2091-LB: Viral Infection Drives Aberrant Pancreatic Beta-Cell Bioenergetics and Autophagy via a Candidate Type 1 Diabetes Gene PGM1

Introduction & Objective: Viral infection is one of the major environmental factors in Type 1 Diabetes (T1D). PGM1 is a T1D GWAS gene encoding phosphoglucomutase 1, which bidirectionally converts G6P to G1P. PGM1 resides at the junction between many arms of metabolic pathways. Our previous study suggests that PGM1 is potentially causal to T1D via epigenetic changes driven by genetic / environmental factors. We hypothesised that PGM1 is a crucial regulator of beta cell metabolism in response to viral infection. Methods: Purified human islets, EndoC-BH1, and INS-1 cells were used. Poly (I:C), a double stranded viral RNA analogue was delivered into the cells via transfection or electroporation. PGM1 was knocked down by shRNA lentivirus. RNA and protein were analyzed using qPCR, western blot, and proteomics. For stable isotope labeling, EndoC-BH1 cells were cultured with 50% U-13C6 glucose. Metabolites and stable isotopes were analysed using LC-/GC-MS. Autophagy and mitophagy were assessed using western blot and live cell imaging. Unpaired t - test was used for statistical analyses. Results: PGM1 expression was significantly lowered after the intracellular delivery of 10 μg/ml Poly(I:C) to human islets and EndoC-BH1 cells. Proteomics identified translational arrest in PGM1 shRNA treated human islets. ATF3 mRNA increased by approximately two-fold, suggesting integrated stress response. In EndoC-BH1 cells, PGM1 suppression increased flux to glycolysis, TCA cycle, pentose phosphate pathway, and hexosamine biosynthetic pathway. We found activation of autophagy but impaired autophagic and mitophagic flux in PGM1 deficient beta cells. Insulin secretion was unchanged, proinsulin content was lowered. Conclusion: PGM1 is a novel driver of beta cell metabolic and energy stress following viral infection. The aberrant autophagic flux additionally suggests lysosomal defects. Activation of PGM1 potentially improves beta cell resistance to viral infection. Disclosure Y. Miller: None. Y. Qiu: None. Y. Sun: None. S.S. Jankauskas: None. R.J. Kulkarni: None. I.J. Kurland: None. Y. Tomer: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK131329-01); Integrated Islet Distribution Program (BS526P)