167-OR: Targeting Alpha Cells to Treat Hypoglycemia in Type 1 Diabetes

Increased glucagon release from alpha cells is the main defense against hypoglycemia, a mechanism lost in Type 1 Diabetes (T1D). We hypothesize that the absence of neighboring beta cells, and consequently the loss of their inhibitory signals, plays a crucial role in the impaired responsiveness of alpha cells to hypoglycemic conditions. We conducted experiments using isolated islets and pancreatic tissue slices from both nondiabetic organ donors and donors with T1D, revealing significant differences between slices and islets. Despite a decline, isolated islets exhibited residual insulin secretion similar to healthy islets, a phenomenon absent in slices. This discrepancy may imply a survival bias during isolation or the influence of the microenvironment, undetectable when using isolated islets. Unlike beta cells, alpha cells did not faithfully track glucose concentrations and their responses were transient, contrasting with the sustained responses of beta cells. Without inhibitory input reset, alpha cells couldn't mount subsequent responses. Remarkably, activating paracrine signals inhibiting alpha cells successfully restored glucagon secretion, with complete recovery observed after a 15-minute or longer reset using high glucose in healthy islets. In tissues from T1D donors, alpha cells failed to respond to declining glucose levels despite maintaining normal glucagon content. We systematically explored the inhibitory effects of three paracrine signaling molecules—serotonin, somatostatin, and GABA, and their potential to revive glucagon secretion. Surprisingly, all molecules demonstrated the ability to increase glucagon secretion in response to low glucose, contrary to anticipated inhibitory responses. This resulted in a significant sustained increase even after stimulus removal. Building on these insights, our latest findings show that these paracrine signaling molecules can rescue glucagon secretion in T1D. Disclosure J. Panzer: None. A.L. Lang: None. A. Pugliese: Advisory Panel; Provention Bio, Inc. Funding American Diabetes Association (4-22-PDFPM-12); The Leona M. & Harry B. Helmsley Charitable Trust (Grant#2018PG-T1D053, G-2108-04793)