St. Louis, May 17, 2000 - AIDS drugs that dramatically prolong the lives of many HIV-infected people also quickly block the body's ability to store glucose, scientists have found. Their research explains why people who take HIV-protease inhibitors are prone to develop diabetes. It suggests that doctors might need to alter the way they test HIV-infected patients for diabetes. And it suggests a way to develop new AIDS drugs without the diabetes risk.
"We hope these findings will help improve AIDS therapy while preventing what can be serious complications from a very effective HIV treatment," says Mike M. Mueckler, Ph.D., the lead scientist for research that will be described in the July or August issue of Journal of Biological Chemistry. The unedited article is available on the journal's Web site.
Mueckler is a professor of cell biology and physiology at Washington University School of Medicine in St. Louis and associate director of the medical school's Diabetes Research and Training Center. He carried out the research with Haruhiko Murata, an M.D. ,Ph.D. student, and Paul W. Hruz, M.D., a fellow in pediatric endocrinology.
The FDA rapidly approved HIV-protease inhibitors in 1996 because the drugs produce a dramatic drop in the level of HIV in patients' blood. They prevent an enzyme from functioning that HIV needs for multiplying and producing a more active infection.
However, studies in the past two years have suggested that long-term use of HIV-protease inhibitors comes at a high price. Up to 83 percent of people taking the AIDS drugs develop excess belly fat and skinnier arms, legs and faces. Moreover, abdominal obesity is associated with type 2 diabetes. And a recent pilot study found that 46 percent of HIV-infected patients on HIV-protease inhibitors had impaired glucose tolerance, a predictor of future diabetes development. An additional 13 percent developed type 2 diabetes within 18 months of taking the drugs.
By comparison, about 6 percent of Americans develop this version of diabetes after years of difficulty handling glucose, the fuel that fat and muscle cells store for future bursts of activity. Type 2 diabetes results from an inability to produce enough of the hormone that stimulates glucose uptake by these cells. And it results from failure of the cells to respond to the hormone insulin. Excess glucose circulating in the bloodstream can damage organs, producing blindness, kidney failure and other complications.
After reviewing results from animal studies, the researchers decided to investigate whether the AIDS drugs inadvertently cripple a protein that serves as the porthole for glucose entry into fat and muscle cells, which store it as fat or glycogen. Genetically modified mice that lack the protein called glucose transporter 4 (glut4), can't store fat. Other mice that have half the normal level of glut 4 respond poorly to insulin and are prone to develop type 2 diabetes.
Mueckler and his colleagues studied the effect of three commonly used HIV-protease inhibitors on fat cells. They found that human fat cells in test tubes took in less glucose after exposure to the drugs at a concentration of 10 micromoles. This drug concentration occurs in the blood of people receiving HIV therapy.
To determine how the drugs inhibit glut4, the researchers analyzed the steps in the complicated molecular pathway that the body uses to prompt glucose storage. The HIV inhibitors didn't prevent fat cells from responding to insulin. Nor did they keep glut4 from traveling to the cell exterior to prepare for glucose uptake. Instead, the protease inhibitors prevented the transporter's from operating. This finding was made by inserting the gene for glut4 into eggs of African clawed toads (Xenopus laevis), which automatically display the transporter on their surface.
The results suggest that doctors need to reconsider how they assess the diabetes risk of people on HIV-protease inhibitors. The researchers estimate that the drugs may hinder glut4 activity within minutes. Yet doctors currently give glucose tolerance tests without considering patients' HIV-medication schedules. "More (HIV-infected) patients are probably glucose-intolerant than we are aware of because of the way diabetes testing is done," Mueckler says.
The School of Medicine researchers are searching for new drugs that won't cripple glut4 function. In addition, they are investigating how the current protease inhibitors thwart the transporter's function.
They also will try to determine whether poor glut4 function causes fat redistribution in patients taking HIV-protease inhibitors. Because glut4 malfunctions in patients taking the inhibitors before body fat is redistributed, the transporter might incite this reorganization. "That would make sense if fat stored in the outer portions of the body is made from blood glucose, whereas stores of belly fat come from fat in the blood," Mueckler says, noting that abdominal obesity is associated with type 2 diabetes.
This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and the Diabetes Training and Research Center at Washington University School of Medicine in St. Louis.
Murata H, Hruz PW, Mueckler M. The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy. Journal of Biological Chemistry. July or August 2000.
The article can be viewed on-line at http://www.jbc.org/cgi/reprint/C000228200v1.
Journal
Journal of Biological Chemistry