|Fetuin-A, in particular the phosphorylated isoform, is a negative regulator of insulin action, inhibiting insulin receptor tyrosine kinase activity and downstream insulin signaling. In obese individuals, serum fetuin-A concentrations are elevated and are associated with insulin resistance. Recent evidence indicates that fetuin-A is an independent risk factor for type 2 diabetes. However, our understanding of fetuin-A responses to a glucose load or exercise is currently limited. Our goal was to characterize the effects of an oral glucose challenge, single and repeated bouts of exercise on serum fetuin-A concentrations in normal weight and obese individuals.
To examine the temporal changes in serum fetuin-A concentrations in response to an oral glucose challenge and a single bout of exercise, we recruited ten obese and seven age-matched, normal weight men, from the Auburn-Opelika area for this study. All participants underwent a single bout of treadmill walking at 60-70% VO2max, expending 500 kcals. Oral glucose tolerance tests (OGTT) were conducted 4 days prior to and 24-hours after the exercise session. Obese individuals were insulin resistant as evidenced by serum insulin concentrations, glucose-to-insulin ratio, and Homeostasis Model Assessment (HOMA) index. Following an oral glucose challenge, total fetuin-A concentrations were significantly decreased at 30, 60, and 120-min time points in normal weight individuals, but not in obese individuals. After a single bout of exercise, the glucose/insulin ratio increased 92%, 24 hr after exercise (p = 0.0067) and the insulin area under the curve (AUC) was reduced significantly by 16% (p < 0.05) post-exercise in obese individuals. Serum Ser-312 phosphorylated fetuin-A (phosphofetuin-A) AUC was significantly lower, 24 hours after a single bout of exercise, in obese men, consistent with improvements in surrogate markers of insulin sensitivity.
Next, we wished to investigate the influence of repeated bouts of exercise on four consecutive days and in the post-exercise period, on plasma fetuin-A concentrations as well as markers of insulin sensitivity. Fifteen obese men, that met the National Cholesterol Education Adult Treatment Panel III (NCEP ATP III) criteria for MetS, were recruited from the Auburn-Opelika area. Participants underwent treadmill walking for four consecutive days, at 70% of their VO2max, expending 350 kcal/exercise session. Fasted blood samples were obtained prior to exercise on days 1 through 4, and 24h and 72h post-exercise. After adjustment for plasma volume, insulin concentrations and HOMA values were decreased significantly on day 2, 3 and 24h post-exercise, compared to baseline, suggesting improved insulin sensitivity. Plasma total fetuin-A concentrations were not altered with repeated bouts of exercise in the post-exercise period. However, a significant decrease in phosphofetuin-A concentrations was observed in the 24h post-exercise period, suggesting that the decreased phosphofetuin-A may contribute to the sustained effects of improved insulin sensitivity following repeated bouts of exercise.
Taken together, these data show for the first time that fetuin-A concentrations are decreased following a glucose load in normal weight, but not obese individuals, suggestive of a physiological role in insulin action. Additionally, the reduced Ser-312 phosphorylated fetuin-A levels observed 24 hours, after a single exercise session
(phosphofetuin-A AUC) and after repeated bouts of exercise, are consistent with improvements in surrogate markers of insulin sensitivity. Given phosphofetuin-A’s role of inhibiting insulin action, exercise-induced lowering of phosphofetuin-A, may be one mechanism by which exercise improves insulin action.