Sex Hormone-Binding Globulin Gene Expression and Insulin Resistance
Abstract
Context: The plasma level of sex hormone binding globulin (SHBG), a glycoprotein produced by hepatocytes, is subject to genetic, hormonal, metabolic, and nutritional regulation, and is a marker for the development of the metabolic syndrome and diabetes. Objective: Because the mechanism for these associations is unclear, and no studies of SHBG gene expression in humans have been published, SHBG mRNA was measured in human liver samples and related to anthropometric data. Setting: Inpatients at a private, nonprofit, university-associated hospital were studied. Participants: Subjects were fifty five adult men and women undergoing hepatic resection as treatment for cancer. Main Outcome Measures: Main outcome measures were SHBG mRNA and serum SHBG levels. Results: SHBG mRNA was a strong predictor of serum SHBG with higher levels of the mRNA and protein in women than in men. The relationship between SHBG mRNA and circulating SHBG differed in males and females consistent with a sex difference in post-transcriptional regulation. A strong positive correlation was found between the level of the mRNA for the transcription factor HNF4α and SHBG mRNA. Insulin resistance (IR), assessed by homeostatis model assessment, was related inversely to SHBG mRNA and to HNF4α mRNA as well as to circulating SHBG levels. These mRNAs, as well as serum SHBG, were higher when the hepatic triglyceride concentration was low, and decreased with increasing body mass index but were unrelated to age. Conclusions: Fat accumulation in liver and IR are important determinants of SHBG gene expression and thereby circulating SHBG levels that are perhaps mediated through effects on the transcription factor HNF4α. These findings provide a potential mechanism to explain why low SHBG predicts the development of type 2 diabetes.
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The pathophysiologic process of decreased SHBG attributed by excessive intake of monosaccharides is also involved in metabolic syndrome (METS).
“The pathophysiologic process of decreased SHBG attributed by excessive intake of monosaccharides is also involved in metabolic syndrome (METS) [133].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [133]
Most cross-sectional study results seem to support the hypothesis that IR initiates a reduction in HNF-4α that eventually leads to lower SHBG expression.
“However, most cross-sectional study results seem to support the hypothesis that IR initiates a reduction in HNF-4α that eventually leads to lower SHBG expression [132–134].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [133]
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Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action
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- Authors
- Winters, S. J., Gogineni, J., Karegar, M., Scoggins, C., Wunderlich, C. A., Baumgartner, R., & Ghooray, D. T.
- Affiliations
- Division of Endocrinology, Metabolism and Diabetes (S.J.W., J.G., M.K., D.T.G.), Louisville, Kentucky 40202
- Division of Surgical Oncology (C.S.), Louisville, Kentucky 40202
- Norton Healthcare (US)
- University of Louisville (US)
- Corresponding author
- Winters, Stephen J.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-12-01
- Volume
- 99
- Issue
- 12
- Pages
- E2780-E2788
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2030089874
- Cited by
- 79
- References
- 8
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 8 · 2015: 6
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- sex hormone-binding globulin, insulin resistance, HNF4α, hepatic triglyceride accumulation, sex differences, post-transcriptional regulation, type 2 diabetes, metabolic syndrome, liver fat, body mass index, hepatectomy
- MeSH terms
- Adult, Aged, Aged, 80 and over, Diabetes Mellitus, Type 2, Fatty Liver, Female, Humans, Insulin Resistance, Liver, Male, Middle Aged, Sex Hormone-Binding Globulin, Gene Expression, Metabolic Syndrome, Hepatocyte Nuclear Factor 4
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