Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey

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Abstract

Aims

We examined interaction of sex steroid hormones and obesity with regard to insulin resistance (IR) and type 2 diabetes (T2D) by using nationally representative data from the US.

Methods

Data of 1461 men aged ≥ 20 years who participated in the Third National Health and Nutrition Examination Survey were analyzed. Multiplicative interaction was calculated by cross-product interaction terms in multivariable logistic regression models. Additive interaction was assessed by the relative excess risk due to interaction (RERI).

Results

After adjusting for demographic and lifestyle covariates, the odds of IR were greatest among obese men with low free testosterone and high androstanediol glucuronide. Multiplicative interactions for total testosterone, free testosterone, and free estradiol index (FEI) were statistically significant with central obesity but not with overweight and obesity regarding to T2D (P < 0.05). Significant additive interactions with obesity or central obesity were detected for total testosterone (RERI = 2.75, 95% CI = 0.92,4.59), SHBG (RERI = 5.71, 95% CI = 0.77,10.64), and FEI (RERI =  9.96, 95% CI =  19.18,-0.74) with regard to IR, beta-cell dysfunction, and T2D.

Conclusions

Our findings add to the evidence suggesting that low testosterone and high estradiol may be associated greater risks of IR and T2D by interacting with overall and central obesity in adult men.

Introduction

Type 2 diabetes (T2D) is a chronic disease characterized by insulin resistance (IR) and malfunction of beta-cell secretion. The prevalence of T2D has been increasing at an alarming rate worldwide. Approximately 439 million people are predicted to live with diabetes by 2030 (Shaw, Sicree, & Zimmet, 2010). People with T2D have much greater risks of cardiovascular disease, blindness, renal disease, and amputation compared to those without T2D (Nathan, 1993). Identifying modifiable risk factors is a top priority for T2D prevention and control.

Cumulative epidemiological studies have demonstrated that endogenous sex steroid hormones such as testosterone and estradiol may be associated with risk of IR and T2D in men (Ding et al., 2006, Tsai et al., 2004). Testosterone is the principle sex hormone in males, which is primarily secreted by testicles. Converted from testosterone, estradiol serves as the main bioactive form of estrogen in men. Testosterone levels were observed to be positively associated with insulin sensitivity measured by hyperinsulinemic–euglycemic clamp (Pitteloud et al., 2005). Men with elevated estradiol levels were more likely to develop IR and diabetes (Ding et al., 2006, Maggio et al., 2010). Many of the pathways underlying the relationships between sex steroid hormones, IR and T2D are associated with pathogenesis of obesity, and the latter is a leading risk factor of T2D.

The global increase in incidence and prevalence of T2D can be largely ascribed to obesity epidemic. Randomized clinical trials have shown that moderate weight loss significantly improved insulin sensitivity and glycemic control (Kelley et al., 2002, McAuley et al., 2002). Concomitantly, decreased testosterone but increased estradiol levels have been widely observed in obese adult males (Glass et al., 1977, Schneider et al., 1979). Yialamas et al. found that testosterone withdrawal may negatively modulate insulin sensitivity without significantly changing body composition (Yialamas et al., 2007), while another group of researchers reported attenuated association between testosterone and insulin sensitivity after controlling for BMI (Pitteloud et al., 2005). Although some researchers thought that the associations of sex steroid hormones with IR and T2D were mediated by visceral adipose tissue (Grossmann, 2014), a number of other studies reported such associations independently of obesity (Ding et al., 2006, Vikan et al., 2010). To our knowledge, none studies have examined possible interactions of endogenous sex steroid hormones (e.g., testosterone, sex hormone binding globulin (SHBG), estradiol) and obesity with regard to IR and T2D in men.

The Third National Health and Nutrition Examination Survey (NHANES) provided data on endogenous sex steroid hormone levels for male participants aged 12 years and older. As compared to other population-based data sources, NAHNES data have several advantages, such as large sample size, stable and robust sampling strategies, standardized laboratory techniques, and etc. (National Center for Health Statistics (U.S.), 2006). The objective of this study was to explore the modification effects of sex steroid hormones including total testosterone, SHBG, calculated free testosterone, and androstanediol glucuronide (3α-diol G) on the relationship between obesity and IR/T2D with the use of nationally representative data of men in the U.S. Although multiplicative interactions in logistic regression are convenient to compute, both multiplicative and additive interactions were examined in this study because additive interactions are more relevant to risk prediction, disease prevention, and public health implications (de Mutsert et al., 2009, Rothman et al., 1980). We also investigated the effects of total estradiol and calculated free estradiol index (FEI). Existing studies have reached inconclusive findings on the associations between estradiol, obesity and IR in males (Biundo & Gogola, 2015). Our study may provide potentially new information to this question as well.

