1097-OR: Secretory Carrier Membrane Protein 1 (SCAMP1) Modulates Pancreatic β-Cell Function Independent of Calcium Influx

Introduction and Objective: Deficiency of APT1 (acyl-protein thioesterase 1), which controls protein palmitoylation cycling, in mice induces hyperinsulinemia that leads to β cell dysfunction and islet cytoskeletal changes. Scamp1 participates in secretory granule fusion, contains an SH3 binding motif, and is biochemically validated as an APT1 substrate. Scamp1 deficiency increases insulin secretion in INS-1 cells. The role of Scamp1 in integrative physiology is unknown. Methods: We generated and characterized the following models: Scamp1 global KO, inducible Scamp1 tissue specific KO using Pdx1CreER, constitutive Scamp1 tissue specific KO using Ins1 Cre, and Scamp1 islet overexpression (OE). The protein-protein proximity network of Scamp1 in INS-1 cells was identified using the biotin ligase miniTurbo. Results: There was no effect on body weight or insulin tolerance in Scamp1 global KO mice, islet specific KO mice, or β cell specific KO mice on chow but each showed improved glucose tolerance as well as increased insulin and C-peptide during GTTs. Scamp1 deficiency did not affect β cell mass. Isolated primary islets from these KO models showed enhanced glucose-stimulated insulin secretion (GSIS). Glucose stimulated Ca2+ influx in primary islets was unaffected by Scamp1 deficiency, the same finding as in APT1 KO mice. Mice with β cell specific Scamp1 KO developed β cell failure with high fat diet without differences in insulin resistance or body weight, confirming that Scamp1 deficiency phenocopies APT1 deficiency. On chow diet, Scamp1 islet specific OE mice had impaired glucose tolerance and decreased insulin and C-peptide during GTTs without affecting body weight or insulin tolerance. Proximity screening in INS-1 cells identified interactions between Scamp1 and three classes of proteins: ATP production (including SLC25a4), exocytosis (including alpha-synuclein), and cytoskeleton (including the SH3 domain proteins Clasp2 and Lima1). Conclusion: An APT1-Scamp1 pathway affects β cell function in mice. Disclosure G. Dong: None. G. Kashgari: None. S. Adak: None. R. Xu: None. W. Zhang: None. M. Remedi: None. X. Wei: None. C.F. Semenkovich: Stock/Shareholder; Current; AirSeal Cardiovascular Inc.