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

Andreas Peter; Konstantinos Kantartzis; Jürgen Machann; Fritz Schick; Harald Staiger; Fausto Machicao; Erwin Schleicher; Andreas Fritsche; Hans-Ulrich Häring; Norbert Stefan


Diabetes. 2010;59(12):3167-3173. 

In This Article

Abstract and Introduction


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 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).
Results—SHBG 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).
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.


Recently, two studies applying the Mendelian randomization approach, an elegant tool to study causal relationships between plasma parameters and traits in humans,[1] suggested that circulating sex hormone–binding globulin (SHBG) may be involved in the pathogenesis of type 2 diabetes in men and women.[2,3] Because circulating SHBG regulates biological action and signaling of sex hormones,[4] these data strengthen the notion that sex hormones play an important role in the pathogenesis of the disease. So far, however, results from several studies revealed that this field of research is very complex. Whereas high testosterone levels were found to be associated with insulin resistance, glucose intolerance, and increased risk of type 2 diabetes in women, in men high testosterone levels appear to protect from insulin resistance and diabetes. In contrast, in both sexes, although not consistent among all studies, high estradiol levels were associated with elevated insulin resistance and increased risk of type 2 diabetes.[5,6]

For relationships of circulating SHBG with insulin sensitivity and risk of type 2 diabetes, the data were more consistent among sexes. Low plasma levels of SHBG were found to be similarly strongly associated with insulin resistance and increased risk of type 2 diabetes, in men and in women in most,[7–11] but not in all, studies.[12–15]

The question now is, besides genetic variability in SHBG, which parameters involved in the natural history of type 2 diabetes regulate plasma levels of SHBG? Studies indicated that high insulin levels decrease the release of SHBG from hepatocytes,[16,17] which represent the major source of SHBG biosynthesis.[18] However, Selva et al. provided convincing evidence that expression of SHBG in hepatocytes could be suppressed by glucose or fructose, strong inducers of hepatic lipogenesis,[19] but not by insulin.[20] This is in agreement with human studies showing that low circulating SHBG was not associated with elevated insulin levels[21] but was associated with obesity and dyslipidemia, conditions that are strongly associated with fatty liver in humans.[22–29] On the basis of the data from Selva et al.,[20] we hypothesized that specifically fatty liver may be associated with low circulating SHBG in humans, and we could recently support this in a small study.[30]

Because of the unexpected finding of no significant relationships between genetic variants in SHBG and metabolic traits in the study by Perry et al.,[3] in the present study we investigated mechanisms behind the association between low SHBG levels and increased risk of type 2 diabetes in our precisely phenotyped subjects. Therefore, we additionally genotyped them for a variant that was found to be strongly associated with plasma SHBG levels and the risk of type 2 diabetes.[3]


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