In this study, we make the novel observation that higher serum fetuin-A levels are associated with incident diabetes mellitus in humans. The association was independent of physical activity, inflammatory biomarkers, and other commonly available measures of insulin resistance, and was similar irrespective of sex, race, and obesity status. Approximately one third of this association appeared to be mediated by the quantity of visceral adiposity. Yet, fetuin-A remained associated with a 1.7 fold risk of diabetes after adjustment for visceral adiposity, an association that was not statistically significant (P=0.06).
In 1989, fetuin-A was reported as an endogenous inhibitor of insulin receptors, through binding insulin receptor tyrosine kinase in adipocytes and skeletal muscle, resulting in decreased rates of auto-phosphorylation and down-stream insulin signaling cascades.(11
) This function was conserved across all species homologs evaluated to date in vitro
) and has been confirmed in vivo
) The human fetuin-A gene resides on chromosome 3q27, previously identified as a metabolic syndrome and diabetes susceptibility locus.(29
) Fetuin-A knock-out mice are insulin sensitive, are resistant to weight gain, have less adiposity, lower free fatty acid and lower triglyceride levels compared to wild-type controls.(13
) and others(15
) have previously demonstrated that higher fetuin-A levels are associated with insulin resistance/metabolic syndrome in cross-sectional studies. However, despite compelling in vitro
and animal data, to our knowledge the association of fetuin-A with incident diabetes has not previously been evaluated. The data presented here are novel in demonstrating the longitudinal link between fetuin-A and incident diabetes in humans. Moreover, the data suggest that that not only adipocyte derived factors and pancreatic hormones, but also hepatocyte derived proteins such as fetuin-A may regulate glucose metabolism in humans.
The association of fetuin-A with incident diabetes was partially attenuated with adjustment for visceral adiposity. Previous studies have demonstrated that fetuin-A stimulates adipogenesis in cell culture models,(31
) and conversely, fetuin-A knock-out mice have less adiposity than wild-type controls.(14
) We hypothesize that the direct correlation of fetuin-A with visceral adiposity observed in this study is a consequence of higher fetuin-A levels, and that accumulation of visceral adiposity may lie on causal pathway between fetuin-A and incident diabetes. However, despite statistical adjustment for visceral adiposity, the association of fetuin-A with incident diabetes was only partially attenuated, suggesting that mechanisms other than accumulated visceral adiposity likely also contribute to the link between fetuin-A and incident diabetes.
On the basis of these data, blockade of fetuin-A’s binding to the insulin receptor might be considered a novel therapeutic target for prevention or treatment of insulin resistant states. However, fetuin-A levels have an inverse association with vascular calcification. Beyond the insulin sensitive phenotype, the fetuin-A knock-out mouse develops wide-spread soft-tissue calcification.(32
) Our group,(34
) and others(35
) have demonstrated that lower fetuin-A levels are associated cross-sectionally with vascular and cardiac valvular calcification in humans, and are associated with mortality after myocardial infarction(38
) and in end-stage renal disease.(37
) Therefore, any novel therapeutic that blocks fetuin-A should be closely evaluated for safety, particularly with respect to cardiovascular consequences.
Our study has limitations. Participation required age 70 to 79, and black or white race. The findings may not generalize to younger persons or other race/ethnicities. Two-hour oral glucose tolerance tests are more sensitive than fasting glucose for diagnosis of diabetes.(42
) This measure was available at baseline, providing accurate classification of diabetes status at entry. However, it was not available at follow-up visits which could have resulted in some incident diabetes cases being misclassified as normal, and therefore should have biased our results towards the null hypothesis. Blind duplicate intra-individual coefficients of variation of fetuin-A were higher in this study than in previous manuscripts.(34
) Again, measurement error misclassification should also have biased our results towards the null. Last, fetuin-A was measured at only one time point. Whether or not longitudinal trajectories of fetuin-A provide additional, or more specific, information regarding future diabetes risk is an important topic for future research.
In conclusion, fetuin-A is independently associated with incident diabetes in older persons. Future studies should evaluate whether the results may generalize to middle age persons where the incidence rate is highest.(46
) If confirmed in future studies, fetuin-A may ultimately prove useful as a target for therapeutics, and its study may provide novel insights to glucose metabolism in humans.