Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study

• Published in: Diabetologia Vol. 66; no. 1; pp. 213 - 222
• Main Authors: Simons, Pomme I. H. G., Valkenburg, Olivier, van de Waarenburg, Marjo P. H., van Greevenbroek, Marleen M. J., Kooi, M. Eline, Jansen, Jacobus F. A., Schalkwijk, Casper G., Stehouwer, Coen D. A., Brouwers, Martijn C. G. J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2023; Springer Nature B.V
• Subjects: Cohort analysis; Cohort Studies; Cross-Sectional Studies; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Fatty liver; Female; Globulins; Glucose tolerance; Human Physiology; Humans; Internal Medicine; Lipids; Liver - metabolism; Liver diseases; Male; Mediators; Medicine; Medicine & Public Health; Metabolic Diseases; Population studies; Risk factors; Sex Hormone-Binding Globulin; Sex hormones; Type 2 diabetes; Sex hormone-binding globulin; Non-alcoholic fatty liver disease; Mediation; Hepatokine
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-022-05790-7

Aims/hypothesis
Serum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes.
Methods
We used cross-sectional data from the Maastricht Study (
n
=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes.
Results
IHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results.
Conclusions/interpretation
In this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine.
Graphical abstract