Physiology & Biophysics
Keck School of Medicine
- Signal Transduction
- Diabetes/Metabolic Diseases
Research OverviewInsulin resistance, reduced insulin's ability to regulate glucose metabolism, is a significant risk factor for type 2 diabetes, hypertension, atherosclerosis, and cardiovascular disease. Despite its significant association with numerous health problems, the mechanisms of development of insulin resistance are not clearly understood. The long term objective of our research is to elucidate the cellular mechanisms by which insulin resistance is developed in skeletal muscle, the major tissue responsible for insulin-mediated glucose uptake.
Our laboratory is equipped to carry out whole body studies of insulin action in rats and to perform various molecular biological procedures, including differential mRNA display, DNA cloning and sequencing, and Northern and Western blot analyses. Currently, there are two lines of research actively pursued in our laboratory.
Cellular Mechanisms of Development of Insulin Resistance in Skeletal Muscle We have been testing the hypothesis that during the development of insulin resistance in skeletal muscle, impairment of intracellular glucose metabolism precedes and causes impairment of insulin's action on glucose transport. The implication of the hypothesis is that reduced insulin action on glucose transport/uptake (insulin resistance) is a secondary and adaptive response of muscle to prevent accumulation of substrate when its capacity for glucose metabolism is reduced. We have already demonstrated that metabolic impairment precedes insulin resistance during high fat feeding in rats and that suppression of intracellular glucose metabolism in skeletal muscle causes subsequent development of insulin resistance. We are currently extending/generalizing our hypothesis by testing it under various pathophysiological conditions. Also, we are investigating the molecular mechanisms by which activities of intracellular glucose metabolism are linked to the regulation of insulin action on glucose transport/uptake.
Identification of Gene Responsible for Development of Insulin Resistance To test the hypothesis that altered gene expression is responsible for insulin resistance, we have examined changes in gene expression in skeletal muscle during the development of insulin resistance using the differential display technique. We have identified a novel mRNA (cDNA) whose expression was decreased rapidly (within 1 h) preceding the development of insulin resistance under various conditions. We now propose the hypothesis that this gene (GAIR,Gene Associated with development of Isulin Resistance) encodes a protein directly involved in insulin action and its downregulation is responsible for induction of insulin resistance in skeletal muscle. We are currently cloning and sequencing full-length cDNAs of GAIR. We will study the function of GAIR protein and the role of GAIR expression in the development of insulin resistance in skeletal muscle.