Jun 13, 2006
An extract of the gardenia fruit, which is used in traditional Chinese medicine, could provide a new lead in the search for drugs to treat the symptoms of type 2 diabetes. The extract contains a chemical that apparently reverses some of the pancreatic dysfunction that underlies the disease, according to researchers writing in the June 7 issue of Cell Metabolism.
The chemical in question is genipin. This compound was previously found to cross-link proteins, but it has also now been shown to inhibit the enzyme uncoupling protein 2 (UCP2) through another mechanism. In both animals and humans, high concentrations of UCP2 appear to inhibit insulin secretion from the pancreas and increase the risk of type 2 diabetes.
“We think the increase in UCP2 activity is an important component of the pathogenesis of diabetes,” said Bradford Lowell of Beth Israel Deaconess Medical Center and Harvard Medical School. “Our goal therefore was to discover a UCP2 inhibitor capable of working in intact cells, as such an inhibitor could theoretically represent a lead compound for agents aimed at improving beta cell function in type 2 diabetes.”
Study coauthor Chen-Yu Zhang’s familiarity with traditional Chinese medicine led the team to consider the extract of Gardenia jasminoides Ellis fruits. Pancreas cells taken from normal mice secreted insulin when treated with the extract, they found, whereas the cells of mice lacking UCP2 did not. The results suggested that the extract worked through its effects on the UCP2 enzyme.
“When I first saw the results, I was in disbelief,” Lowell said. “I didn’t think we could ever be that lucky.” However, blinded repetition of the initial experiments confirmed the results every time, he said.
Through a series of chemical analyses, the researchers then zeroed in on genipin as the active compound. Genipin, like the extract, stimulated insulin secretion in control but not UCP2-deficient pancreas cells.
They further found that acute addition of genipin to isolated pancreatic tissue reversed high glucose- and obesity-induced dysfunction of insulin-producing beta cells. A derivative of genipin that lacked the chemical’s cross-linking activity continued to inhibit UCP2, they reported.
That’s a good sign for the therapeutic potential of genipin-related compounds, according to Lowell, as such indiscriminate cross-linking would likely have adverse effects. However, further work will need to examine whether inhibition of UCP2 itself might also have some negative consequences.