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Published on: May 11, 2015
Potential of PKM2 as a drug target in mouse models with type 1 diabetes mellitus
Junbin Liu1,2, Zhixia Li1,2, Gan Huang1,2
1Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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.
Insights
Knocking out PKM2 in type 1 diabetes mellitus (T1D) mouse models reduced blood glucose and inflammation. This suggests PKM2 is a potential drug target for T1D treatment.
Area of Science:
- Biochemistry
- Cell Biology
- Endocrinology
Background:
- Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by pancreatic beta-cell destruction.
- Pyruvate kinase M2 (PKM2) plays a role in cellular metabolism and has been implicated in various diseases.
- The specific role of PKM2 in T1D pathogenesis remains unclear.
Purpose of the Study:
- To investigate the effect of PKM2 knockout in beta cells on STZ-induced T1D mouse models.
- To elucidate the underlying mechanisms by which PKM2 influences T1D progression.
Main Methods:
- Generated beta-cell-specific PKM2 knockout mice using CRISPR-Cas9 technology.
- Induced T1D in mice using streptozotocin (STZ).
- Assessed metabolic parameters, oxidative stress, inflammation, and beta-cell apoptosis.
Main Results:
- Successful generation of beta-cell-specific PKM2 knockout mice.
- PKM2 knockout significantly reduced blood glucose levels in T1D mice.
- PKM2 knockout attenuated STZ-induced beta-cell apoptosis, oxidative stress, and inflammation.
Conclusions:
- PKM2 knockout in beta cells ameliorates T1D progression by reducing oxidative stress and inflammation.
- PKM2 represents a promising therapeutic target for T1D treatment.
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