiles of SSPG score (p = 0.0001). However, when comparing the PCOS and control subjects, at each BMI grouping (<25, 25–29.9, and ≥30 kg/m²), there was no difference in the likelihood that a larger percent of subjects fell into a different quartile (p = 0.12, 0.69, 0.32, respectively). Conclusions PCOS subjects have increased magnitudes of insulin resistance when compared to ovulatory controls, when controlling for age, BMI, fasting glucose, and insulin levels. However, the magnitude of this insulin resistance in lean subjects is mild. Quantity of excess body fat, particularly subjects with a BMI of at least 30 kg/m² is the primary predictor of insulin resistance of sufficient magnitude to put PCOS subjects at increased risk for metabolic abnormalities.


Baseline characteristics by race/ethnicity and sex.
SSPG by sex and race/ethnicity (unadjusted).
SSPG by race/ethnicity (adjusted for age, sex and BMI).
TG level by race/ethnicity (adjusted for age, sex, SSPG and BMI).
Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia

March 2019

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74 Reads

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62 Citations

Diabetes and Vascular Disease Research

Objective: Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups. Research design and methods: In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance. Results: Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations. Conclusion: Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.


Relationship between surrogate estimates and direct measurement of insulin resistance in women with polycystic ovary syndrome

January 2019

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27 Reads

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16 Citations

Journal of Endocrinological Investigation

Purpose To evaluate the relationship between surrogate estimates of insulin resistance and a direct measurement of insulin-mediated glucose uptake women with and without PCOS. Methods Retrospective cohort study of 75 PCOS and 118 controls. Fasting plasma glucose and insulin concentrations, insulin resistance as determined by the insulin suppression test, calculation of multiple surrogate estimates of insulin resistance, total and free testosterone concentrations, and correlations between the direct measure and surrogate estimates of insulin resistance were evaluated. Result(s) Surrogate markers of insulin resistance were correlated to a variable, but statistically significant degree with the direct measure of insulin resistance in control population and the women with PCOS. There was no correlation between the surrogate estimates of insulin resistance and total or free plasma testosterone concentrations. Conclusion(s) The surrogate estimates of insulin resistance evaluated were significantly related to a direct measure of insulin resistance, and this was true of both the control population and women with PCOS. The magnitude of the relationship between the surrogate estimates and the direct measurement was comparable and not significantly altered by androgen levels. Fasting plasma insulin concentration seems to be at least as accurate as any other surrogate estimate, and is by far the simplest.


Citations (80)


... Interestingly, developmental genes that are targets for the PRC2 complex, the molecular machinery responsible for the repressive mark of bivalency H3K27me3, are the most variably expressed amongst PSC lines, often varying in different clones from genetically identical donors and showing little correlation with the genetic background. 86 This is in line with our conclusions that developmental genes are particularly sensitive to transient patterning signalling, which persistently changes proportions of H3K27me3 and H3K4me3 marks, thus inducing lineage priming. ...

Reference:

Epigenetic restoration of differentiation competency via reversal of epiblast regionalisation
Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity
  • Citing Article
  • October 2022

Cell Stem Cell

... Recently, an open-label clinical trial of atorvastatin 40 mg daily in 71 adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline investigated the effects on insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test during the graded-glucose infusion test after 10 weeks [19]. Atorvastatin reduced LDL-cholesterol by 53% but did not change body weight. ...

Statins Are Associated With Increased Insulin Resistance and Secretion
  • Citing Article
  • August 2021

Arteriosclerosis Thrombosis and Vascular Biology

... [24] Atherosclerosis is an important contributor to the occurrence of coronary heart disease, and vascular endothelial cell injury and the accumulation of low-density lipoprotein (LDL) are the main factors behind the incidence of atherosclerosis. [26] In this study, the effects of A. elata root, leaf, and stem extracts on human umbilical vein endothelial cells (HUVECs) induced by oxidized LDL (ox-LDL) were assessed. In addition to reinioside C, analogues of triterpene saponins have been isolated from Polygala fallax Hemsl that protect HUVECs induced by Ox-LDL. ...

