Metabolic reprogramming of pancreatic beta cells in type 2 diabetes and its therapeutic strategy

Pancreatic beta cells are highly specialized cells that possess unique metabolic programs to ensure insulin secretion matches nutritional status for maintaining glucose homeostasis. However, in type 2 diabetes mellitus (T2DM), prolonged exposure to excessive nutrients (glucose, lipids) induces toxicity that leads to progressive beta cell failure and impaired insulin secretion, whose underlying mechanisms remain unclear. This review summarizes the distinctive metabolic features of pancreatic beta cells under physiological conditions and the mechanisms of glucolipotoxicity-driven metabolic reprogramming in pathological states (T2DM). Under chronic nutrient overload, beta cells undergo dynamic metabolic remodeling, resulting in the loss of characteristic metabolic programs and triggering interconnected stress damage networks including inflammation, oxidative stress, and endoplasmic reticulum stress. Meanwhile, disrupted transcriptional programs under metabolic stress also lead to the loss of beta cell identity. In response, beta cells attempt to evolve unique carbon flux metabolic reprogramming mechanisms to achieve fuel "detoxification." These processes are critical for identifying key nodes in beta cell metabolic reprogramming. Finally, the review outlines therapeutic strategies targeting beta cell metabolic reprogramming, particularly emerging approaches focusing on microRNAs and restoring beta cell identity and function. This article aims to delineate the key nodes in the transition of beta cells from physiological to pathological metabolic states, providing a theoretical basis for identifying reversible stages in disease progression and restoring metabolic flexibility to achieve beta cell functional protection.