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. 2013 Oct 1;115(7):988-94.
doi: 10.1152/japplphysiol.00237.2013. Epub 2013 Aug 8.

Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease

Steven K Malin  1 , Anny Mulya, Ciaran E Fealy, Jacob M Haus, Mangesh R Pagadala, Amanda R Scelsi, Hazel Huang, Chris A Flask, Arthur J McCullough, John P Kirwan
Affiliations

Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease

Steven K Malin et al. J Appl Physiol (1985). .

Abstract

Fetuin-A is synthesized in the liver and may be associated with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Lifestyle-induced weight loss reduces fetuin-A, but the effect of exercise alone is unknown. We determined the effect of short-term exercise training on plasma fetuin-A in 13 (50.5 ± 3.4 yr) obese adults (body mass index, 33.3 ± 0.9 kg/m(2)) with clinically diagnosed NAFLD. Subjects participated in 7 days of supervised exercise training (60 min/day at ∼85% maximum heart rate) and were instructed to maintain their normal caloric and macronutrient intake. Insulin resistance was assessed by an oral glucose tolerance test. Hepatic triglyceride content (HTGC) was determined by proton MRI. We used C2C12 skeletal muscle cells to examine the direct effect of fetuin-A on 2-deoxyglucose uptake, insulin signaling [phosphorylation of Akt and AS160 (pAkt and pAS160, respectively)], and glucose transporter-4 (GLUT-4) translocation. Insulin resistance was reduced by 29% (P < 0.05), and glucose area under the curve (AUC) was decreased by 13% (P < 0.01) after the 7 days of exercise. Furthermore, circulating fetuin-A was decreased by 11% (4.2 ± 03 vs. 3.6 ± 0.2 nM; P < 0.02), and this change correlated with reduced insulin resistance (r = 0.62; P < 0.04) and glucose AUC (r = 0.58; P < 0.04). Importantly, the exercise program did not change body weight (P = 0.12), HTGC (P = 0.73), or aerobic capacity (P = 0.14). In vitro experiments revealed that fetuin-A decreased skeletal muscle glucose uptake by downregulating pAkt and pAS160 and subsequent GLUT-4 translocation to the plasma membrane. Together, our findings highlight a role for fetuin-A in skeletal muscle insulin resistance and suggest that part of the exercise-induced improvement in glucose tolerance in patients with NAFLD may be due to lowering fetuin-A.

Keywords: hyperglycemia; inflammation; insulin sensitivity; obesity.

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Figures

Fig. 1.
Fig. 1.
Effects of a 7-day exercise training program on plasma fetuin-A concentrations. Data are mean ± SE. *Pre- vs. postexercise training (Pre vs. Post, respectively), P < 0.02.
Fig. 2.
Fig. 2.
Correlation between the change (Δ) in fetuin-A concentrations and the Δ in insulin resistance (A), Δ in glucose tolerance (B), and Δ in hepatic triglyceride content (HTGC; C). Insulin resistance index (n = 12 of 13). AUC, area under the curve.
Fig. 3.
Fig. 3.
Effect of fetuin-A on insulin-mediated glucose uptake in skeletal muscle (A), glucose transporter-4 (GLUT-4) translocation (B), Akt phosphorylation (C), and AS160 phosphorylation (D). C2C12 cells were plated and differentiated as described in the experimental protocol. Differentiated C2C12 myotubes were treated with or without 50 and 100 nM fetuin-A for 24 h and then stimulated with 100 nM insulin. Results represent the mean ± SE from 3 independent experiments. All experiments were run in duplicate. *Compared with control (fetuin-A main effect, P < 0.02).
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