Signaling by Insulin and Other Homones
Group leaders are Drs. Mitch Lazar and Morrie BirnbaumThis Scientific focus of the DERC is linked to the IDOM Type 2 Diabetes Unit.
Insulin resistance is a hallmark of type 2 diabetes. Current understanding of the mechanism of action of insulin has resulted from a constant exchange of information derived from studies of insulin itself and more numerous experiments addressing the action of other hormones and growth factors. Much is known about insulin signaling, and exciting new therapies such as the antidiabetic thiazolidinediones improve the defect in type 2 diabetes. However, insulin signaling mechanisms are also increasingly complicated, and the actual defect(s) in type 2 diabetes remain elusive. The Penn DERC is focused on understanding basic mechanisms of action of insulin as well as other hormones.
Highlights of Significant Findings
Since first identifying the insulin responsive glucose transporter, Dr. Birnbaum has been at the forefront of research on insulin action. His group made several important findings in the past grant period, the most significant of which was the discovery of insulin resistance in mice lacking Akt2, but not Akt1. This work proved that Akt plays a key role in signaling downstream of the insulin receptor, and that this effect was isoform specific. Dr. Lazar is a leader in studies of nuclear hormone receptors, and provided the first genetic evidence that PPAR g is an endogenous regulator of insulin sensitivity. More recently, his group demonstrated that the orphan nuclear receptor Rev-erb a , which is a constitutive repressor of metabolic and circadian gene expression, is regulated at the level of protein stability by GSK3 b. These studies have made extensive use of the DERC Cores. Dr. Lemmon's studies of EGF receptor signaling represent another highlight, with the identification of structural and biological determinants of receptor antagonism; Dr. Ferguson, a DERC pilot grant-funded investigator, has been studying the regulation and function of EGF dimerization. This work has major implications not only for EGF but for all receptors that signal at the cell surface.