LDHA induces beta cell dedifferentiation in diabetes through metabolic and epigenetic reprogramming.

aims/hypothesisPancreatic beta cell dedifferentiation underlies the reversible reduction in beta cell mass and function in diabetes. Exploratory research into interventional targets and adjuvant therapies to prevent or reverse beta cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, although the underlying molecular mechanism remains elusive.

methodsLactate dehydrogenase A (LDHA) expression and activity were analysed in islets obtained from human donors 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 beta cell function and identity was also investigated in HFD-fed mice and db/db mice. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on histone H3 lysine 9 lactylation (H3K9la) increases and beta cell function under glucotoxic conditions.

resultsWe demonstrate that inhibition of LDHA effectively preserves beta cell identity, which not only delays disease progression in individuals with impaired fasting glucose, but also improves insulin output and glucose homeostasis in diabetic models. Mechanistically, activation of LDHA led to a marked increase in H3K9la in the promoter region of the beta cell dedifferentiation marker genes Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering beta cell dedifferentiation as well as impaired glucose homeostasis and beta cell function in mice. CONCLUSIONS/

interpretationWe unravelled the role of LDHA-mediated metabolic and epigenetic reprogramming in beta cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.