Abstract MP37: The Triglyceride to High-density Lipoprotein Cholesterol Ratio, an Estimate of Insulin Resistance, is Associated with Incident Coronary Heart Disease. The Atherosclerosis Risk in Communities (ARIC) Study
  • Citing Article
  • March 2016

Circulation

... For example, two novel loci harbored genes with well-known roles in glucose metabolism (IRS1 and PPARG). In addition, recent studies have implicated HNF4A and PROX1-AS1 in insulin resistance and T2D [66,67], whereas loci harboring FAM13A, RSPO3, and EBPL have been associated with body fat distribution and hepatic steatosis [68][69][70]. Genes at other loci are likely involved in the synthesis or degradation of glycine itself. For instance, HOGA1 catalyzes the breakdown of hydroxyproline into glyoxylate, which can serve as a substrate for glycine production [71]. ...

FAM13A affects body fat distribution and adipocyte function

... Due to these strict inclusion criteria in embryo grade at transfer we can draw better conclusions about the uterine environment or embryo potential irrespective of grade. We controlled for BMI with its substantial effect on insulin resistance [52,57]. ...

Cardiovascular disease in PCOS is related to severe insulin resistance, not mild
  • Citing Article
  • September 2017

Minerva Endocrinologica

... Los efectos beneficiosos del ejercicio físico sobre el SMet han sido evidenciados, cada componente del SMet es favorecido por la actividad física y los mecanismos subyacentes Tabla 3. Comparación pre y post intervención de las variables antropométricas, de composición corporal, condición física y salud mental, entre grupos control e intervenido incluyen una mejoría de la aptitud cardiorrespiratoria [32][33][34] . El presente estudio concluye que 95% de la población de mujeres con alteraciones metabólicas propias del SMet, presentaron baja y muy baja ACR y, que una intervención vía m-Health mejoró la ACR, el perímetro de cintura y la PAD luego de 10 semanas de intervención. ...

Cardiorespiratory Fitness, Body-Mass Index, and Markers of Insulin Resistance in Apparently Healthy Women and Men
  • Citing Article
  • January 2020

The American Journal of Medicine

... One reason for this phenomenon may stem from a lower prevalence of gallstones in Asian countries compared to western countries [24,27]. In addition, there are recognized ethnic differences in the levels of baseline triglycerides; these are highest in East Asians, followed by Caucasians, and lowest in South Asians and African Americans [29]. However, we also observed from Table 7 that APIP etiologies differ between countries and regions on the same continent, even in the context of similar geographical and racial factors. ...

Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia

Diabetes and Vascular Disease Research

... The presence of many risk factors for cardiovascular diseases (CVD), including hypertension, insulin resistance, metabolic syndrome, elevated BMI and dyslipidemia in women with T1DM and PCOS as well as in those with T2DM contributes to a significantly higher risk of CVD events [10][11][12]. ...

Relationship among obesity, insulin resistance, and hyperinsulinemia in the polycystic ovary syndrome

Endocrine

... • Insulin resistance [63,77,107,108] • Obesity and visceral adiposity [109][110][111][112] • Metabolic syndrome [111][112][113] • Pro-atherogenic lipid profile [114,115] • Increased uric acid [116] • Increased viscosity [117] • Reduced Vitamin D [118] • Increase in pro-inflammatory markers [119,120] • Increase in oxidative stress markers [85,121] • Reduction in molecules with anti-inflammatory properties [119,122] • Increase in platelet activation markers [85] • Increase in advanced glycated end-products (AGEs) and decrease in endogenous secretory receptor for advanced glycation end products secreted RAGE (esRAGE) [123,124] • Decrease in circulating adiponectin [103] Association with target-organ damage: ...

Plasma glucose concentration 60 min post oral glucose load and risk of type 2 diabetes and cardiovascular disease: Pathophysiological implications

Diabetes and Vascular Disease Research

... The euglycemic clamp technique is the gold standard for evaluating IR; however, it is not ideal for large-scale epidemiological studies due to the technique complexity. Hence, surrogate indices, such as the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI), have been introduced [10,11]. ...

Relationship between surrogate estimates and direct measurement of insulin resistance in women with polycystic ovary syndrome
  • Citing Article
  • January 2019

Journal of Endocrinological Investigation