The mitochondrial pyruvate dehydrogenase complex (PDC) is the gate-keeping enzyme that controls glucose oxidation through the Krebs cycle. PDC is negatively regulated by pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4). In patients with type 1 and type 2 diabetes (T1D and T2D), PDK 4 is up-regulated resulting in the inhibition of glucose oxidation. Similar to PDC, the mitochondrial branched-chain ?-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting step that sets pace for the oxidative degradation of branched-chain amino acids (BCAA) also via the Krebs cycle. Similar to PDC, BCKDC is negatively regulated by the intrinsic BCKDC kinase (BDK). In patients with obesity and T2D, hepatic BDK is also up-regulated, resulting in the elevation of BCAA concentrations and insulin resistance. In this application, we will test the central hypothesis that the highly related mitochondrial PDK and BDK are novel pharmacological targets for reducing glucose level and restoring insulin sensitivity in obesity and T2D.
The specific aims are: 1) to improve the potency and selectivity of novel PDK inhibitors developed in the PI's laboratory using structure-based design;2) to test the hypothesis that increased glucose oxidation and reduced lipogenesis occurs concurrently through PDK inhibitor augmented pyruvate flux in obesity and T2D;3) to test the hypothesis that increased BCAA oxidation ameliorates hyperglycemia and restores insulin sensitivity in T2D. The available novel PDK and BDK inhibitors and animal models including diet-induced obese mice, ob/ob mice and Zucker obese rats will be utilized in the proposed studies. A successful outcome of this investigation will provide the framework for developing new therapeutic approaches to the treatments of obesity and T2D.

Public Health Relevance

Obesity has reached epidemic proportions in the United States and is strongly linked to type 2 diabetes. In this application, we will utilize small-molecue inhibitors to deactivate specific mitochondrial protein kinases thereby mitigating hyperglycemia and insulin resistance in animal models. A successful outcome of this research will provide the framework for developing more effective therapeutic approaches to obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK062306-11
Application #
8898266
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sechi, Salvatore
Project Start
2002-07-01
Project End
2015-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
11
Fiscal Year
2014
Total Cost
$159,000
Indirect Cost
$59,000
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390