GHSU team looking at cause, prevention of diabetes

Discovering exactly how people at higher risk for diabetes go on to develop the disease and serious complications such as heart or kidney disease, and perhaps preventing that, will be the focus of a team of researchers at Georgia Health Sciences University.

Dr. William Caldwell, the chairman of the Department of Pharmacology and Toxicology, is part of a group using a $450,000 seed grant from the National Institute of Diabetes and Digestive and Kidney Diseases to come up with a five-year research plan that will include human and animal trials.

The group is focusing on prediabetes – elevated fasting blood glucose levels but not quite diabetes. The Centers for Disease Control and Prevention estimates there are 79 million Americans in that category who are at high risk of developing Type 2 diabetes.

If present trends continue, one in three people born in 2000 will develop diabetes in his lifetime, said Dr. Ann Albright, the director of the Division of Diabetes Translation at the CDC.

“If we progress down this road, we are in trouble,” she told a recent gathering of fellows of the Association of Health Care Journalists.

The exact mechanisms for how that develops is not yet well understood, the GHSU group contends. It is focusing on two specific enzymes that appear to be implicated in that process – arginase and indoleamine 2,3-dioxygenase, or IDO. The latter enzyme brought worldwide attention to the university when researchers Andrew Mellor and David Munn showed it was a key part of the mechanism that protects a developing fetus from being attacked by the mother’s immune system. It has since been studied in a number of other diseases, such as cancer.

In this instance, IDO is elevated in chronic inflammation, “but we don’t know about its role in diabetes,” Caldwell said. “But we suspect it is there.”

Arginase is known to be involved in pro-inflammatory pathways, and preliminary testing has already found it is elevated in the prediabetes population, said Dr. Yanbin Dong, a professor of pediatrics and graduate studies at GHSU. There are already drugs that inhibit arginase that are used to treat parasitic infections, Caldwell said.

“In the end, it is theoretically possible to treat patients with an arginase inhibitor if we prove that it really is a bad player …,” said Dr. Ruth Caldwell, a professor in cellular biology and anatomy at GHSU.

Arginase is also tied into another known factor for diabetes called the tumor necrosis factor. People have tried to inhibit it, but doing so places a patient at risk because it is part of the body’s antibacterial defense, said Dr. Rudolf Lucas, an associate professor in pharmacology and toxicology.

GHSU will be studying a specific peptide which seems to knock that factor out without harming the body’s defenses, he said.

“So that would be a major advantage,” Lucas said.

Arginase might turn out to be a more sensitive indicator of the progressive damage in a patient that is leading toward type 2 diabetes and might then help identify patients in need of more aggressive treatment, Dong said.

“Kind of like an early identification and an early management (tool),” he said.

The CDC is pushing a prevention strategy that urges people to lose 5-7 percent of their body weight and get 150 minutes a week of moderate activity, which in clinical trials reduced diabetes by 58 percent, Albright said. Elevated arginase levels could give clinicians more ammunition to talk patients into a lifestyle change, Ruth Caldwell said.

“If we know that some people are more likely to develop prediabetes and move onto diabetes, if we can predict it, we would have a better argument to those patients that they have a special need to lose weight,” she said.

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