The diabetes research unit carries out research centered around the AMP-activated protein kinase (AMPK)/malonyl CoA fuel sensing and signaling network.
The Diabetes Research Unit, is under the direction of Neil Ruderman, M.D., D.Phil., Professor of Medicine. Investigators explore the notion that impaired oxidation of fatty acids, leading to an increase in their esterification, is a major cause of the insulin resistance that predisposes people to Type 2 diabetes, coronary heart disease, and obesity. Their work has focused on malonyl CoA, a molecule that inhibits fatty acid oxidation, and the enzyme AMP-activated protein kinase, which, among its other effects, regulates malonyl CoA metabolism.
Studies by Asish Saha, Ph.D., Assistant Professor of Medicine, and co-workers have helped to elucidate the enzymes controlling malonyl CoA levels in muscle. They have observed that the AMP-activated protein kinase, which is activated in muscle during exercise, both causes a decrease in malonyl CoA levels and increases insulin sensitivity. More recent work has established the possibility that AMPK may also be a target molecule for obesity therapy.
Yasuo Ido, M.D., Ph.D., head of the vascular disease and diabetes group, and Assistant Professor of Medicine, has demonstrated that the same malonyl CoA regulatory mechanisms that the group has delineated in skeletal muscle operate in human arterial endothelial cells. Dr. Ido has shown that sustained hyperglycemia causes increases in malonyl CoA, insulin resistance, and programmed cell death (apoptosis) in these cells. In addition, activation of AMPK by the drug AICAR or by molecular biological means prevents these events from occurring. Dr. Ido has found evidence that free fatty acids, as well as glucose, may contribute to vascular damage in diabetes and that here, too, AMPK activation can exert a protective effect. He has shown that AMPK’s protective effect may be related to its ability to decrease oxidative stress and NFB-mediated gene expression.
Zhijun Luo, M.D., Ph.D., head of the molecular biology and signal transduction group, and Assistant Professor of Medicine, has carried out seminal studies describing a novel mechanism by which insulin-signaling complexes move around in a cell. He has demonstrated that an intracellular protein, referred to as 14-3-3, plays a key role in the movement of signaling complexes containing insulin receptor substrate (IRS) and PI 3-kinase. Dr. Luo has also shown that it is likely involved in the mechanism by which insulin action in cells is down-regulated.