Liver Protein Linked to Diabetes Risk in Older Adults

By Crystal Phend
SAN DIEGO, 14 july 2008-- The hepatic protein fetuin-A may predict diabetes onset in older adults independently of recognized risk factors, researchers found.
The highest serum levels of fetuin-A were associated with a 2.41 times higher risk of incident diabetes compared with the lowest protein levels (P=0.007), reported Joachim H. Ix, M.D., of the University of California San Diego, and colleagues in the July 9 issue of the Journal of the American Medical Association.
This association in the longitudinal Health, Aging, and Body Composition (Health ABC) Study was independent of physical activity, weight, blood pressure, fasting glucose, lipid levels, C-reactive protein level, and other factors.
The results strengthen the link between fetuin-A and insulin resistance found in prior cross-sectional studies, the researchers said.
Fetuin-A is secreted by the liver and is thought to cause insulin resistance in muscle and fat by binding to the insulin receptor tyrosine kinase.
"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," the researchers said.
They conducted a case-control study within the larger Health ABC study of well-functioning Medicare beneficiaries ages 70 to 79.
The analysis included 406 randomly selected participants who did not have diabetes at baseline. Half were women, and half were black.
During six years of follow-up, 135 participants developed incident diabetes for a rate of 10.1 cases per 1,000 person-years.
Diabetes incidence rose with fetuin-A levels (P=0.005). Specifically, incidence was:
6.5 per 1,000 person-years among participants in the lowest third with fetuin-A levels at 0.76 g/L or less
10.3 per 1,000 person-years in the intermediate group
13.3 per 1,000 person-years in the highest tertile with fetuin-A levels of 0.97 g/L or higher
After adjustment for clinical predictors and demographic factors, the incidence of diabetes was more than twice as high among those in the highest fetuin-A levels compared with those in the lowest level group (adjusted hazard ratio 2.41, 95% confidence interval 1.28 to 4.53).
However, the risk was not significantly elevated for those in the intermediate group with fetuin-A levels of 0.77 to 0.97 g/L in the multivariate adjusted analysis (adjusted HR 1.82, 95% CI 0.94 to 3.53, P=0.07).
Diabetes risk jumped 57% with a doubling in fetuin-A level (HR 1.57, 95% CI 0.99 to 2.49, P=0.05).
The results were similar for men and women regardless of race and obesity status, but visceral fat appeared to account for at least one-third of the association between fetuin-A and diabetes incidence.
After additional adjustment for visceral adiposity, men and women in the highest tertile remained 1.7-times more likely to develop diabetes than those with the lowest fetuin-A levels, although the association lost statistical significance (P=0.06).
"On the basis of these data, blockade of fetuin-A binding to the insulin receptor might be considered a novel therapeutic target for prevention or treatment of insulin-resistant states," Dr. Ix and colleagues wrote.
They cautioned, though, that this protein is also involved in vascular calcification, so any agents would need to be carefully evaluated for cardiovascular effects.
The researchers noted that the study included only a single measurement of fetuin-A whereas tracking levels over time could potentially provide better insight into diabetes risk.
"Future studies should evaluate whether the results may generalize to middle-age individuals, in whom the incidence rate is highest," they added.
The study was supported by an award sponsored by the Atlantic Philanthropies, American Diabetes Association, John A. Hartford Foundation, and Association of Subspecialty Professors; an award from the American Heart Association; and contracts from the National Institute on Aging. The research was also supported in part by the National Institutes of Health. The researchers reported no conflicts of interest.
Primary source: Journal of the American Medical AssociationSource reference:Ix JH, et al "Fetuin-A and Incident Diabetes Mellitus in Older Persons" JAMA 2008; 300: 182-188.