Potential of PKM2 as a drug target in mouse models with type 1 diabetes mellitus

Abstract

Abstract Background This study aimed to determine the effect of PKM2 knockout in STZ induced type 1 diabetes mellitus (T1D) mouse models and to explore the possible mechanism. Method PKM2fl/fl C57BL/6 mouse was backcrossed with Ins‐1cre C57BL/6 mouse to generate β‐cell‐specific PKM2 knockout mouse after tamoxifen administration. The expression level of PKM2 in pancreas tissues was detected by quantitative reverse‐transcription polymerase chain reaction and western blot analysis. The blood glucose levels in STZ induced T1D mouse models were measured to validate the establishment of T1D models. The pathological changes of T1D mouse were examined by hematoxylin and eosin. The oxidative stress (OS) and inflammatory response in T1D mouse were determined by measuring the expression levels of malondialdehyde, superoxide dismutase, and 8‐OHdG in pancreatic tissues and the serum levels of interleukin‐6 and tumor necrosis factor‐α. The ability to catabolize glucose was assessed through intraperitoneal glucose tolerance test and insulin tolerance test. Results β‐cell‐specific PKM2 knockout was successfully achieved in PKM2fl/flcre+ mouse. T1D mouse with PKM2 knockdown had decreased blood glucose level and suppressed cell apoptosis. PKM2 knockout in T1D mouse attenuated β cell injury. OS and inflammatory response in T1D mouse with PKM2 knockout were also suppressed compared with T1D mouse without PKM2 knockout. Conclusion PKM2 knockout in T1D mouse can attenuate OS and inflammatory response as well as decrease blood glucose level, suggesting the potential of PKM2 as a drug target for T1D treatment.

Keywords

• inflammation
• oxidative stress
• PI3K/AKT
• PKM2
• type 1 diabetes mellitus