New Research Suggests Novel Insulin Sensitizer Works Through a New Mechanism to Treat Root Cause of Type 2 Diabetes

Washington University School of Medicine researchers show MSDC compound has anti-diabetic efficacy without side effects profile of current drugs to treat insulin resistance

May 2012

A study published online in the Journal of Biological Chemistry, titled “Insulin Resistance and Metabolic Derangements in Obese Mice are Ameliorated by a Novel Peroxisome Proliferator-Activated Receptor g-sparing Thiazolidinedione” (http://www.jbc.org/content/early/2012/05/23/jbc.M112.363960), showed a new drug to treat diabetes being developed by Metabolic Solutions Development Company (MSDC), MSDC-0602, improved insulin resistance and inflammation in obese mice. These findings suggest that MSDC-0602, a novel anti-diabetic drug which is in Phase 2 clinical trials, may constitute the first in a class of next generation insulin sensitizers that appear to work through a new biochemical mechanism to treat insulin resistance and type 2 diabetes.

Currently-approved insulin sensitizing drugs are effective but their use is limited by side effects believed to be caused by the over-activation of the peroxisome proliferator-activated receptor gamma (PPARg). These recent findings provide the framework for the discovery and development of a new class of insulin sensitizers that can operate independent of the activation of PPARg.

Previously, it was believed that both the anti-diabetic activity and the side-effects of these agents were mediated through activation of a nuclear receptor called PPARg. However, it is now generally accepted that over-activation of PPARg drives the unwanted and often unacceptable side effects associated with the currently-approved insulin sensitizers, which are PPARg agonists, and emerging evidence suggests that the potent anti-diabetic efficacy can be separated from the ability to activate PPARg. Some, including MSDC researchers, have suggested that key aspects of the insulin sensitizing actions remained to be identified.

This study evaluated MSDC-0602 for its effects on insulin resistance in obese mice. These researchers found that MSDC-0602 markedly improved several measures of multi- organ insulin sensitivity, fat tissue inflammation, and metabolic disturbances in the liver including suppressing fat and glucose production, which are increased in diabetic liver cells. These beneficial effects were mediated, at least in part, via direct actions on liver cells and were preserved in liver cells lacking PPARg, indicating that PPARg was not required to suppress the formation of fat and glucose.

The study was conducted by the Department of Medicine at Washington University School of Medicine and the Department of Internal Medicine at the University of Michigan, in collaboration with scientists at MSDC.