Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women

The relationship between circulating estrogen levels and cardiometabolic risk factors such as insulin resistance is unclear in postmenopausal women. High estradiol (E2) levels have been reported to predict increased risk of type 2 diabetes in this population. We aimed to examine associations among estrogen levels, adiposity measurements, and cardiometabolic risk variables including insulin resistance in postmenopausal women. One hundred-one healthy participants (mean ± SD: age 57 ± 4 yr, BMI 27.9 ± 4.8 kg/m2) were included in the analysis. Fifteen plasma steroids or metabolites were measured by liquid chromatography-tandem mass spectrometry. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Body composition and fat distribution were determined with hydrostatic weighing and computed tomography, respectively. Blood lipids and circulating cytokines were also measured. Circulating E2 was positively correlated with all adiposity indexes ( r = 0.62 to 0.42, P < 0.0001) except waist-to-hip ratio. E2 was positively correlated with VLDL-cholesterol, plasma-, VLDL-, and HDL-triglyceride levels ( r = 0.31 to 0.24, P < 0.02) as well as with hs-CRP and IL-6 ( r = 0.52 and 0.29, P < 0.005) and negatively with HDL-cholesterol, adiponectin, and insulin sensitivity ( r = −0.36 to −0.20, P < 0.02). With adjustments for percent body fat, correlations between E2 and metabolic risk variables were no longer significant. Similar results were observed for circulating estrone (E1) and estrone-sulfate (E1-S) levels. In conclusion, circulating estrogen concentrations are proportional to adipose mass in postmenopausal women, although they remain in the low range. Insulin resistance as well as altered blood lipids and cytokines are observed when circulating estrogen levels are high within that range, but these differences are explained by concomitant variation in total adiposity.

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Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia

Acta Endocrinologica ◽

10.1530/eje-09-0523 ◽

2009 ◽

Vol 161 (6) ◽

pp. 887-894 ◽

Cited By ~ 7

Author(s):

Jeanne Margot Kroese ◽

Christiaan F Mooij ◽

Marinette van der Graaf ◽

Ad R M M Hermus ◽

Cees J Tack

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Insulin Sensitivity ◽

Body Fat ◽

Matched Control ◽

Fat Distribution ◽

Body Fat Distribution ◽

Adrenal Hyperplasia ◽

Insulin Resistant ◽

Steroid Profiles

ContextPatients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.ObjectivesTo assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.DesignRandomized placebo controlled crossover trial.ParticipantsTwelve CAH patients and 12 body mass and age-matched control subjects.InterventionSixteen-week treatment with pioglitazone (45 mg/day) or placebo.Main outcome measureInsulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.ResultsCAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5±11.6 to 38.9±11.0 μmol/kg per min, P=0.000, GIR in controls 46.2±23.4 μmol/kg per min, P<0.05 versus CAH). Treatment with pioglitazone decreased blood pressure (systolic: 124.0±13.6 vs 127.0±14.9 mmHg, P<0.001, diastolic: 72.8±11.5 vs 77.4±12.6 mmHg, P<0.001). No changes in body fat distribution, lipid, and steroid profiles were observed.ConclusionsCAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.

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Relationship between hormone replacement therapy use with body fat distribution and insulin sensitivity in obese postmenopausal women

Metabolism ◽

10.1053/meta.2001.24878 ◽

2001 ◽

Vol 50 (7) ◽

pp. 835-840 ◽

Cited By ~ 37

Author(s):

Cynthia K. Sites ◽

Martin Brochu ◽

Andr[eacute] Tchernof ◽

Eric T. Poehlman

Keyword(s):

Hormone Replacement Therapy ◽

Insulin Sensitivity ◽

Replacement Therapy ◽

Postmenopausal Women ◽

Body Fat ◽

Hormone Replacement ◽

Fat Distribution ◽

Body Fat Distribution

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Body Fat Distribution, Cardiometabolic Traits, and Risk of Major Lower-Extremity Arterial Disease in Postmenopausal Women

10.2337/figshare.16775866.v1 ◽

2021 ◽

Author(s):

Guo-Chong Chen ◽

Rhonda Arthur ◽

Victor Kamensky ◽

Jin Choul Chai ◽

Bing Yu ◽

...

Keyword(s):

Risk Factors ◽

Lower Extremity ◽

Postmenopausal Women ◽

Body Fat ◽

Positive Association ◽

Fat Distribution ◽

Arterial Disease ◽

Hip Circumference ◽

Lower Extremity Arterial Disease ◽

Cardiometabolic Traits

OBJECTIVE To assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD). RESEARCH DESIGN AND METHODS We included 155,925 postmenopausal women with anthropometric measures from the Women’s Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by dual energy X-ray absorptiometry (DXA). Incident cases of symptomatic LEAD were ascertained and adjudicated via medical record review. RESULTS We identified 1152 incident LEAD cases during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumference was positively and inversely associated with risk of LEAD, respectively (both P-trend values <0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA-IR (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend <0.0001) was associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082). CONCLUSIONS Among US postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors.

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Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416412112 ◽

2015 ◽

Vol 112 (14) ◽

pp. 4363-4368 ◽

Cited By ~ 37

Author(s):

James E. N. Minchin ◽

Ingrid Dahlman ◽

Christopher J. Harvey ◽

Niklas Mejhert ◽

Manvendra K. Singh ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

High Fat ◽

Type V ◽

Visceral Adipose

Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans.

