Conditional Knockout of Pyruvate Dehydrogenase in Mouse Pancreatic Β‑cells Causes Morphological and Functional Changes

Xiao Wang,Shuchang Lai,Yanshi Ye,Yuanyuan Hu,Daoyan Pan,Xiaochun Bai,Jie Shen

Molecular medicine reports（2020）SCI 4区

Southern Med Univ

Cited 4|Views13

Abstract

Diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic beta-cells. This dysfunction is partly caused by the dysregulation of pyruvate dehydrogenase (PDH), which acts as an important mediator of pyruvate oxidation after glycolysis and fuels the tricarboxylic acid cycle. Previous studies have reported decreased PDH expression in rodent models and humans with type 2 diabetes mellitus (T2DM), suggesting that PDH may play an important role in the development of T2DM. However, the mechanism by which PDH affects insulin secretion and beta-cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase E1-alpha subunit (PDHA1; encoded by the PDHA1 gene) in the islets of type 2 diabetic mice (db/db mice) was lower than in wild-type mice, which indicated the possible association between PDHA1and diabetes. To further understand this mechanism, an inducible, islet-specific PDHA1 knockout mouse (beta KO) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the beta KO and control mice were compared. Though no changes were found in food intake, development status, fasting blood glucose or weight between the groups, the level of insulin secretion at 30 min after glucose injection in the beta KO group was significantly lower compared with the control group. Furthermore, the performed of the beta KO mice on the intraperitoneal glucose tolerance test was visibly impaired when compared with the control mice. Pancreatic tissues were collected for hematoxylin and eosin staining, immunohistochemical and confocal laser-scanning microscopy analysis. Examination of the islets from the beta KO mouse model indicated that abolishing the expression of PDH caused a compensatory islet enlargement and impaired insulin secretion.

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Key words

pancreatic beta-cell,pyruvate dehydrogenase,insulin,knockout mice,diabetes mellitus

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