Researchers Pinpoint Causes of Adverse Reactions to Popular Type 2 Diabetes Drugs

Used by several million people worldwide, rosiglitazone (RSG) is an oral agent that helps patients with type 2 diabetes maintain good blood glucose levels by improving how their bodies use insulin.

But RSG, like all the other thiazolidinedione (TZD) drugs that can lower blood glucose levels, can cause fluid retention (edema), a condition that puts patients at greater risk for weight gain, vascular complications and heart failure.

Recently, the U.S. Food and Drug Administration and GlaxoSmithKline, which manufactures the drugs, reported cases of new onset or worsening macular edema (an eye disorder that leads to blurred or distorted vision) among patients who took RSG. While reports of these complications remain rare, GlaxoSmithKline has added a warning about the risks to the drugs labels.

Now a new study at Joslin Diabetes Center has uncovered a mechanism that leads to these complications and suggests a way to prevent them. The study was led by George L. King, M.D., the Director of Research and Head of Vascular Cell Biology at Joslin and Professor at Harvard Medical School. It appears in the June edition of the FASEB Journal, a publication of the Federation of American Societies for Experimental Biology.

Treating rats with RSG over several weeks and comparing their tissues with those of rats in the control group, the researchers documented increases in blood vessel leakage and fluid retention in fat tissue and the retina. They also showed that the rats experienced weight gain similar to that observed in patients. What gave them the clue to the cause of these changes came when they examined the activity levels of one form of the protein kinase C (PKC) enzyme in the affected tissues.

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PKCs comprise a group of about a dozen enzymes (proteins that promote chemical reactions) that are essential to normal cell functions. During the 1980s, Dr. King and his colleagues at Joslin showed that the activity of PKC-beta enzyme increases with high blood glucose levels. In subsequent studies, they were able to link this increased PKC-beta activity to diabetic complications of the eye, kidney, arteries and heart.

Examining blood vessels in the fat tissues of RSG-treated rats in their new study, the researchers observed increased PKC-beta activity, suggesting that PKC-beta is the culprit behind the RSG fluid side effects. They were able to confirm this suspicion by treating two types of mice with RSGwild-type (normal) mice and PKC-beta knockout mice, animals that have been genetically engineered so their bodies no longer produce the enzyme. We found increased capillary leakage and weight gain in the wild-type mice but not in the knockout mice, demonstrating that RSG-induced activation of PKC-beta is involved in these side effects, says Dr. King.

The finding also suggests a potential treatment. Over a decade ago, Joslin researchers began working on PKC-beta inhibitors that would block PKC-beta activity without interfering with the cells normal functions. Now being tested for clinical use, a PKC-beta isoform selective inhibitor drug will make it potentially possible for patients to take RSG or other TZDs without increasing their risk of developing edema and increased capillary leakage.

RSG attacks type 2 diabetes head on by helping patients overcome insulin resistance, but because of its complications, it has had limited clinical use in patients with diabetes and heart disease, says Dr. King. There is now a potential way to make this drug more widely available.

Other Joslin researchers participating in the study include Lloyd P. Aiello, M.D., Ph.D., Allen Clermont, Kim Della Vecchia, Tatsuya Kondo, M.D., Ph.D., Motonobu Matsumoto, Ph.D., Christian Rask-Madsen, M.D., Ph.D., Konstantinos B. Sotiropoulos, M.D., D.Sc., Junichi Takahashi, M.D., and Yutaka Yasuda, M.D., Ph.D.

The study was funded by GlaxoSmithKline and the National Institutes of Health.

Source: Joslin Diabetes Center