Recently, a research team led by Professor Xiao Han, Professor Fang Chen, and Associate Professor Yaqin Zhang from the School of Basic Medical Sciences, in collaboration with Professor Qingguo Li and his team from the Second Affiliated Hospital with Nanjing Medical University(NMU), published a research article entitled "LDHA Induces Beta Cell Dedifferentiation in Diabetes through Metabolic and Epigenetic Reprogramming" in the international journal Diabetologia.
This study systematically investigated the dynamic changes of lactate dehydrogenase A (LDHA) in pancreatic islet β cells during the progression of type 2 diabetes. The findings revealed that LDHA activation drives metabolic and epigenetic reprogramming, thereby promoting β cell dedifferentiation and uncovering a previously unrecognized molecular mechanism underlying diabetic pathogenesis.
Based on these discoveries, the team further demonstrated that inhibition of LDHA effectively prevents β cell dedifferentiation, promotes β cell redifferentiation, and improves insulin secretion and glucose homeostasis, effectively delaying disease progression in both prediabetic and diabetic states. This work identifies LDHA as a key regulator of β cell dysfunction and proposes its suppression as a promising therapeutic strategy for preserving β cell identity and function in type 2 diabetes.
Pancreatic β cell dedifferentiation, characterized by the loss of insulin synthesis and secretory capacity, is a critical contributor to the development of type 2 diabetes. However, the molecular mechanisms underlying this process remain poorly understood. Moreover, reversing this dedifferentiated state to restore functional β cells represents a major challenge in diabetes therapy.
This study reveals that LDHA is significantly upregulated and activated in islet β cells across multiple models of type 2 diabetes. Elevated LDHA activity leads to increased intracellular lactate accumulation and enhanced histone H3K9 lactylation (H3K9la), resulting in chromatin remodeling and subsequent activation of genes associated with dedifferentiation. Consequently, β cells lose their identity and functionality, thereby accelerating the development of diabetic phenotypes.
Notably, targeted inhibition of LDHA, achieved through genetic interference or pharmacological reduction of its activity, not only delays the onset of hyperglycemia during the prediabetic stages but also restores insulin output and metabolic balance in established diabetes. These findings highlight the pivotal role of LDHA-mediated metabolic-epigenetic crosstalk in regulating β cell fate and suggest that modulation of this pathway may offer a novel therapeutic approach for diabetes intervention.
Professor Xiao Han, Professor Fang Chen, Associate Professor Yaqin Zhang from the School of Basic Medical Sciences, and Professor Qingguo Li from the Second Affiliated Hospital with NMU are the co-corresponding authors of this paper. Xirui Li, a doctoral student at NMU, is the first author. This work was supported by grants from the National Natural Science Foundation of China General Program and the Jiangsu Provincial Natural Science Foundation.
Original article link: https://pubmed.ncbi.nlm.nih.gov/41381887/
(Drafted by the research team of Xiao Han, Chen Fang and Yaqin Zhang; Reviewed by Feng Chen and Juejin Wang; Translation revised by Bei Zhang)
