Researchers have identified a mitochondrial target through which insulin sensitizers achieve their anti-diabetic effects….
New insights into this protein complex and its role in metabolic signaling are expected to enable the pursuit of alternative approaches to the discovery of novel, insulin sensitizing agents.
The newly identified mitochondrial protein complex is being referred to as the mitochondrial Target of Thiazolidinediones (TZDs), or mTOT™. Key proteins in the mTOT complex have recently been identified as playing an important role in the metabolism of pyruvate, an important chemical compound at the crossroads of metabolic regulation (EASD Abstract #593).
The mTOT complex appears to function as part of a molecular "sensor switch" connecting mitochondrial metabolism to important cellular activities, such as carbohydrate, lipid, and amino acid metabolism, all of which are out of balance in patients with type 2 diabetes.
Modulation of mTOT in some cells favors increases in cell differentiation and fat oxidation. The overall effects of compounds acting by this mechanism include increased insulin sensitivity, generation of brown fat, and preservation of pancreatic β-cells (beta cells).
"For the first time, we are beginning to understand that the mechanism by which insulin sensitizers reduce insulin resistance is through a direct mitochondrial action," said Jerry Colca, PhD, Metabolic Solutions Development Company’s co-founder, president and chief scientific officer. "Moreover, this new insight, coupled with our recent Phase 2 clinical results, suggests that we have taken a significant step forward to designing a new class of therapeutic agents for use in effectively treating patients with type 2 diabetes."
Using a novel photo-catalyzable affinity probe modeled after one of their drug candidates together with mass spectrometry-based proteomics, MSDC scientists identified two phylogenetically-conserved proteins in the inner mitochondrial membrane. The conservation of these proteins in different species form yeast and fruit flies to humans suggests that they play a fundamental role in cell regulations. Proof of identity has been demonstrated by gene expression and knockdown of expression.
The discovery by MSDC researchers shows the lowering of plasma glucose can be achieved without having to activate a nuclear transcription factor 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.
MSDC is developing two novel insulin sensitizing agents that selectively modulate mTOT, a protein complex located in the inner mitochondrial membrane. Data from recently completed Phase 2 clinical studies of a prototype mTOT Modulator™, MSDC-0160, as well as Phase 2 clinical studies in diabetic patients of a second mTOT Modulator, MSDC-0602, support the company’s hypothesis that the insulin sensitizing pharmacology can occur without the side effects associated with currently marketed insulin sensitizers.
mTOT Modulators appear to play a central role in the regulation of biochemical pathways essential to maintaining the appropriate level of glucose. These new drugs are intended to improve the body’s sensitivity to insulin into cells, where it is stored and later used for energy, lower the percent of calorie-storing "white" fat, increase the production of calorie-burning "brown" fat, preserve the function of pancreatic beta cells, and possibly protect neurons in the brain (which could be important in treating diseases such as Alzheimer’s and Parkinson’s disease).
Data presented at 48th Annual Meeting of the European Association for the Study of Diabetes