New biological pathway discovery may help scientists redesign certain diabetes drugs to reduce adverse side effects

October 9, 2012

University of Iowa team discovers new biological pathway in blood vessel cells, which may contribute to the blood pressure-lowering effects of TZD drugs used to treat Type 2 diabetes. This finding may help to develop new therapies that retain the beneficial effect of TZDs but eliminate the adverse side effects.

Many drugs work by "fixing" a particular biological pathway that's gone awry in a disease. But sometimes drugs affect other pathways too, producing undesirable side effects that can be severe enough to outweigh the drug's benefits.

Such is the case for the thiazolidinedione drugs (also known as TZDs), which are used to treat type 2 diabetes. These are highly effective in controlling and have an added benefit of in some patients. However, TZDs cause unrelated but potentially severe side effects in some patients, including heart failure, , and to a lesser degree heart attack or depending on the specific TZD. The actual risks vary depending upon a patient's specific circumstances. Nonetheless, because of increased recognition of these unwanted effects, the rate of new TZD prescriptions is on the decline.

"We wanted to discover how TZDs , so that more specific drugs might be developed that retain the beneficial effect of TZDs but eliminate the detrimental side effects," says Curt Sigmund, Ph.D., professor and head of pharmacology at the UI Carver College of Medicine, and senior author of a new study published Oct. 3 in the journal .

The TZD drugs activate a protein called PPAR-gamma. in this protein disrupt the normal function of blood vessels and cause high blood pressure in people.

Sigmund and his colleagues wanted to home in on the function of PPAR-gamma in blood vessel, so they created a genetically modified mouse where the PPAR-gamma expressed in the blood vessels was mutated. These mice developed high blood pressure.

Using these mice to study how disruption of PPAR-gamma leads to , the researchers uncovered a new biological pathway (called the Cullin-3 pathway) in blood vessels, which may be the key to the blood pressure-lowering effects of TZD drugs.

The study showed that the activity of Cullin-3 in blood vessels is important for maintaining normal blood pressure, and decreased activity of Cullin-3, through disruption of PPAR-gamma, leads to increased blood pressure.

The study results may also help explain another recent finding that mutations in Cullin-3 cause early onset hypertension in people.

Sigmund notes that early research in mice has shown that new molecules, which target PPAR-gamma in new ways, do not have the side effects of TZDs. Whether these new drugs work through the Cullin-3 pathway identified by the UI team will require additional research, he says.

"Our study has added importance because some drugs, which target Cullin-3 and other Cullin proteins, are currently being tested as chemotherapies," adds Sigmund, who also directs the Center for Functional Genomics of Hypertension. "Our findings suggest that blood pressure will have to be monitored in patients undergoing these treatments."

Explore further: Popular diabetes drugs' cardiovascular side effects explained

Related Stories

Diabetes drug side effects traced to fat action

July 5, 2011

For better or worse, a popular class of anti-diabetic drugs does more than lower blood sugar. One known as rosiglitazone (trade name Avandia) has been in the spotlight for its possible link to increased cardiovascular events, ...

Recommended for you

How does friendly fire happen in the pancreas?

October 21, 2016

In type 1 diabetes, the body attacks its own insulin-producing cells. Scientists at Helmholtz Zentrum München, partner in the German Center for Diabetes Research, and their colleagues at Technical University of Munich have ...

Diabetes opens floodgates to fructose

October 11, 2016

Fructose, once seen as diabetics' alternative to glucose, is fast-tracked to the liver in diabetic mice and contributes to metabolic diseases, according to new research from Harvard University.

Type 2 diabetes and obesity—what do we really know?

October 6, 2016

Social and economic factors have led to a dramatic rise in type 2 diabetes and obesity around the world. In a review in Science, Mark McCarthy, professor at the University of Oxford, UK, and Paul Franks, professor at Lund ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.