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


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.
Peter
Andreas
A
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
Kantartzis
Konstantinos
K
Machann
Jürgen
J
Schick
Fritz
F
Staiger
Harald
H
Machicao
Fausto
F
Schleicher
Erwin
E
Fritsche
Andreas
A
Häring
Hans-Ulrich
HU
Stefan
Norbert
N
D000273:Adipose Tissue / Q000033:anatomy & histology* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000517:prevention & control; D005260:Female; D005838:Genotype; D005858:Germany; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008019:Life Style; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D008487:Medical History Taking; D008875:Middle Aged; D012727:Sex Characteristics; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D011795:Surveys and Questionnaires; D044465:White People; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D012738:Sex Hormone-Binding Globulin