(489c) Light-Induced Regulation for Enhancing the Secretion of Insulin in Pancreatic β-Cells

Type 2 diabetes (T2D) is associated with a severe loss of insulin secretory function due to peripheral tissue resistance to the hormone. Available pharmacological treatments (e.g. sulfonylureas) boost the amount of insulin released by β-cells in T2D by acting on targets which mediate this secretory function. Although effective, such regimens are often linked to side effects including weight gaining and imprecise regulation of the blood glucose-insulin balance. One mediator of β-cell glucose-stimulated insulin secretion (GSIS) is cyclic AMP (cAMP). The increase in cAMP observed during exposure of β-cells to high glucose concentrations leads to GSIS. In this work, we utilized an adenylyl cyclase with activity that is regulated by light (ACL). The protein consists of two subunits αACL and βACL. Each subunit contains a light-sensitive domain and an adenylyl cyclase moiety. Activation by light results in the increase in cAMP. FLAG and 6xHis epitope tags were engineered into these subunits and the corresponding genes were used to generate recombinant adenoviruses. Delivery of these transgenes to β-cells and subsequent irradiation with light resulted in an increase in cAMP. The amount of insulin secreted by these cells upon induction with glucose was determined. The light-based regulation of insulin secretion by β-cells can be utilized in high-throughput diagnostic assays and drug screening platforms, and in bioartificial pancreas devices for diabetes therapies.