Exercise-Induced Lowering of Fetuin-A May Increase Hepatic Insulin Sensitivity

Introduction: Fetuin-A is a novel hepatokine, and there is preliminary evidence that it may contribute to the pathogenesis of type 2 diabetes. Exercise reduces fetuin-A, but the specific metabolic effects particularly as they relate to the regulation of insulin resistance are unknown. This led us to examine the effect of exercise training on circulating fetuin-A in relation to skeletal muscle and/or hepatic insulin resistance in obese adults. Methods: Twenty older adults (66.3 +/- 0.9 yr; body mass index, 34.1 +/- 1.2 kg.m(-2)) participated in this prospective 12-wk study and underwent supervised exercise training (5 d.wk(-1), 60 min.d(-1) at approximately 85% HRmax). Insulin resistance was assessed using the euglycemic-hyperinsulinemic clamp (40 mU.m(-2).min(-1)) with isotope dilution ([6,6-H-2(2)]-glucose). Skeletal muscle insulin sensitivity (rate of glucose disposal), hepatic insulin resistance (rate of glucose appearance x fasting insulin), metabolic flexibility (respiratory quotient(clamp) - respiratory quotient(fasting)), fetuin-A, high-molecular weight adiponectin, high-sensitivity C-reactive protein, leptin, and body fat (dual energy x-ray absorptiometry) were measured before and after the intervention. Results: Exercise reduced body fat, high-sensitivity C-reactive protein, leptin and hepatic as well as skeletal muscle insulin resistance (each, P < 0.05). Fetuin-A was decreased by approximately 8% (pre, 1.01 +/- 0.08, vs post, 0.89 +/- 0.06 g.L-1; P < 0.05) after the intervention, and lower fetuin-A after exercise correlated with lower hepatic insulin resistance (r = -0.46, P < 0.01), increased metabolic flexibility (r = -0.70, P < 0.01) and high-molecular weight adiponectin (r = -0.57, P < 0.01). Conclusions: Fetuin-A may contribute to exercise training-induced improvements in hepatic insulin resistance, CHO utilization, and inflammation in older obese adults. Further work is required to determine the cellular mechanism(s) of action for fetuin-A because this hepatokine is related to type 2 diabetes risk.