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 C/EBP homologous protein (CHOP) and thioredoxin-interacting protein (TXNIP) expression, whereas MANF deficiency elevated Chop and TXNIP levels in β cells. Collectively, these findings identify MANF as a dual-acting therapeutic target that alleviates β cell stress and reduces immunogenicity in T1D.
Li et al. (Sun,) studied this question.