Published in UAB Insight, Spring 2008
NR4A Family May Offer Novel Type 2 Diabetes Treatment
UAB scientists recently identified two genes that appear to play a role in the molecular and biochemical causes of insulin resistance (IR). This discovery advances understanding of the biologic underpinnings of diseases caused by IR, such as type 2 diabetes and metabolic syndrome, and may lead to novel therapies for treatment and prevention (J Biolog Chem. 2007;282:31525-31533).
“We found that these genes in the NR4A family help sensitize muscle to insulin, promoting glucose uptake and thus keeping glucose levels within healthy limits,” says study author and UAB Department of Nutrition Sciences Chair W. Timothy Garvey, MD. Nutrition scientist Yuchang Fu, PhD, served as coinvestigator.
Garvey and his team found that NR4A1 and NR4A3 genes are underexpressed in animal models and humans with diabetes, and increasing their expression sensitizes skeletal muscle cells to insulin in the bloodstream. Garvey says a third of American adults have some degree of IR, although most produce enough insulin to maintain nondiabetic glucose levels. IR is the earliest detectable prediabetic metabolic defect and the greatest risk factor for subsequent progression to overt diabetes.
Garvey found the genes belong to a little-studied gene family with only three members — two of them found in skeletal muscle. “These orphan nuclear receptors [so called because ligands that activate the receptor complex have yet to be identified] appear to be a perfect target for drugs or small molecules that can activate them to predictably increase insulin sensitivity and forestall or control diabetes,” he says.
“A future goal will be screening large combinatorial libraries to find compounds that increase expression or activate orphan receptors and thus increase insulin sensitivity of tissues. Identifying such compounds would help us look at pathways, transcription factors, and other ways we can define the activity,” he says.
Pharmaceuticals are now available for the three metabolic defects in diabetes that work together to create hyperglycemia: Exenatide and dipeptidyl peptidase (DPP)-IV inhibitors treat sluggish insulin secretion; metformin reduces hepatic glucose output; and thiazolidines (TZDs) treat IR in skeletal muscle.
“Knowing which drug corrects which defect allows for more rational combination therapy,” he says. Using diabetes drug combinations that target multiple metabolic defects takes advantage of the synergistic effects of these drugs; eg, combining a drug that increases insulin production, such as a DPP-IV inhibitor, with a TZD that increases sensitivity to the insulin that is produced.” Because TZD agents cause significant unwanted side effects, additional drugs that sensitize muscle tissue to insulin are needed.
While hoping for new pharmaceutical therapies directed at IR, Garvey stresses the benefits of lifestyle modification. “Weight loss and exercise increase insulin sensitivity. Losing just 5% to 10% of body weight can produce results,” he says. One way to achieve this is by eating a low fat diet rich in fiber and complex carbohydrates, as taught in UAB’s EatRight Program.
Garvey adds, “We are in an exciting time for diabetes research at UAB, with a new Comprehensive Diabetes Center, a federally funded Diabetes Research and Training Center, and a Comprehensive Diabetes Clinic at The Kirklin Clinic®.”
For more information:
Dr. Timothy Garvey
1.800.UAB.MIST
mist@uabmc.edu