LDHA induces β cell dedifferentiation in diabetes through metabolic epigenetic reprogramming

Aims/hypothesis Pancreatic β cell dedifferentiation underlies the reversible reduction in β cell mass and function in diabetes. Interventional targets and adjuvant therapies to prevent/reverse β cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, while the underlying molecular mechanism remains elusive. Methods LDHA expression and activity were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on β cell function and identity was investigated in high-fat diet (HFD) feeding mice and db/db mice. ChIP-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on the H3K9la enhancement and beta cell function under glucotoxic conditions. Results We demonstrated that inhibition of LDHA effectively preserved β cell identity, which not only delay disease progression in prediabetic stage, but also improve insulin output and glucose homeostasis in diabetic models. Mechanistically, the activation of LDHA led to a marked increase in histone H3 lysine 9 lactylation (H3K9la) in the promoter region of the β cells dedifferentiation markers Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering β cell dedifferentiation as well as impaired glucose homeostasis and β cell function in mice. Conclusions/interpretation We unraveled the role of lactate dehydrogenase A (LDHA)-mediated metabolic and epigenetic reprogramming in β cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.