Human haptoglobin gene mutation increases risk of diabetic complications

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is a multifactorial disease of complex etiology characterized by the autoimmune destruction of pancreatic beta cells. In addition to genetic susceptibility, it is generally accepted that environmental factors play important roles in triggering disease, with virus infection having perhaps the strongest association. Multiple viral infections including cytomegalovirus, mumps, rubella, enteroviruses, and parvovirus have all been associated with human T1D. Indeed, the effects of diverse viruses in triggering T1D may explain the heterogeneous nature of disease onset and kinetics in the general population.

The recent availability of novel immunomodulatory therapies that may preserve residual beta cell mass in new onset diabetics has generated a demand for noninvasive testable biomarkers that can identify the development of the autoreactive process before it becomes clinically apparent. In the work published in the November issue of Experimental Biology and Medicine, Kruger and coworkers have utilized several well-established rat models of virus-induced T1D to search for serum biomarkers that occur early in disease development. Annie Kruger, working together with Rita Bortell and other colleagues at the University of Massachusetts Medical School, carried out the work. Dr. Kruger, a recent MD/PhD graduate, investigated the viral induction of autoimmune diabetes as part of her PhD thesis.

In a proteomics study of serum from rats treated with diabetogenic virus, the research team utilized 2D gel analysis and mass spectrometry and found increased levels of serum haptoglobin very early in the time course of diabetes induction. This result was confirmed by western and ELISA analyses, and sustained elevations of serum haptoglobin were generally predictive of ensuing diabetes. "Intriguingly," Dr. Bortell stated, "mutations in the human haptoglobin gene are associated with increased risk of diabetic complications such as retinopathy, nephropathy and cardiovascular disease. In our rat studies, however, haptoglobin was identified very early following virus infection, well prior to the development of diabetes or its complications, and thus may represent a biomarker for the pathogenesis of autoimmune diabetes as well."

To the researchers' knowledge, this is the first study that investigates T1D serum biomarkers found specifically in response to virus infection. Dr. Bortell said "As virus infections have historically been associated with the development of T1D in children, these rat models have particular relevance to the human disease. Reliably identifying children in the earliest phases of diabetes (pre-diabetes) would provide clinicians with a window of opportunity when pharmacotherapy could be most effective in slowing or halting the disease."

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