Final Report Summary - CUL7 AND DIABETES (Role of the Cullin7 E3 ubiquitin ligase in insulin signaling and diabetes.)
Dysfunctional regulation of signaling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this research project we investigated the role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) for the regulation of insulin signaling and glucose homeostasis. We show that Cul7(-/-) mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signaling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase/AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7(+/-) or Fbxw8(+/-) mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase/AKT activities in skeletal muscle cells. Delineating the metabolic functions of CRL7 will pave the way towards the development of novel therapeutic strategies to modulate insulin sensitivity for the treatment of insulin resistance and type 2 diabetes.
Contact details: Antonio Sarikas, MD. Technische Universität München, Munich, Germany. Email: sarikas@ipt.med.tum.de website: www.sarikaslab.de
Contact details: Antonio Sarikas, MD. Technische Universität München, Munich, Germany. Email: sarikas@ipt.med.tum.de website: www.sarikaslab.de