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

Malin, Steven K.1,2; del Rincon, Juan Pablo1; Huang, Hazel1; Kirwan, John P.1,2,3

Medicine & Science in Sports & Exercise: November 2014 - Volume 46 - Issue 11 - p 2085–2090
doi: 10.1249/MSS.0000000000000338
Basic Sciences

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 ([6,6-2H2]-glucose). Skeletal muscle insulin sensitivity (rate of glucose disposal), hepatic insulin resistance (rate of glucose appearance × fasting insulin), metabolic flexibility (respiratory quotientclamp − respiratory quotientfasting), 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.

1Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; 2Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH; and 3Metabolic Translational Research Center, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH

Address for correspondence: John P. Kirwan, Ph.D., Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave (NE40), Cleveland, OH 44195; E-mail:

Submitted for publication December 2013.

Accepted for publication March 2014.

© 2014 American College of Sports Medicine