Signaling by Insulin and Other Hormones
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 DRC is focused on understanding basic mechanisms of action of insulin as well as other hormones.
Highlights From 2006-Present:
Penn DRC investigators are on the forefront of the fields of insulin action as well as action of other hormones and receptors that modulate insulin sensitivity, and several key discoveries were made in the past grant period. The Transgenic and Chimeric Mouse, Mouse Phenotyping, Physiology, and Metabolism, Functional Genomics, Vector, and RIA/Biomarker Cores have been essential for the success of this Focus Area.
Highlight one: Signaling by insulin receptor and related receptor tyrosine kinases. Through their studies on receptor tyrosine receptor kinases, Drs. Lemmon and Ferguson have discovered a novel mechanism for ligand-dependent activation (Schmiedel Cancer Cell 2008; Klein Nature 2008; Alvarado Nature 2009, Cell 2010). In addition, Dr. Birnbaum made important discoveries related to the reaultion of hepatic metabolism by insulin in mammals (Li Nature 2007; Leavens Cell Metabolism 2009) and developed an intriguing model of insulin resitance in flies (DiAngelo, PNAS 2009).
Highlight two: Regulation of metabolism by nuclear receptors and coregulators. Dr. Lazar's group discovered that heme is the ligand for the orphan receptor Rev-erba, which regulates circadian rhythm and metabolism (Yin Science 2007), and that the corepressor complex that consisting of NCoR and HDAC3, which modulates the function of Rev-erba and other nuclear receptors, plays a major role in regulating circadian rhythms and metabolism (Alenghat Nature 2008; Feng Science 2011).
Highlight three: Translational research in type 2 diabetes. In collaborative patient-oriented investigation, Drs. Grant, Hakonarson, Rader, and Reilly were involved in the genome-wide association studies leading to the discovery that genetic variation in the TCF7L2 gene is a risk factor for type 2 diabetes (Grant, Nature Genetics 2006). The team also identified other loci involved in diabetes and related metabolic disorders (Hakonarson Diabetes 2008; Zhao Diabetes 2009). The Transgenic and Chimeric Mouse, Mouse Phenotyping, Physiology, and Metabolism, Functional Genomics, Biomarker, and Viral Vector Cores have beenxse5 particularly valuable for this Focus Area. In addition a DRC pilot and feasibility grant helped to advance the independent research career of Drs. Ferguson.