New Insights into Anti-diabetic Drugs

Research published this month in Nature Communications has revealed a novel binding site for common drugs used to treat type II diabetes. This serendipitous finding could pave the way for new drugs for diabetic patients with fewer adverse side-effects.

The work was carried out by scientists at The Scripps Research Institute (TSRI) in Florida. Douglas Kojetin led the study, which investigated the peroxisome proliferator-activated receptor-γ, or PPARG, typically bound by insulin-sensitising drugs. Such drugs act to alter the body’s response to glucose in the diet, thereby improving insulin secretion in patients. Type II diabetic patients respond inappropriately to dietary glucose, and if left untreated, elevated blood glucose in type II diabetes may cause systemic dangerous effects, including cardiovascular disease, stroke, renal failure and retinopathy.

PPARG-binding drugs were previously thought to bind to a single receptor binding site. However, Kojetin’s work used a simple screening protocol to unexpectedly reveal the presence of another, alternative binding site. This causes a conformational change in the receptor; downstream effects of this may include altered interactions with regulatory protein partners, or possibly changes in gene expression. Such effects could form the basis of future work.

Associate researcher Travis Hughes termed the team’s chosen technique as one that yields ‘easy-to-interpret results’ and stated that this approach is not typically used to characterise drug-receptor interactions. The team will continue to work to characterise function of the alternative site. It is hoped that further work may explain some of the adverse effects of insulin-sensitising drugs; these include risk of bone loss and congestive heart failure. This study is an example of how a serendipitous finding may alter the course of current clinical research!