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

Disclosures

Diabetes. 2010;59(12):3167-3173.

Abstract and Introduction

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 ¹H-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.

Introduction

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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Table 1. Subject characteristics at baseline and at follow-up in all 225 subjects
Parameter	Baseline	Follow-up	P value
Sex (male/female)	90/135	90/135
Age (years)	47 (19–69)	48 (20–70)	<0.0001
Body wt (kg)	86.2 (52.5–144.7)	84.0 (52.0–142.8)	<0.0001
Waist circumference (cm)	96.5 (63.0–135.0)	92.0 (66.5–131.5)	<0.0001
BMI (kg · m⁻²)	29.0 (19.4–43.5)	27.9 (18.9–42.9)	<0.0001
Total body fat_MRT (kg)	24.9 (4.0–61.0)	21.9 (0.2–57.5)	<0.0001
Visceral fat_MRT (kg)	2.59 (0.25–9.73)	2.04 (0.15–10.72)	<0.0001
Liver fat_MRS (%)	3.10 (0.16–30.88)	2.09 (0.00–23.21)	<0.0001
HPA score	8.13 (3.510–11.00)	8.50 (5.32–11.38)	<0.0001
VO_2max (ml · min⁻¹ · kg ⁻¹)^*	24.5 (9.5–54.1)	25.0 (2.0–47.1)	0.03
Fasting glucose (mM)	5.17 (4.33–7.42)	5.11 (4.11–7.31)	0.0012
2-h glucose (mM)	6.67 (4.17–11.17)	6.39 (3.50–13.39)	0.004
Fasting insulin (pM)	50 (19–373)	43 (14–175)	<0.0001
2-h insulin (pM)	395 (47–2,132)	310 (37–3,112)	<0.0001
Insulin sens._OGTT (arb. units)	11.7 (1.6–32.1)	13.2 (2.4–39.2)	<0.0001
Insulin sens._Clamp (μmol · kg⁻¹ · min⁻¹ · pM⁻¹)^§	0.057 (0.008–0.347)	0.065 (0.021–0.267)	0.047
Insulin secretion_OGTT (pM/mg/dl)	109 (25–2,346)	110 (16–9,197)	0.28
Insulin secretion_ivGTT (pM)^§	6,937 (1,731–16,162)	7,152 (2,527–26,462)	0.54
hs-CRP (mg/dl)	0.12 (0.01–2.31)	0.08 (0.01–1.78)	0.001
SHBG (nM)	29.8 (7.2–283.0)	33.6 (9.0–287.0)	<0.0001
Adiponectin (μg/ml)	12.0 (3.0–53.0)	14.0 (4.0–117.2)	<0.0001
Fetuin-A (μg/ml)	258 (126–478)	.	.

Data represent unadjusted medians (range). Differences between baseline and follow-up were tested using the matched-pairst test. MRT, magnetic resonance tomography; MRS, magnetic resonance spectroscopy; HPA, habitual physical activity. *Available in 200 subjects at baseline and at follow-up. §At baseline available in 172 subjects, and at follow-up available in 47 subjects.

Table 2. Correlations between circulating SHBG and fat compartments at baseline adjusted for sex and age in the subgroup of 118 subjects
Visceral fat		Liver fat		Circulating SHBG
r	P	r	P	r	P
0.72	<0.0001	0.35	0.0002	−0.22	0.016	Total body fat
		0.54	<0.0001	−0.28	0.0022	Visceral fat
				−0.40	<0.0001	Liver fat

Total body and visceral fat were measured by MR tomography, and liver fat was measured by ¹HMR spectroscopy.

Table 3. Determinants of insulin sensitivity in multivariate linear regression models
Covariates	Insulin sensitivity_OGTT		Insulin sensitivity_Clamp
Covariates	Estimate ± SE	P	Estimate ± SE	P
Model 1
Female sex	0.16 ± 0.04	<0.0001	0.17 ± 0.04	<0.0001
Age	−0.004 ± 0.130	0.98	−0.06 ± 0.13	0.66
Total body fat	−0.58 ± 0.09	<0.0001	−0.60 ± 0.09	<0.0001
Model 2
Female sex	0.11 ± 0.04	0.01	0.08 ± 0.04	0.06
Age	−0.29 ± 0.14	0.04	−0.27 ± 0.14	0.06
Total body fat	−0.47 ± 0.09	<0.0001	−0.50 ± 0.09	<0.0001
Adiponectin levels	0.25 ± 0.09	0.007	0.38 ± 0.09	<0.0001
Fetuin-A levels	−0.76 ± 0.20	0.0002	−0.47 ± 0.21	0.027
Model 3
Female sex	0.06 ± 0.04	0.19	0.03 ± 0.05	0.46
Age	−0.30 ± 0.14	0.03	−0.26 ± 0.14	0.07
Total body fat	−0.42 ± 0.09	<0.0001	−0.47 ± 0.09	<0.0001
Adiponectin levels	0.22 ± 0.09	0.01	0.37 ± 0.09	<0.0001
Fetuin-A levels	−0.83 ± 0.20	<0.0001	−0.50 ± 0.21	0.018
SHBG levels	0.16 ± 0.06	0.0096	0.14 ± 0.06	0.029

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