Protease inhibitors cause diabetes in some patients

Data could help in developing better PIs

New research shows how protease inhibitor drugs cause some patients to develop insulin resistance and can even lead to type 2 diabetes.

"A small number of patients at this point have developed full-blown diabetes after being placed on protease inhibitor [PI] therapy," says Michael M. Mueckler, PhD, professor of cell biology and physiology at the Washington University School of Medicine in St. Louis.

More than 80% of the people on protease inhibitor therapy in one study developed lipodystrophy, and a smaller fraction developed diabetes, all within an 18-month time period. This shows the potential growth of the problem as people stay on PI therapy for years and even decades.

"Diabetes is a disease that takes a long time to develop, and it’s quite possible that a good fraction of people who continue to be on PI therapy will develop type 2 diabetes, especially if they have predisposing factors like obesity and a family history," Mueckler adds. "So this is not at all trivial."

PIs are also associated with the metabolic abnormalities of peripheral fat wasting, central adiposity, hypertriglyceridemia, and hypercholesterolemia. The Cardiovascular Disease Focus Group established by the U.S. AIDS Clinical Trials Group has released guidelines for managing lipid abnormalities in HIV patients on antiretroviral therapy. (See summary of guidelines for managing dyslipidemia, p. 93.)

PIs inhibit glucose transportation

Mueckler and other investigators studied the mechanism in PIs that causes insulin resistance. Aided by research on mice, investigators discovered a Glut4 glucose transporter that is necessary for full-body glucose disposal. In patients on PI therapy, the Glut4 glucose transporter is not working properly or responding adequately to insulin that’s released with increased activity.

"What this Glut4 protein does is to take up glucose from the blood into muscle tissue and fat tissue," Mueckler explains. "So we tested the hypothesis that HIV protease inhibitors were inhibiting the function of the Glut4 gene, and we found that was indeed the case," he adds.

Researchers further theorized that PIs were binding directly to the Glut4 protein and somehow altering and inhibiting its activity. Lab tests using oocytes confirmed that PIs were blocking activity of the Glut4 transporter, but not the Glut1 transporter that is responsible for transporting glucose to the brain.

"If PIs inhibited all glucose transporters, including Glut1, it would probably kill people," Mueckler says. "And obviously, PIs are not killing people and are not affecting brain function as far as we know, either."

The next step is to determine how PIs are inhibiting the Glut4 transporter.

"Once we know that, it hopefully will assist in the design of a new generation of protease inhibitors that hopefully will inhibit HIV protease but not inhibit the glucose Glut4 transporter," Mueckler says. "And we think that’s the most important ramification of this work."

Pharmaceutical companies could use a simple assay that measures Glut4 activity to determine whether new protease inhibitors have the propensity for causing the metabolic syndrome, he adds.

Until new PI drugs that do not cause glucose/ insulin imbalances become available, clinicians should treat patients on PI therapy as if they could develop diabetes, Mueckler suggests.

Regularly monitor patients’ blood sugar

HIV clinicians need to be aware of the insidious nature of diabetes, which can cause heart disease, kidney failure, and blindness.

"The important thing is to have patients’ blood sugar monitored on a regular basis, especially if they have the two major predisposing factors of obesity and a family history of type 2 diabetes," Mueckler says.

Because PIs work so well in controlling HIV infection, putting patients on an alternative therapy is a less viable option that should be decided on a case-by-case basis, he adds.

On the positive side, the insulin problems caused by PIs are probably reversible.

"The effect we saw in PIs on the glucose transporter occurred very rapidly, within minutes, and also was rapidly reversible," Mueckler says. "We feel it will restore insulin sensitivity if they stop the drugs."

The study will be published in the Journal of Biological Chemistry. An unedited version of the article is available on the journal’s Web site at www.jbc.org/cgi/reprint/C000228200v1.