Prediabetes in adult GH deficiency is associated with a substantial reduction in serum and adipose tissue expression levels of zinc-α2-glycoprotein
M. Balaz1, B. Ukropcova1, T. Kurdiova1, A. Penesova1, P. Skyba2, M. Vlcek1, V. Belan3, I. Klimes1, J. Payer3, R. Imrich1, S. Smith4, R. Tkacova2, D. Gasperikova1 & J. Ukropec1
Adult GH deficiency (GHD) is associated with prediabetes and low levels of GH are found in obesity. We hypothesized that zinc-α2-glycoprotein (ZAG), a novel adipokine reduced in obesity, is regulated by GH. ZAG serum and adipose tissue expression were measured in three study populations: i) cachectic (BMI=19.3±0.5 kg/m2), lean/overweight (BMI=26.0±0.5 kg/m2) and obese (BMI=36.0±1.6 kg/m2) patients with chronic obstructive pulmonary disease (COPD, 62.5±1.1 years); ii) GHD adults (n=16, 30.6±1.1 years, BMI=27.1±1.2 kg/m2) and 16 healthy matched controls; iii) patients with metabolic syndrome subjected to 6-months therapy with rhGH (n=10, 4070 years, BMI=2735 kg/m2). Metabolic phenotyping included insulin sensitivity (EHC), body composition (MRI), OGTT and muscle lipid content (1H-MRS). Adipose tissue samples were taken by needle biopsy. Adipocyte diameter was measured histomorphometrically. Gene expression was assessed by qRT-PCR, protein by immunoblotting and serum ZAG with ELISA. Compared to obese, cachectic COPD patients had fourfold increased ZAG in adipose tissue and serum (P<0.01). Both ZAG serum and mRNA levels correlated positively with circulating GH (r=0.40, P<0.01; r=0.60, P<0.001). Furthermore, serum and adipose tissue of prediabetic GHD adults displayed 71 and 62% decrease in ZAG mRNA and serum levels (P<0.001). Treatment with rhGH led to 1.8-fold increase in ZAG mRNA (P<0.001). ZAG protein decreased in response to euglycemic hyperinsulinemia. In addition, ZAG mRNA was positively associated with insulin sensitivity (r=0.69, P<0.001), serum adiponectin (r=0.48, P<0.01) and adiponectin mRNA (r=0.49, P<0.01). Negative correlations were found with fat cell size (r=−0.56, P<0.001) and intramyocellular lipids (r=−0.61, P<0.05). Our results clearly demonstrate the down-regulation of ZAG in serum and adipose tissue of prediabetic GHD adults as well as positive regulation of ZAG by rhGH, suggesting the regulatory role for GH independent on obesity. Associations of ZAG with insulin sensitivity, molecular adipose tissue phenotypes and intramyocellular lipids suggest the role for reduced ZAG in the development of metabolic disease.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.