Relationships of circulating sex hormone-binding globulin with metabolic traits in humans

Abstract

Objective: Recent data suggested that sex hormone-binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes.

Research design and methods: Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by (1)H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (IS(OGTT)) and measured by a euglycemic hyperinsulinemic clamp (IS(clamp), n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172).

Results: SHBG levels correlated positively with insulin sensitivity (IS(OGTT), P = 0.037; IS(clamp), P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (IS(OGTT), P = 0.0096; IS(clamp), P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = -0.17, P = 0.009) and after (r = -0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P ≤ 0.025) but not with metabolic characteristics (all P > 0.18).

Conclusions: Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function.

FIG. 1.

Hypothetical picture regarding cause and metabolic consequences of circulating SHBG in humans. Conditions regulating fat accumulation in the liver and the SNP rs1799941of SHBG are candidates affecting circulating SHBG. In contrast, visceral adiposity does not appear to directly affect circulating SHBG. The relationships of SHBG levels with whole-body insulin sensitivity are most probably explained by liver fat. The significant relationship of SHBG levels with fasting glycemia, which was independent of liver fat, supports that SHBG may have direct effects on hepatic glucose production. Increased hepatic glucose output in concert with a β-cell defect might explain the association of circulating SHBG and SHBG genetic variants with type 2 diabetes. (A high-quality color representation of this figure is available in the online issue.)