Conditional knockout of pyruvate dehydrogenase in mouse pancreatic β‑cells causes morphological and functional changes

Abstract

diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic β-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 β-cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase e1-α 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 (βKo) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the βKo 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 βKO group was significantly lower compared with the control group. Furthermore, the performed of the βKo 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 βKo mouse model indicated that abolishing the expression of PdH caused a compensatory islet enlargement and impaired insulin secretion.

Cuproptosis: potential new direction in diabetes research and treatment

“…This suggested the correlation between the cause of hyperglycemia in bKO mice and impaired pancreatic b-cell function and insulin secretion dysfunction rather than peripheral tissue insulin resistance. The finding further indicated the essential role of PDHA1 in pancreatic islet development, and its absence significantly impacted the morphology and function of pancreatic islet cells (69). Furthermore, research has also suggested that T cells may mediate tubular injury in diabetic nephropathy via impaired PDHA1 and autophagy in Type 1 Diabetes (14).…”

Kinetic and data-driven modeling of pancreatic β-cell central carbon metabolism and insulin secretion

“…Thus, the pdh reaction initiates mitochondrial metabolic processes (especially pyruvate cycling), which drive insulin secretion. Furthermore, decreasing pdh has been shown to impair insulin secretion[98–100].…”