Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function

Area of Science:

• Endocrinology
• Metabolism
• Cell Biology

Background:

• Type 2 diabetes is characterized by impaired pancreatic beta-cell function and mass.
• Sodium glucose co-transporter 2 (SGLT2) inhibitors are used to manage hyperglycemia.
• The protective mechanisms of SGLT2 inhibitors on beta-cells require further elucidation.

Purpose of the Study:

• To investigate the mechanism by which luseogliflozin preserves pancreatic beta-cell mass and function in a mouse model of type 2 diabetes.
• To explore the effects of luseogliflozin on mitochondrial function and oxidative stress in pancreatic islets.

Main Methods:

• db/db mice were treated with luseogliflozin or standard chow for 4 weeks.
• Analyses included DNA microarray, real-time PCR, mitochondrial respiratory capacity, reactive oxygen species (ROS) generation, immunohistochemistry, electron microscopy, and capillary electrophoresis mass spectrometry.
• Gene expression, mitochondrial function, ROS levels, metabolite profiles, and beta-cell morphology were assessed.

Main Results:

• Luseogliflozin upregulated genes in the tricarboxylic acid (TCA) cycle and electron transport chain.
• Mitochondrial complex II-linked oxidative phosphorylation capacity was improved, and ROS generation was reduced.
• NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites were increased, with normal mitochondrial morphology maintained.

Conclusions:

• Luseogliflozin protects pancreatic beta-cells by reducing mitochondrial ROS generation and enhancing complex II-linked mitochondrial respiration.
• This mechanism involves increased NKX6.1 expression and improved glucose metabolism within the TCA cycle.
• Protection of mitochondrial complex II in pancreatic beta-cells is a potential novel therapeutic strategy for type 2 diabetes.