43-OR: Islet Autophagic Flux Is Impaired Prior to the Onset of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of pancreatic beta cells. Early events within the islet leading to T1D include increased beta cell ER and oxidative stress and increased inflammatory cytokines. Autophagy is a cellular pathway activated by cell stressors which leads to decreased cellular levels of ER stress and oxidative stress, and inactivates inflammatory pathways. While there is a good amount of data suggesting impaired autophagy in type 2 diabetes, relatively little is known about changes in autophagy during the development of T1D. In the following study we characterized changes in the autophagy pathway during development of T1D using NOD mice. We compared gene expression and autophagic flux in islets from female NOD mice prior to the onset of diabetes at 4, 8,10, and 12 weeks of age. At 10 weeks of age the inflammatory cytokines IL1-B and IL-6 and the ER stress marker CHOP were markedly elevated in NOD islets. In addition, at 10 weeks of age, TFEB expression was also significantly elevated in islets; indicating activation of the autophagy pathway. We then evaluated autophagic flux in NOD islets by measuring LC3-II accumulation in the presence or absence of chloroquine, an inhibitor of autophagosome to lysosomal fusion. LC3-II accumulation after CQ exposure was significantly lower in islets starting at 8 weeks of age, demonstrating an impairment in autophagic flux which precedes the development of islet ER stress and diabetes. This study demonstrates activation of the autophagy pathway when islets are expressing high ER and inflammatory stress markers during the development of T1D. However, despite activation, autophagic flux is reduced. Impairments in the autophagy pathway may worsen beta cell ER, oxidative and inflammatory stress, ultimately leading to cell death and hastening the progression to diabetes. These data suggest that therapies targeting restoration of autophagy should be evaluated as interventions to delay or prevent T1D. Disclosure A. L. Clark: None. Z. Yan: None. M. S. Remedi: None. A. Diwan: None. Funding Washington University Diabetes Research Center (P30DK020579 to A.L.C.); National Institutes of Health (R01DK123163, R56DK098584 to M.S.R.)