ORIGINAL ARTICLE
Role of sex steroids, intrahepatic fat and liver enzymes in the
association between SHBG and metabolic features
Fabrice Bonnet*, Fritz-Line Velayoudom Cephise†, Alain Gautier*, S everine Dubois‡, Catherine Massart§,
Alioune Camara*, Laurent Larifla¶, Beverley Balkau**
,
†† and Pierre-Henri Ducluzeau‡
*Department of Endocrinology, CHU Rennes, Univ Rennes 1, Inserm UMR 991, Rennes, †Department of Endocrinology-
Diabetology, University Hospital of Pointe- a-Pitre, Pointe- a-Pitre, ‡Department of Diabetology, University Hospital of Angers,
Angers, §Laboratory of hormonology, CHU de Rennes, Inserm 0203 Centre d’Investigation Clinique CIC-P, Univ Rennes 1, Rennes,
¶Research Group, Clinical Epidemiology and Medicine, University Hospital of Guadeloupe, University of Antilles and Guyane,
Pointe- a-Pitre, **INSERM CESP Centre for Research in Epidemiology and Population Health, U 1018, Epidemiology of Diabetes,
Obesity and Chronic Kidney Disease Over the Lifecourse and ††University Paris Sud 11, UMRS 1018, Villejuif, France
Summary
Background SHBG and liver enzymes levels are both associated
with the risk of type 2 diabetes. However, the relationship
between SHBG with liver enzymes and intrahepatic fat content
remain poorly understood.
Objective To investigate whether SHBG is correlated with
glucose and lipids levels and whether this association depends on
fatty liver content, liver enzymes or sex hormone concentrations.
Design and Patients We studied 233 dysmetabolic men with
measures of plasma SHBG, total testosterone, 17b-oestradiol,
glucose, adiponectin, liver enzymes and hepatokines. Intrahepat-
ic liver fat and visceral fat contents were measured by magnetic
resonance imaging in 108 of these individuals.
Results After adjustment for age, SHBG concentration was
inversely correlated with fasting glucose (b
standardized
= 021,
P = 00007), HbA1c (b
standardized
= 027, P < 00001), triglyce-
rides (b
standardized
= 019, P = 0003) and positively correlated
with HDL-Cholesterol (b
standardized
= 014, P = 003). These cor-
relations persisted after adjustment for either total testosterone
or 17b-oestradiol levels. SHBG was not related to either fetuin A
or FGF 21 concentrations. The inverse association of SHBG with
HbA1c and glycaemia was not altered after adjusting for liver
markers but was no longer significant after adjustment for hepa-
tic fat content.
Conclusion The significant association between SHBG and
fasting glycaemia, HbA1c and lipid levels in dysmetabolic men
was not related to either sex hormones or markers of liver func-
tion, but was dependent on intrahepatic fat. This suggests that
intrahepatic fat, but not alterations in liver function markers,
may be involved in the association between SHBG and glucose
and lipid metabolism.
(Received 14 September 2012; returned for revision 23 September
2012; finally revised 30 September 2012; accepted 29 October
2012)
Introduction
SHBG is a protein transporter of sex steroids and is synthesized
by the liver. Low levels of SHBG have been shown to be associ-
ated with visceral adiposity, fatty liver and an increased risk of
type 2 diabetes.
1–4
Furthermore, studies applying the Mendelian
randomization approach suggest that SHBG may be directly
involved in the pathogenesis of type 2 diabetes.
5
However, the
pathophysiological mechanisms underlying the inverse associa-
tion between SHBG and both the presence of the metabolic syn-
drome and the onset of hyperglycaemia remain poorly
understood. Hyperinsulinaemia and intrahepatic fat content
have been proposed as possible determinants of the molecular
expression of SHBG.
6
However, whether the relationship between plasma SHBG
concentration and glucose levels depends on hepatic lipogenesis
or intrahepatic fat content has not been fully investigated.
Furthermore, it has been consistently shown that markers of
liver function, specifically c–glutamyltransferase (GGT) and ala-
nine aminotransferase (ALT), are predictive of the development
of type 2 diabetes.
7,8
Sex hormones have a direct impact on the
liver and may modulate the release of liver markers. Whereas
both a high GGT and a low SHBG concentration are associated
with incident type 2 diabetes, it is not known whether liver
function markers modulate or interact in the relationship
between SHBG and the risk of hyperglycaemia.
The aim of this study was therefore to determine whether
hepatic fat content, and GGT and ALT levels modulate or
Correspondence: Fabrice Bonnet, Department of Endocrinology,
University Hospital of Rennes, 2 rue Henri le Guilloux-35033 RENNES
CEDEX 9, France. Tel.: +33 2 99 26 71 42; Fax: +33 2 99 26 71 49;
E-mail: fabrice.bonnet@chu-rennes.fr
© 2012 John Wiley & Sons Ltd 517
Clinical Endocrinology (2013) 79, 517–522 doi: 10.1111/cen.12089