Description:

Julien A. Sebag, Ph.D.
Associate Professor
Department of Molecular Physiology and Biophysics
F.O.E.D.R.C
University of Iowa

Abstract: Current treatments for insulin resistance and type 2 diabetes do not sufficiently improve glycemiccontrol. Mechanistically, these therapies target liver glucose production or increase insulin secretion rather than actually reversing the root cause of the disease, insulin resistance and loss of insulin-mediated glucose uptake in storage tissues. Clearance of blood glucose is largely mediated by the action of insulin on skeletal muscle and adipose tissues in which it stimulates the translocation of the glucose transporter GLUT4 from intracellular compartments to the plasma membrane, a process that is greatly impaired in insulin resistant individuals. To identify molecules that improve insulin-stimulated GLUT4 translocation, we developed a high-throughput kinetic assay for measurement of surface GLUT4 density and optimized it to function both in cells, for screening, and in mice, for in vivo compound validation. Using this assay, we screened 50,000 molecules and identified multiple insulin sensitizers of which one was selected for chemical optimization. The optimized compound significantly potentiates the translocation of GLUT4 both in vitro and in vivo. Treatments of insulin resistant mice results in lowering of blood glucose, plasma insulin and drastically improves glucose uptake in storage tissue and glucose tolerance.
Using Proteome Wide Cellular Thermal Shift Assay we identified the molecular targets of this compound and validated this finding in vitro using CRISR/Cas9 KO cell models. This new molecule is the first PPAR gamma-independent insulin sensitizer described and thus is a promising lead compound for the development of a new type 2 diabetes treatment.