NIH-funded project to discover biomarkers for type 2 diabetes

ASU, Phoenix VA, UA and Pfizer collaborate to discover molecular markers

Arizona State University will lead a four-year, $5 million expanded initiative sponsored by the National Institutes of Health to discover proteins, or biomarkers, to help predict cardiovascular disease and to assess potential new treatments in people with type 2 diabetes.

Nearly 26 million Americans have diabetes, the seventh leading cause of death in the U.S. The disease is a major cause of heart disease, stroke, kidney disease, blindness and amputation. The national cost of diabetes was an estimated $174 billion in 2007, the majority for direct medical costs.

Controlling blood sugar (glucose) levels is vital for treating diabetes and preventing or slowing complications. However, heart attack and stroke remain leading causes of death in diabetes.

"There are no standard biomarkers to identify people with type 2 diabetes who are more likely to develop cardiovascular disease. We assembled a highly integrated, multidisciplinary research team to discover, validate and translate novel protein biomarkers for cardiovascular complications in type 2 diabetes and their use in drug development," said project leader Randy Nelson, director of the Molecular Biosignatures Analysis Unit at ASU's Biodesign Institute. Nelson is an expert in proteomics, a scientific discipline that studies the structure and function of the proteins that constitute an organism.

The project is supported under an NIH program that encourages scientists from different disciplines to collaborate on a single, critically important research problem that has the potential to advance clinical research.

"Identifying markers to predict heart and blood vessel diseases in people with type 2 diabetes is challenging but important," said Salvatore Sechi, Ph.D., who oversees the project for the NIH's National Institute of Diabetes and Digestive and Kidney Diseases. "We are looking to the project's team of experts in proteomics, drug development, biostatistics and clinical studies to advance the difficult search for markers that may be useful for both diagnosis and for assessing potential new drug therapies."

The study will examine and validate biomarkers in people with diabetes, some of whom will have had a heart attack. It is unlikely that a single biomarker will have enough predictive power to assess heart attack risk; rather, panels of biomarkers will be needed to identify drug targets.

"There is a great need for more-effective biomarkers of macrovascular complications of diabetes and for surrogate indicators of favorable response to potential diabetes therapies," said Peter Reaven, M.D., who will oversee the selection of target biomarkers and clinical work, including patient recruitment at the Phoenix VA Health Care System. "Our goal is to identify novel proteins and relevant protein modifications that reflect many of the critical mechanisms that underlay vascular disease in diabetes to develop a more comprehensive panel of biomarkers. One advantage to our team approach is that it will integrate, from the very beginning, the many aspects and disciplines required for a pipeline of biomarker discovery, validation and translation." Pfizer will play a key role in translating prognostic biomarkers of cardiovascular disease risk for decision-making during drug development for type 2 diabetes.

"Prognostic markers of cardiovascular disease risk have been an essential need for type 2 diabetes drug development ever since Nissen published his influential report suggesting some drugs may increase heart attack rates," said Jim Pearson, Ph.D., head of Personalized Medicine at Pfizer in Kalamazoo, MI. "The FDA now requires patients with a higher risk for cardiovascular events to be enrolled in Phase III clinical trials for two years instead of three-to-six months. The problem is that a useful directed proteomics CVD risk panel has yet to be translated. A biomarker panel that is more comprehensive than HbA1c alone and correlates with CVD phenotype outcomes has great potential for influencing industry-wide type 2 diabetes drug development decisions."

HbA1c, or hemoglobin A1c, is a form of hemoglobin that is elevated in people with poorly controlled diabetes. In the 6-month life of a red blood cell, blood sugar molecules react with hemoglobin, forming glycated hemoglobin. In individuals with poorly controlled diabetes, the quantities of these glycated hemoglobins are much higher than in healthy people.

Researchers use state-of-the-art technology including protein sequencing by mass spectrometer, an instrument used to determine the composition of a physical sample by generating a spectrum representing the masses of sample components. The team uses mass spectrometers not only to identify new diabetes biomarkers and their functional states, but also to measure the quantity of particular proteins. For example, people with type 2 diabetes may produce too much of a given protein that would normally be present in lower amounts in a healthy individual.

Others collaborators include Chad Borges at Biodesign; Juraj Koska of the Phoenix VA Health Care System; and Serrine Lau, Craig Stump and Yassine Hussein at the University of Arizona's BIO5 Institute.

"The envisioned biomarkers will better predict the onset of cardiovascular disease in the context of type 2 diabetes and help define the optimal therapeutic or pharmaceutical interventions to significantly improve patient outcomes," said Nelson.

Source: Arizona State University