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Body Fat Distribution, Cardiometabolic Traits, and Risk of Major Lower-Extremity Arterial Disease in Postmenopausal Women

10.2337/figshare.16775866 ◽

2021 ◽

Author(s):

Guo-Chong Chen ◽

Rhonda Arthur ◽

Victor Kamensky ◽

Jin Choul Chai ◽

Bing Yu ◽

...

Keyword(s):

Risk Factors ◽

Lower Extremity ◽

Postmenopausal Women ◽

Body Fat ◽

Positive Association ◽

Fat Distribution ◽

Arterial Disease ◽

Hip Circumference ◽

Lower Extremity Arterial Disease ◽

Cardiometabolic Traits

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Regulation of glucose metabolism in nondiabetic, metabolically obese normal-weight Asians

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00382.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. E494-E502 ◽

Cited By ~ 12

Author(s):

Cherlyn Ding ◽

Zhiling Chan ◽

Yu Chung Chooi ◽

John Choo ◽

Suresh Anand Sadananthan ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Body Fat ◽

Postprandial Glucose ◽

Normal Weight ◽

Increased Risk ◽

Total Body Fat ◽

Metabolically Obese Normal Weight ◽

Total Body

Type 2 diabetes in Asia occurs largely in the absence of obesity. The metabolically obese normal-weight (MONW) phenotype refers to lean subjects with metabolic dysfunction that is typically observed in people with obesity and is associated with increased risk for diabetes. Previous studies evaluated MONW subjects who had greater body mass index (BMI) or total body fat than respective control groups, making interpretation of the results difficult. We evaluated insulin sensitivity (hyperinsulinemic-euglycemic clamp); insulin secretion (mixed meal with oral minimal modeling); intra-abdominal, muscle, and liver fat contents (magnetic resonance); and fasting and postprandial glucose and insulin concentrations in 18 MONW subjects and 18 metabolically healthy controls matched for age (43 ± 3 and 40 ± 3 yr; P = 0.52), BMI (both 22 ± 1 kg/m2; P = 0.69), total body fat (17 ± 1 and 16 ± 1 kg; P = 0.33), and sex (9 men and 9 women in each group). Compared with controls, MONW subjects had an approximately twofold greater visceral adipose tissue volume and an approximately fourfold greater intrahepatic fat content (but similar muscle fat), 20–30% lower glucose disposal rates and insulin sensitivity, and 30–40% greater insulin secretion rates (all P < 0.05). The disposition index, fasting glucose, and HbA1c concentrations were not different between groups, whereas postprandial glucose and insulin concentrations were ~15% and ~65% greater, respectively, in MONW than control subjects (both P < 0.05). We conclude that the MONW phenotype is associated with accumulation of fat in the intra-abdominal area and the liver, profound insulin resistance, but also a robust β-cell insulin secretion response that compensates for insulin resistance and helps maintain glucose homeostasis.

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Associations of Adiponectin with Body Fat Distribution and Insulin Sensitivity in Nondiabetic Hispanics and African-Americans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2614 ◽

2007 ◽

Vol 92 (7) ◽

pp. 2665-2671 ◽

Cited By ~ 80

Author(s):

Anthony J. G. Hanley ◽

Donald Bowden ◽

Lynne E. Wagenknecht ◽

Aarthi Balasubramanyam ◽

Carl Langfeld ◽

...

Keyword(s):

Insulin Resistance ◽

African American ◽

Insulin Sensitivity ◽

African Americans ◽

High Density Lipoprotein ◽

Body Fat ◽

Density Lipoprotein ◽

Fat Distribution ◽

High Density ◽

Adiponectin Concentration

Abstract Context: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance have been reported, very little data are available from studies using detailed measures of insulin sensitivity (SI) and/or body fat distribution in ethnic groups at high risk for metabolic disease. Objective: The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans. Design: A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. SI was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration. Setting: A multicenter study using a family-based design was conducted. Participants: A total of 1636 nondiabetic Hispanic and African-American subjects participated. Main Outcome Measures: Circulating adiponectin concentration was measured. Results: Age, female gender, high-density lipoprotein, SAT, and SI were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics. Conclusion: Directly measured SI, VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.

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Body fat distribution, menopausal hormone therapy and incident type 2 diabetes in postmenopausal women of the MESA study

Maturitas ◽

10.1016/j.maturitas.2016.06.020 ◽

2016 ◽

Vol 91 ◽

pp. 147-152

Author(s):

Imo A. Ebong ◽

Karol E. Watson ◽

Kristen G. Hairston ◽

Mercedes R. Carnethon ◽

Pamela Ouyang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Hormone Therapy ◽

Postmenopausal Women ◽

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

Menopausal Hormone Therapy ◽

Incident Type ◽

Incident Type 2 Diabetes

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Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study

Acta Endocrinologica ◽

10.1530/eje.1.02065 ◽

2006 ◽

Vol 154 (1) ◽

pp. 131-139 ◽

Cited By ~ 18

Author(s):

Lenora M Camarate S M Leão ◽

Mônica Peres C Duarte ◽

Dalva Margareth B Silva ◽

Paulo Roberto V Bahia ◽

Cláudia Medina Coeli ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Postmenopausal Women ◽

Fat Mass ◽

Visceral Fat ◽

Increased Risk

Background: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. Objective: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. Design: Thirty-seven postmenopausal women aged 42–62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. Methods: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. Results: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. Conclusion: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.

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