New Drug Target Identified for Treatment of Type 2 Diabetes

June 9, 2012

A mitochondrial protein complex has been identified by researchers at Metabolic Solutions Development Company (MSDC) through which anti-diabetic drugs exert their insulin sensitizing effects when used to treat patients diagnosed with type 2 diabetes. The mitochondrial protein complex is being referred to as the mitochondrial Target of Thiazolidinediones (TZDs), or mTOT.

The mTOT complex functions as a molecular “sensor switch” connecting mitochondrial metabolism to important cellular activities, such as carbohydrate, lipid, and amino acid metabolism, that are out of balance in patients with type 2 diabetes. Such imbalances may also play a role in other diseases of aging such as Alzheimer’s disease and Parkinson’s disease, as well certain genetic diseases such as polycystic kidney disease.

Using a novel drug analog photo-catalyzable affinity probe and mass spectrometry-based proteomics, MSDC scientists identified two phylogenetically-conserved proteins in the inner mitochondrial membrane, meaning these proteins are present in, and play an important role in the development of, organisms from yeast and fruit flies to humans. Proof of identity has been demonstrated by gene expression and knockdown of expression.

The discovery by MSDC researchers suggests the lowering of plasma glucose can be achieved without having to activate a nuclear receptor called PPARg. Previously, it was believed that both the activity and the side-effects of the only approved class of drugs used to treat insulin resistance — the core problem for persons diagnosed with type 2 diabetes — were mediated through 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 anti-diabetic insulin sensitizers, which are PPARg agonists.

Data from recently completed Phase 2 clinical studies of MSDC-0160, as well as studies in obese mice and Phase 2 clinical studies in diabetic patients of a second compound, MSDC-0602, support the company’s hypothesis that the insulin sensitizing pharmacology of these first in class mTOT Modulators can occur independent of the activation of PPARg.

Two papers published online by two separate groups in the May 24, 2012 Science Express (and subsequently in the July 6, 2012 edition of Sciencehttp://www.sciencemag.org/content/337/6090/93.abstract and http://www.sciencemag.org/content/337/6090/96.abstract) have coincidentally found that two proteins in the mTOT complex, which they renamed Mpc1 and Mpc2, are part of a pyruvate carrier mechanism.  Together these findings place the mTOT recognition complex at the “crossroads of metabolism” and provide a new way to look at insulin sensitizers.