The mechanism for the association between obesity and low testosterone and SHBG has received considerable attention. Many studies have shown that testosterone levels are inversely correlated with insulin and c-peptide concentrations (50,51). This association is partly through SHBG, because fasting insulin likewise correlates negatively with SHBG levels (52), and insulin infusion lowered circulating SHBG, albeit slighty (53). Moreover, lowering circulating insulin levels with diazoxide increased plasma SHBG in men (54) and in obese women with PCOS (55). The regulation of SHBG expression by insulin has been studied directly using cultures of HepG2 hepatoma cells that express the SHBG gene (56). In these cells, adding insulin reduced SHBG mRNA levels (13) and protein secretion (12). As noted in the section on the SHBG gene, this insulin effect may be mediated by the liver-enriched transcription factor HNF-4 (hepa-tocyte nuclear factor-4) that transactivates the SHBG promoter (57). Interestingly, maturity onset diabetes of the young (MODY-1) is caused by mutation in HNF-4a.
In men with type 2 diabetes, in whom insulin sensitivity was estimated using the hyperinsulinemic euglycemic glucose clamp technique, there was a strong positive correlation between SHBG level and insulin sensitivity (58,59). In the latter study, SHBG levels were comparable in men with type 2 diabetes mellitus and weight-matched controls and correlated negatively with all measures of adiposity in the groups as a whole. However, only fasting insulin levels were similar, whereas glucose-stimulated insulin secretion was reduced in the men with diabetes (59). These findings and imperfect correlations between insulin levels and SHBG in obese men suggest that other factors related to obesity and insulin resistance, including GH and IGFs and their binding proteins, glucorticoids, or adipose-derived factors may contribute to low SHBG as well. In the Massachussetts Male Aging Study, fiber and protein intakes were positively correlated with SHBG levels (60). In a second study, a high-fat diet was associated with decreased SHBG, whereas a weight-reducing high-protein diet increased SHBG levels in normal men (24).
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