COLORADO SPRINGS — Serum fetuin-A level is an independent risk factor for subsequent development of diabetes in the well-functioning elderly, according to results from a case-cohort substudy of 519 elderly subjects randomly selected from a larger longitudinal study.
The burning issue now becomes whether fetuin-A is a modifiable risk factor or simply a marker of increased risk. That remains to be determined in future studies, observed Dr. Joachim H. Ix of the University of California, San Diego.
Fetuin-A is a multifunctional hepatic secretory protein involved in glucose homeostasis. It binds insulin receptors in fat and muscle and, in vitro, inhibits insulin action.
Moreover, the fetuin-A gene keeps interesting company. It is located on chromosome 3C27, which has been mapped as a metabolic syndrome and type 2 diabetes susceptibility locus.
At a conference of the American Heart Association, Dr. Ix presented the case-cohort study involving the 519 randomly selected participants in the National Institutes of Health-sponsored longitudinal Health, Aging, and Body Composition study, which enrolled more than 3,000 well-functioning white and black subjects aged 70–79 years.
All participants in the substudy were without diabetes at entry. During 6 years of follow-up, 135 of them developed new-onset diabetes. The incidence among participants in the lowest quartile for baseline serum fetuin-A was about 7%, roughly half the rate in those in the highest quartile.
After full adjustment for age, gender, race, blood pressure, fasting glucose, physical activity, HDL cholesterol, waist circumference, C-reactive protein, and triglycerides, individuals in the top fetuin-A tertile—that is, greater than 0.97 g/L on a commercial ELISA assay marketed by Epitope Diagnostics Inc.—had an adjusted 2.4-fold greater risk of developing diabetes than did those in the bottom tertile, with a level of 0.76 g/L or less. Those in the middle tertile had a 1.8-fold increased risk.
Results of this new longitudinal study are consistent with an earlier cross-sectional study in which Dr. Ix and coworkers showed higher fetuin-A was strongly associated with prevalent metabolic syndrome (Circulation 2006;113:1760–7).
Also relevant is the fact that knockout mice lacking the fetuin-A gene demonstrate greater insulin sensitivity, less weight gain, less adiposity, lower free fatty acids, and lower triglycerides than do mice producing the hepatic protein, Dr. Ix continued.
Dr. Jeremiah Stamler was particularly intrigued by Dr. Ix's earlier work demonstrating an inverse association between fetuin-A levels and mitral annular calcification in patients with coronary heart disease (Circulation 2007;115:2533–9).
This seems contradictory: High levels of fetuin-A independently predict an atherogenic lipid profile, metabolic syndrome, and diabetes, all strongly associated with increased risk of coronary disease, yet high fetuin-A might also protect against valvular and vascular calcification, said Dr. Stamler, professor emeritus of preventive medicine at Northwestern University, Chicago.
Dr. Ix agreed this is an exciting area, but one where the research is still at quite an early stage. It's plausible there is a U-shaped relationship between fetuin-A level and cardiovascular risk, he noted.
Dr. Ix and his associates' study was a finalist for the annual Jeremiah and Rose Stamler Research Award for Young Investigators.