Relationships of Circulating Sex Hormone–Binding Globulin With Metabolic Traits in Humans

Abstract

OBJECTIVERecent 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 METHODSBefore 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 1H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (ISOGTT) and measured by a euglycemic hyperinsulinemic clamp (ISclamp, n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172).RESULTSSHBG levels correlated positively with insulin sensitivity (ISOGTT, P = 0.037; ISclamp, 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 (ISOGTT, P = 0.0096; ISclamp, 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).CONCLUSIONSPossible 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.

Comment on Hedderson et al. Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus. Diabetes Care 2014;37:1296–1303

“…In this respect, they highlighted that loss of body weight induced by changes in diet and physical activity may result in an increase of circulating SHBG. In this respect, we showed that loss of liver fat content most strongly correlated with increase in circulating SHBG during a lifestyle intervention (2,3). This is in agreement with published information indicating that reduction in hepatic inflammatory signaling and hepatic lipogenesis mediates this increase (5).…”

“…In our studies, circulating SHBG correlated stronger with liver fat content, both in cross-sectional and longitudinal analyses, than with total body and visceral fat mass or whole-body insulin sensitivity (2,3). Interestingly in their most recent article, Hedderson and colleagues (4) found in the same study that increased g-glutamyl transferase levels were associated with increased odds of the development of GDM.…”

Quality of life in patients with primary hypothyroidism related to BMI

“…However, this relationship of SHBG with QOL disappeared in most of the subscales after correction for BMI. The level of SHBG varies with nutritional status (and thus BMI), age and sex hormones, which interferes with its use as a sensitive parameter of TH action (40). As the majority of hypothyroid patients are female (with fluctuations in estrogen levels during life), SHBG is not a suitable marker of TH status.…”

Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients

“…This concept is supported by an in vitro experiment in which human HepG2 hepatoblastoma cells produce less SHBG when treated with insulin (11,12). However, a few of the subsequent studies have found no direct association between SHBG and insulin or insulin resistance (13,14,15). A recent study by Selva et al (16) reports that SHBG is not regulated by insulin but rather repressed by monosaccharide-induced lipogenesis in human HepG2 cells.…”