Once-Promising Diabetes Drugs’ Side-Effects Can Be Limited, Study Finds

diabetes drugs

A group of diabetes drugs that have fallen out of favor due to side-effects may merit renewed attention after scientists at Scripps Research discovered a way to capitalize on the insulin-sensitizing talent of the drug receptor while limiting its ability to cause weight gain, brittle bones and other impacts. 

The class of diabetes drugs called thiazolidinediones (TZDs) have proven highly effective in helping to manage blood sugar, but long-term use comes with the unacceptable consequences of increased risk for heart failure, brittle bones and weight gain, says structural biologist Douglas Kojetin, PhD, an associate professor at Scripps Research.

In a recent study published in Nature CommunicationsKojetin and colleagues, including Scripps Research scientists Patrick Griffin, PhD, and Theodore Kamenecka, PhD, describe a method for keeping the drugs’ therapeutic response and limiting the undesirable side effects by altering the activity of the receptor—essentially changing how the lock and key connect.

The drugs, known as TZDs, work by binding to a type of protein that can act as a switch for gene expression, called nuclear receptors. The specific receptor for TZDs, peroxisome proliferator-activated receptor gamma (PPARg), when activated by the drug, initiates a series of steps that fight high blood sugar.  Unfortunately, if activated in bone, it can also stimulate the development of fat cells. That also causes bones to become brittle and boosts weight gain.

In their paper, Kojetin and colleagues lay out the steps by which PPARg receptors can be targeted to produce therapeutic benefits without degrading bone tissue. Specifically, PPARg activity can be modulated with specially designed molecules called “inverse agonists” that repress, or inactivate, the unwanted biological activities.

“There have been studies that show that repressive drug-like molecules allow bone formation to occur while maintaining diabetic efficacy,” says Kojetin. “Our study is probably one of the first to give the molecular blueprint on how to design a new class of inactivating drug-like molecules that repress PPARg activity.”

The researchers identified a compound that enabled the PPARg receptor to shift between two different shapes. One of these conformations enabled an opposite effect compared to anti-diabetic TZD drugs.

More studies are needed to investigate how these findings may influence the development of new anti-diabetic drugs with a bone-protective benefit, Kojetin says.

“Beyond diabetes, repressive molecules have been implicated as potential therapies in cancer and the differentiation of stem cells from cord blood,” says Kojetin. “We simply don’t know all the potential benefits of repressive PPARγ drug-like molecules because very few are available, and they have not been studied as extensively as the TZDs.”

The authors of the study, “A structural mechanism for directing corepressor-selective inverse agonism of PPARg” were Richard Brust, Jinsai Shang, Jakob Fuhrmann, Sarah Mosure, Jared Bass, Andrew Cano, Anne-Laure Blayo, Patrick Griffin, and Theodore Kamenecka at Scripps Research in Jupiter, FL; Zahra Heidari, Ian M. Chrisman, Michelle Nemetchek, and Travis Hughes at the University of Montana in Missoula.This research was made possible by the National Institutes of Health (NIH) grants R01DK101871, F32DK108442, R01DK105825, R00DK103116, and P20GM103546; and an American Heart Association (AHA) fellowship award (16POST27780018). A portion of this work was performed at the National High Magnetic Field Laboratory (NHMFL/MagLab), which is supported by the National Science Foundation (NSF; DMR-1157490).