Joslin researchers pinpoint causes of adverse reactions to popular type 2 diabetes drugs

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Public release date: 1-Jun-2006

http://www.eurekalert.org/pub_releases/2006-06/jdc-jrp060106.php

Contact: Marjorie Dwyer

marjorie.dwyer@...

Joslin Diabetes Center

Joslin researchers pinpoint causes of adverse reactions to popular type

2 diabetes drugs

Findings suggest potential way to prevent side effects

BOSTON -- Used by several million people worldwide, rosiglitazone (RSG)

is an oral agent that helps patients with type 2 diabetes to 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 GlaxoKline, 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, GlaxoKline 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 L. King, M.D., the Director of Research and Head

of Vascular Cell Biology at Joslin and Professor at Harvard Medical

School. It will appear 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.

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 RSG--wild-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 cell's 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., 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.

--

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