163-OR: Evidence for Circadian Control of Glucose-Stimulated Insulin Secretion in Transplanted Human Stem-Cell-Derived Pancreatic ß-Cells

Cell replacement strategies utilizing stem cell-derived β-cells (SC-β cells) hold therapeutic potential for patients with diabetes. In order for cell therapy to be effective, transplanted SC-β cells must recapitulate physiological features of insulin secretion in humans. In this regard, circadian regulation of insulin release is critical for normal β cell physiology, where intrinsic β cell circadian clocks function to optimize glucose-stimulated insulin secretion (GSIS) during the active/feeding phase of the circadian cycle. Thus, to elucidate whether transplanted SC-β cells retain capacity for circadian control of insulin secretion, SC-β cells were generated using a six-step directed differentiation protocol and transplanted (n=13 independent transplants) under the kidney capsule into immunocompromised (SCID-beige) mice. Prior to transplantation, differentiated SC-β cells were confirmed to express core circadian clock genes (e.g.,BMAL1, CLOCK, PER1 and REV-ERBα). Provided this information, we next assessed in vivo glucose tolerance and corresponding insulin secretory response (using human insulin ELISA) in SCID-beige mice during the inactive/sleep and active/feeding circadian cycles. Both parameters demonstrated robust diurnal rhythmicity (p Disclosure S. K. Sen: None. S. Hassoun: None. Q. P. Peterson: Other Relationship; Self; Semma Therapeutics, Inc. A. Matveyenko: None. Funding National Institutes of Health (R01DK098468 to A.M.)