(316d) Optogenetic Regulation of Insulin Secretion in Pancreatic Beta-Cells

Proper insulin production by pancreatic beta-cells, which is central to blood glucose homeostasis, is orchestrated by a complex circuitry involving intracellular molecules including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of beta-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in beta-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from the bacterium Beggiatoa (bPAC) was delivered to beta-cells. Upon illumination a cAMP increase was noted within 5 minutes and a significant drop at 12 minutes post-irradiation. The concomitant augmented insulin secretion was comparable to that from beta-cells treated with secretagogues. Greater insulin release was also observed over repeated cycles of photoinduction without adverse effects on viability and proliferation. PAC-expressing beta-cells cultured as pseudoislets displayed a more pronounced light-triggered increase in insulin secretion versus that from monolayers. The enhanced hormone release was curtailed upon Ca²⁺ channel blocking. This optogenetic system for modulating cAMP and insulin release can be employed for the study of beta-cell function and for enabling new therapeutic modalities for diabetes.