Linking autophagy to type 1 diabetes onset and progression

The National Institute of Diabetes and Digestive and Kidney Diseases awarded $763,766 to Trustees of Indiana University (Indiana University Indianapolis) on August 10, 2026, for Project Grant R01DK149554 under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847).

The award funds research investigating the role of autophagy dysfunction in type 1 diabetes onset and progression. The project will examine how impaired autophagy in beta cells promotes autoimmune vulnerability through disrupted lysosomal function and altered antigen presentation. Aim 1 will define mechanisms by which impaired autophagy promotes lysosomal exocytosis using genetic and chemical perturbations in primary human islets, EndoC-BH1 cells, and iPSC-derived islet cells, combined with advanced imaging and molecular assays. Aim 2 will determine how beta-cell-derived lysosomal cargo modulates human antigen-presenting cells to heighten autoreactive T cell recognition. The research leverages expertise from three established investigators in the field to clarify why only some beta cells become autoimmune targets and which intrinsic pathways determine vulnerability versus resistance to autoimmune attack.

Work is performed in Indianapolis, Indiana. The period of performance extends from August 10, 2026, through May 31, 2031.

Abstract

Type 1 diabetes (T1D) is classically considered a disease of failed immune tolerance in which autoreactive T cells destroy insulin-producing Β-cells. However, human autopsy studies reveal that many individuals with T1D retain insulin-positive Β-cells, indicating that Β-cell loss is incomplete and heterogeneous. This highlights a critical GAP in understanding why only some Β-cells become autoimmune targets, and which Β-cell-intrinsic pathways determine vulnerability versus resistance. Environmental stressors, including proinflammatory cytokines, likely act on genetically susceptible Β-cells to disrupt homeostasis and break immune tolerance. Autophagy, a conserved lysosomal quality-control pathway essential for maintaining Β-cell function, is emerging as a potential central regulator of this process. Preliminary data from human T1D donors and prediabetic NOD mice demonstrate impaired autophagy, dysfunctional lysosomes, and altered antigen handling early in disease. Moreover, Β-cells with defective autophagy exhibit increased antigen release and heightened immunogenicity. Together, these findings support a model in which autophagy impairment sensitizes Β-cells to autoimmune attack by promoting lysosomal exocytosis, inflammatory antigen presentation, and enhanced recognition by autoreactive T cells. This collaborative project will take advantage of the expertise of three established investigators in the field to dissect how defective autophagy in human Β-cells reshapes communication with the immune system and drives autoimmune vulnerability. Aim 1 will define the mechanisms by which impaired autophagy promotes lysosomal exocytosis, using genetic and chemical perturbations in primary human islets, endoc-ΒH1 cells, and ipsc-derived islet cells, combined with advanced imaging and molecular assays. Aim 2 will determine how Β-cell-derived lysosomal cargo modulates human antigen-presenting cells (APCS), evaluating APC polarization, activation, and MHC-II immunopeptidomes following exposure to lysosomal fractions or conditioned media from autophagy-impaired Β-cells. Aim 3 will test whether T cells primed by APCS presenting these lysosome-derived peptides specifically recognize and kill peptide-displaying Β-cells, and how Β-cell autophagy impairment or rescue shapes the Β-cell MHC-I immunopeptidome and susceptibility to cytotoxicity. Successful completion of this work will identify defective Β-cell autophagy as a mechanistic driver of autoimmune targeting in T1D and define how altered lysosomal biology supplies antigens and danger signals that activate host immune responses. This project has strong translational potential to reveal novel therapeutic targets aimed at restoring Β-cell homeostasis, interrupting autoimmune priming, and T1D onset/progression.