α2-Heremans-Schmid Glycoprotein/ Fetuin-A Is Associated With Insulin Resistance and Fat Accumulation in the Liver in Humans

Abstract

OBJECTIVE -The ␣ 2 -Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver.RESEARCH DESIGN AND METHODS -Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by 1 H magnetic resonance spectroscopy.RESULTS -AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P ϭ 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r ϭ Ϫ0.22, P ϭ 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r ϭ 0.27, P ϭ 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P ϭ 0.02).CONCLUSIONS -We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance. Diabetes Care 29:853-857, 2006I nsulin resistance plays a crucial role in the development of type 2 diabetes (1). Multiple mechanisms are thought to be involved in its pathogenesis. Among them, the human ␣ 2 -Heremans-Schmid glycoprotein (AHSG) was found to be important in animals and in in vitro studies. It is an abundant serum protein in mammals. Bovine and murine fetuin-A and pp63 in rats are homologues of AHSG (2,3). In humans, except for the tongue and the placenta, it is exclusively expressed in the liver (4). It is a natural inhibitor of the insulin-stimulated insulin receptor tyrosine kinase (3). Acute injection of human recombinant AHSG inhibi t e d i n s u l i n -s t i m u l a t e d t y r o s i n e phosphorylation of the insulin receptor and insulin receptor substrate-1 in rat liver and skeletal muscle (3). In addition, AHSG knockout mice display improved insulin sensitivity and are resistant to weight gain on a high-fat diet (5).While these data reflect that AHSG is an important candidate among the factors that induce insulin resistance, the role of this protein in the natural history of type 2 diabetes is still unclear (6). Recent reports from genetic studies suggest that single nucleotide polymor...

Association of Insulin Resistance, β-Cell Function Impairment and Calcium, Magnesium, and Fetuin-A Concentrations in Women with Type 2 Diabetes Mellitus

“…Our study demonstrated that serum fetuin-A was related to IR, and HOMA2IR index and fasting insulin serum levels were increased; this result is consistent with previous results (4,(22)(23)(24). Therefore, fetuin-A may be used as a new factor implicated in T2DM pathology and physiology; IR also plays an important role in the T2DM mechanism (25).…”

Global proteomic profiling reveals altered proteomic signature in schizophrenia serum

“…Stefan et al 161 reported that a-2HSG is associated with insulin resistance and fat accumulation in the liver in humans, which may link it with the alteration in apolipoproteins found in this study. Until now, however, there has been no published data correlating schizophrenia and a-2HSG.…”

Comprehensive and quantitative proteome profiling of the mouse liver and plasma

“…Most reported concentrations were obtained from Specialty Laboratories (www.specialtylabs.com). The remaining reported concentrations were obtained from the literature as referenced: interleukin-3 28 ; CSF1 29 ; PLAU 30 ; beta-enolase 31 ; enolase 1, alpha 32 ; IGF1 33 ; uromodulin 34 ; lactotransferrin 35 ; HGFAC, serum amyloid A protein, IGFALS, factor XII, apolipoprotein C-II 4 ; beta-2-microglobulin 36 ; PROZ 37 ; protein C 38 ; apolipoprotein D 39 ; apolipoprotein C-III 40 ; vitamin D-binding protein 41 ; alpha-2-HS-glycoprotein 42 ; hemopexin. 43 teins were common to both data sets and corresponded to 25.6% of the proteins identified in the liver tissue and to 38.5% of the proteins identified in plasma (Fig.…”