Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Aroda, Vanita R.; Christophi, Christopher; Edelstein, Sharon L.; Perreault, Leigh; Kim, Catherine; Golden, Sherita Hill; Horton, Edward S.; Mather, Kieren J.

doi:10.1136/bmjdrc-2020-001841

Cited by 10 publications

(5 citation statements)

References 39 publications

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“…For men, results of different models were inconsistent, but for women, models using SNPs to instrument degree status and two-sample MR both suggested a positive impact of education on SHBG and a negative impact on bioavailable and free testosterone. These results are consistent with previously reported associations in women of sex hormones with adiposity (negative for SHBG and positive for testosterone) ( 43 ) and negative associations of education with adiposity. Together will null associations for the impact of testosterone on SEP, these results further suggest that multivariable-adjusted estimates and previously reported associations of testosterone and SEP may reflect influence of SEP on testosterone.…”

Section: Discussionsupporting

confidence: 93%

Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

et al. 2021

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Men with more advantaged socioeconomic position (SEP) have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP. In 306,248 participants of UK Biobank, we performed sex-stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and body mass index; and on risk-taking behavior. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest that it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest that previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation.

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Section: Discussionsupporting

confidence: 93%

Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

et al. 2021

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“…To the best of our knowledge, only one prospective study has analyzed the effects of changing circulating SHBG levels on cardiometabolic outcomes. In this prospective study, lifestyle interventions directed to obtain favorable changes in circulating levels of SHBG in men and women could not show to influence the risk of developing type 2 diabetes mellitus in the participants [137].…”

Section: International Journal Of Endocrinologymentioning

confidence: 70%

Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men

Basualto-Alarcón

García‐Rivas

Troncoso

et al. 2021

International Journal of Endocrinology

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In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.

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“…Identification of gestational diabetes, by revealing a predisposition to glucose intolerance in a young adult population, represents an opportunity for diabetes prevention that could be capitalized upon to address increasing diabetes rates in the general population. 16 The findings reported by Shah et al 7 reinforce that it is time to get serious about curbing increasing rates of gestational diabetes, particularly in pregnant people from racial and ethnic minority populations.…”

Section: Related Article Page 660mentioning

confidence: 87%

Racial and Ethnic Differences in Gestational Diabetes

Powe

Carter

2021

JAMA

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During pregnancy, profound metabolic changes may reveal a predisposition toward glucose intolerance, manifesting as gestational diabetes. Gestational diabetes increases the risk of adverse pregnancy outcomes, including macrosomia, preeclampsia, birth trauma, and neonatal hypoglycemia. 1,2 Notably, this diagnosis has implications that outlast pregnancy. Estimates from systematic reviews suggest a markedly elevated risk of future diabetes in people with gestational diabetes, with as many as 50% to 70% of affected individuals developing overt diabetes later in life. 3,4 In addition, individuals with a history of gestational diabetes have a higher risk of future cardiovascular disease compared with those who do not develop this common pregnancy complication. 5 In the context of an ongoing epidemic of diabetes in the general population, 6 the findings by Shah and colleagues reported in this issue of JAMA are particularly concerning: gestational diabetes rates among nulliparous women have increased in the US. 7 This retrospective analysis of US birth certificate data from the National Center for Health Statistics included 12 610 235 individuals with a singleton first live birth and demonstrated that age-standardized gestational diabetes rates among nulliparous individuals increased from 2011 to 2019, from 47.6 (95% CI, 47.1-48.0) to 63.5 (95% CI, 63.1-64.0) per 1000 live births. 7 This increase occurred during a time of up-trending prevalence of established gestational diabetes risk factors among the study population (overweight: 42.7% in 2011 and 50.7% in 2019; obesity: 19.4% in 2011 and 24.9% in 2019). Increasing maternal age in nulliparous individuals over this time period (mean age of 25.5 years in 2011 and 27.0 years in 2019) likely contributed further to the higher prevalence of gestational diabetes, although the increase in gestational diabetes rates was independent of age.Rates of gestational diabetes in specific race and ethnicity groups (Hispanic/Latina, non-Hispanic Asian, non-Hispanic Black, and non-Hispanic White groups) were a primary focus of this analysis. 7 Rates of gestational diabetes increased across all race and ethnicity groups, compared with the non-Hispanic White group, during the study period. Among the groups studied, the authors found the highest rates of gestational diabetes among individuals who identified as Asian/Pacific Islander and the second-highest rates of gestational diabetes among individuals who identified as Hispanic/Latina. This observation is similar to previous studies of gestational diabetes and parallels known differences in type 2 diabetes prevalence by race and ethnicity. 6,8 Although

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Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Cited by 10 publications

References 39 publications

Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men

Racial and Ethnic Differences in Gestational Diabetes

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