A major factor in the development of Type 2 Diabetes is the insulin resistance of tissues such as liver and skeletal muscle. Although the mechanisms involved are not fully understood, there is a close association between insulin resistance and increased lipid availability. We have previously identified roles for protein kinase C (PKC) and specific inhibitory lipid intermediates, especially the sphingolipid ceramide.
We employ in vivo models and knockout mice, as well as cell culture systems and proteomic and lipidomic technologies, to investigate novel pathways and identify new strategies for the therapy of Type 2 Diabetes. We also pursue the translation of our findings, using novel or existing drugs that target PKCs and inhibitory lipids to improve glucose homeostasis.
Our Research Goals
1) To define the interactions between PKC, lipid metabolism and insulin action.
The currently-held view that PKCs act solely to suppress proximal insulin signal transduction is clearly an oversimplification, and we will extend our novel findings which show that these kinases and their specific downstream mediators play key roles in the control of lipid storage and oxidation in liver and other insulin target tissues. This work will have relevance not only to diabetes but also hepatic steatosis, cardiovascular disease and the metabolic syndrome.
2) To identify the enzymes and intermediates of sphingolipid metabolism which affect insulin sensitivity.
PKC activation does not wholly explain the inhibitory effects of fat oversupply to muscle and liver. High fat diets elevate ceramide levels in skeletal muscle, and our lipidomic data indicate specific roles for distinct ceramide species with particular acyl side chains. We will address the importance of these species by modulating their levels in vivo using adeno-associated virus and tissue specific knockout mice.
3) To examine the effectiveness of targeting key molecules for the treatment of diabetes, using new and existing drugs.
We will further pursue the translation of our basic research findings. Existing inhibitors of PKC isoforms will be tested in vivo and in vitro to determine their effectiveness in improving insulin action. Because of specificity problems with targeting kinase catalytic activity, we have also initiated a project to generate novel PKC inhibitors using other strategies.