Elevated MANF expression in β cells protects mice from streptozotocin-induced diabetes by attenuating islet stress and immunogenicity

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing β cells, driven in part by endoplasmic reticulum (ER) stress and chronic unfolded protein response (UPR). We previously found that mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-regulating protein with protective and immunomodulatory roles, is essential for mouse and human β cell survival and proliferation. To assess the therapeutic potential of elevated endogenous MANF, we generated β cell-specific transgenic MANF-overexpressing mice and induced diabetes using multiple low-dose streptozotocin (MLDS) injections. In this study, we demonstrate that elevated MANF levels protected against MLDS-induced hyperglycemia, preserved β cell mass, enhanced proliferation, and reduced β cell DNA damage responses and islet lymphocyte infiltration. Transcriptomic profiling of MANF-overexpressing islets revealed downregulation of genes linked to ER and oxidative stress, inflammation, immune responses, antigen presentation, and p53-mediated senescence. Immunophenotyping further showed a reduction in CD4+ T cells in pancreatic lymph nodes. Mechanistically, elevated MANF suppressed MLDS-induced terminal UPR markers, including DNA damage inducible transcript 3 (Ddit3) and thioredoxin-interacting protein (TXNIP) expression, whereas MANF deficiency elevated their expression in β cells. Collectively, these findings identify MANF as a dual-acting therapeutic target that alleviates β cell stress and reduces immunogenicity in T1D.