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Designing New Diabetes Drugs

Building on recent insights into how diabetes medications work, researchers have designed experimental drugs that are as effective in mice as current medications, but cause fewer side effects. The finding may lead to new drugs to combat diabetes.

Almost 26 million Americans have diabetes, a disease in which the body has problems producing or using insulin. The body needs this hormone to convert sugars into energy. Diabetes is the main cause of kidney failure, limb amputations and new-onset blindness in adults nationwide. It’s also a major cause of heart disease and stroke.

Some people with diabetes need to take medications. The thiazolidinedione class of drugs, which includes rosiglitazone (Avandia) and pioglitazone (Actos), is effective for treating type 2 diabetes, the most common form of the disease. But these drugs can cause side effects ranging from uncomfortable to dangerous, such as fluid retention, bone loss, weight gain, bladder cancer and congestive heart failure. Recently, the Food and Drug Administration severely restricted the sale of drugs containing rosiglitazone because of the elevated risk of heart attack and stroke.

These drugs work by increasing the body’s sensitivity to insulin. They attach to a receptor in the cell’s nucleus called PPARγ. PPARγ affects gene expression and drives fat cell development. The drugs activate PPARγ, but their molecular modes of action were unclear. Last year, researchers found that anti-diabetic PPARγ compounds activate the receptor to varying extents. Many don’t block the ability of PPARγ to drive fat cell development. However, the effective compounds are similar in one respect: they block the addition of a phosphate group to PPARγ — a process called phosphorylation.

The scientists thus set out to design an improved generation of anti-diabetic drugs by specifically preventing the phosphorylation of PPARγ, which is carried out by a protein called Cdk5. The team was led by Drs. Patrick R. Griffin and Theodore Kamenecka at Scripps Florida and Dr. Bruce Spiegelman at the Dana-Farber Cancer Institute and Harvard Medical School. The research was supported by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Mental Health (NIMH) and National Institute of General Medical Sciences (NIGMS).

As described in Nature on September 22, 2011, the scientists first selected a compound that binds strongly to PPARγ but doesn’t broadly affect gene expression. They then synthesized a series of similar compounds and searched for ones that block Cdk5 phosphorylation of PPARγ. To find a compound specific for PPARγ, they ruled out compounds that also blocked Cdk5 phosphorylation of an additional protein.

One compound called SR1664 specifically blocked the Cdk5 phosphorylation of PPARγ in fat cells but didn’t interfere with gene expression or with fat cell growth and development. When tested in diabetic mice, SR1664 lowered glucose levels and insulin resistance. However, it didn’t cause fluid retention and weight gain. It also didn’t interfere with bone formation in laboratory cultures.

These preliminary results are far from use in the clinic. Still, they illustrate that it’s possible to develop drugs that specifically target the phosphorylation of PPARγ.

“It appears that we may have an opportunity to develop entire new classes of drugs for diabetes and perhaps other metabolic disorders,” says Spiegelman.

— by Harrison Wein, Ph.D.