New Compound Shows Promise for Novel Diabetes Treatment

A powerful new drug discovery technique may have uncovered a candidate compound for treating type 2 diabetes.

Scripps Research Institute scientists on both coasts collaborated to screen millions of molecules to find candidate compounds that can elicit a specific therapeutic effect. The study was published online ahead of print on December 7, 2015 in Nature Communications.

The technique, developed by Richard A. Lerner, MD, Lita Annenberg Hazen Professor of Immunochemistry at the La Jolla, CA campus and colleagues, is called autocrine selection. It allows scientists to screen up to 100 million peptides, or proteins, to find a given cellular receptor that can be activated for a specific effect.

In this study, Lerner’s lab used this technique to target the GLP-1 receptor, which is expressed by the insulin-producing beta cells in the pancreas. GLP-1 receptors, one of a class of G protein-coupled receptors, can trigger signals via distinct pathways, called G protein and beta-arrestin.

Although several GLP-1 receptor agonists have been approved, the team wanted to find a version that works differently from the others. In some instances, an agonist that only activates one of the pathways may work better. In this case, the team wanted to find one that preferentially activated the G protein pathway.

So they created a million new peptides by randomly varying one end of a known candidate molecule, Exendin-4, which is already used diabetes treatment, to find a variation that would only activate the preferred pathway. “The idea was that at least one of these many variants would induce a change in the shape of the GLP-1 receptor that would activate the G-protein pathway without activating the beta arrestin pathway,” Hongkai Zhang, PhD, senior staff scientist in the Lerner lab and first co-author.

In the end, they isolated one peptide called P5 that potently and actively the GLP-1 receptor’s G-protein pathway.

Across the country at Scripps’ Jupiter, FL campus, Patricia H. McDonald, PhD, an assistant professor, and her team tried out this peptide in a mouse model. They found that P5 worked very well at boosting glucose tolerance in mice, and did so at a 100fold lower dose than the current drug. At the same time, it only stimulated insulin production weakly. “We didn’t expect that, but in fact, it was a nice finding because less reliance on stimulating insulin could mean less stress on the beta cells,” said Emmanuel Sturchler, PhD, staff scientist in the McDonald lab and co-first author.

P5 also triggered the growth of new fat cells, without affecting the weight of the mice. This is actually a positive because in obesity-induced diabetes, existing fat cells grow larger and less sensitive to insulin. The new fat cells showed signs of increased insulin sensitivity, indicating a reduction in insulin resistance.

The team is now looking into ways to develop a new diabetes drug using P5.