Research Projects

Pancreatic ? cell mass and function are compromised in both Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM), with insulin resistance being a significant pathogenic factor in T2DM. This proposal aims to develop a small molecule that can protect and restore functional ?-cell mass to combat diabetes. The team designed and synthesized a series of small molecule GLP1R agonists, testing the top three compounds for their effect on maintaining or restoring functional ?-cell mass. One compound, PK2, displays stable binding with GLP1R, induces GLP1R internalization, and increases cAMP levels. PK2 also increases insulin secretion in vitro and protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Treatment of PK2 induces ?-cell replication and attenuates ?-cell apoptosis in STZ-treated mice. The central hypothesis is that PK2 is an orally active, non-peptide GLP-1R agonist that will preserve or restore functional ?-cell mass following ?-cell injury and replicates several important properties of native GLP-1 to combat diabetes. Preliminary data provides a strong position to test this hypothesis. The lead molecule PK2 will be explored in a HFD-induced NAFLD model, assessing its effect on body weight gain, food intake, energy expenditure, glucose intolerance, insulin resistance, and ?-cell dysfunction in diabetic mice. Further studies will provide deeper insight into PK2's mechanism of action.