Section snippets

Study population

The Third National Health and Nutrition Examination Survey (NHANES) was administered by the National Center for Health Statistics (NCHS) between 1988 and 1994, which cross-sectionally assessed the health and nutritional status of the general US population for both children and adults. Since 1999, NHANES becomes a continuous surveillance program and is annually administered. Participants in NHANES were sampled from the civilian, non-institutionalized Americans using stratified multistage

Sex steroid hormone concentration by selected demographic variables

A total of 1461 males who participated in the phase I NHANES III (1988–1991) were sampled to have serum sex steroid hormones and fasting insulin (or glucose) measured (Table 1). Approximately 54.7% of the 1461 male participants were overweight or obese. The prevalence of central obesity was 24.9%. The weighted mean sex hormone levels were 5.47 ng/mL (± 0.09 ng/mL) for total testosterone, 38.49 nmol/L (± 0.80 nmol/L) for SHBG, 0.110 ng/mL (± 0.002 ng/mL) for free testosterone, 37.23 pg/mL (± 0.71 pg/mL) for

Discussion

This study used a nationally representative sample of American males aged ≥ 20 years to examine the joint effects of serum sex steroid hormones and obesity on insulin resistance and T2D. To our knowledge, it is the first study to investigate such possible interaction effects in a large-scale population-based sample of adult men. We found that obese participants with low free testosterone concentrations had greater risks of IR and T2D than normal weight or obese participants with higher free

Conclusion

In conclusion, we found that sex steroid hormones such as total testosterone, SHBG, free testosterone, and estradiol modified the associations between obesity, central obesity, and IR as well as T2D. We also found that obese males suffered most from low serum testosterone and high estradiol levels. Biomedical experiments, longitudinal studies, and clinical trials are warranted to confirm our findings, examine the underlying mechanisms, clarify their temporal relationships, and evaluate possible

References (60)

  • E.L. Ding et al.

    Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis

    JAMA

    (2006)
  • R.H. Eckel et al.

    Obesity and type 2 diabetes: What can be unified and what needs to be individualized?

    Diabetes Care

    (2011)
  • T. Endre et al.

    Low testosterone and insulin resistance in hypertension-prone men

    Journal of Human Hypertension

    (1996)
  • R.J. Feise

    Do multiple outcome measures require p-value adjustment?

    BMC Medical Research Methodology

    (2002)
  • J.S. Finkelstein et al.

    Gonadal steroids and body composition, strength, and sexual function in men

    The New England Journal of Medicine

    (2013)
  • M.N. Fui et al.

    Lowered testosterone in male obesity: Mechanisms, morbidity and management

    Asian Journal of Andrology

    (2014)
  • A.R. Glass et al.

    Low serum testosterone and sex-hormone-binding-globulin in massively obese men

    The Journal of Clinical Endocrinology and Metabolism

    (1977)
  • M. Grossmann

    Testosterone and glucose metabolism in men: current concepts and controversies

    The Journal of Endocrinology

    (2014)
  • E.W. Gunter et al.

    Laboratory procedures used for the Third National Health and Nutrition Examination Survey (NHANES III) 1988–1994

    (1996)
  • D.W. Hosmer et al.

    Confidence interval estimation of interaction

    Epidemiology

    (1992)
  • S.M. Kabadi et al.

    Joint effects of obesity and vitamin D insufficiency on insulin resistance and type 2 diabetes: Results from the NHANES 2001-2006

    Diabetes Care

    (2012)
  • D. Kapoor et al.

    Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes

    International Journal of Andrology

    (2007)
  • D.E. Kelley et al.

    Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial

    Diabetes Care

    (2002)
  • D.M. Kelly et al.

    Testosterone: A metabolic hormone in health and disease

    The Journal of Endocrinology

    (2013)
  • D.M. Kelly et al.

    Testosterone and obesity

    Obesity Reviews

    (2015)
  • P. Knoblovits et al.

    Erectile dysfunction, obesity, insulin resistance, and their relationship with testosterone levels in eugonadal patients in an andrology clinic setting

    Journal of Andrology

    (2010)
  • M.J. Knol et al.

    When one depends on the other: Reporting of interaction in case–control and cohort studies

    Epidemiology

    (2009)
  • H.Y. Lin et al.

    Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor

    Diabetes

    (2005)
  • M. Maggio et al.

    Estradiol and metabolic syndrome in older Italian men: The InCHIANTI study

    Journal of Andrology

    (2010)
  • P. Marin et al.

    Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: Effects of androgens

    The Journal of Clinical Endocrinology and Metabolism

    (1995)
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    Conflicts of interest: None.

    Role of the funding source: This study was supported by grants DA12777, DA25524, and DA035632 from National Institute on Drug Abuse, National Institutes of Health. The funding source had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision about the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

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