Xiao Jian Sun, PhD

Insulin resistance is a major pathophysiological problem in many human diseases including type 2 diabetes. It defines as a failure to respond to normal circulating insulin level. Major research interests in my lab are involved in the investigation of insulin resistance at molecular levels and our goal is to identify the molecules that may play causative roles in the development of insulin resistance.

Over the past 30 years of research in the insulin signal transduction, most of the molecules that mediate insulin action has been identified and characterized; however, the molecular mechanism of insulin resistance is largely unknown. It has been recognized until recently that insulin resistance is most likely the result of defects in insulin signaling pathway that hindered the normal flow of insulin signaling.

Insulin signal pathway is influenced by various environment and cellular cues. Hormones, cytokines, nutrients, metabolites and other factor can modulate the pathway and make it more sensitive or less sensitive according to various needs (see figure). Insulin resistance may result from abnormal control of insulin signaling pathway at one or more steps.

Our investigation focuses on insulin receptor substrates (IRS-proteins) for several reasons: IRS-proteins are specific substrates for insulin signaling pathway and placed immediate down-stream of insulin receptor; genetic studies confirmed that they are required for normal insulin sensitivity; they are heavily modified in response to different conditions; more importantly, defects in IRS-proteins has been found in many animal models and human subjects with insulin resistance.

Mounting evidence has accumulated recently that insulin signaling pathway can be regulated through serine/threonine phosphorylation of IRS-proteins. Our current hypothesis is that insulin resistance may be the consequence of serine phosphorylation of IRS-proteins due to abnormal activation of serine/threonine kinases. We are investigating how insulin signaling pathway is modulated by nutrient, cytokines and metabolites via activation of serine/threonine kinases and phosphorylation of IRS-proteins in primary hepatocytes as well as in insulin resistant animals. Our goal is to identify serine/threonine kinases that may play causative role in the development of insulin resistance.

Serine/threonine phosphorylation has been also recognized as a signal for protein degradation via ubiquiting-proteosome degradation pathway. Our initial data suggest that levels of IRS-proteins are regulated by the ubiquiting-proteosome degradation. Investigation is carried to identify key elements in the ubiquitin-proteosome degradation pathway that controls the IRS-protein levels.