Canagliflozin-Induced Adaptive Metabolism in Bone

Area of Science:

• Metabolic research
• Bone biology
• Pharmacology

Background:

• Sodium-glucose transporter-2 inhibitors (SGLT2i) are insulin-independent glucose-lowering drugs.
• SGLT2i use is associated with weight loss and potential bone integrity issues.
• The mechanism of SGLT2i-induced skeletal changes is not fully understood, as SGLT2 is not expressed in bone cells.

Purpose of the Study:

• To investigate the skeletal effects of canagliflozin (CANA), an SGLT2i, in a mouse model.
• To explore the metabolic and molecular adaptations in bone tissue following SGLT2i treatment.
• To identify potential sex-specific responses to SGLT2i therapy.

Main Methods:

• UM-HET3 mice were treated with canagliflozin (CANA) for 1, 3, or 6 months.
• Metabolic parameters, bone remodeling markers, and bone tissue metabolome were analyzed.
• Integrative analysis of bone metabolome and bone marrow RNA sequencing was performed.

Main Results:

• CANA treatment led to significant metabolic adaptations in male mice, including weight loss and reduced bone remodeling.
• Male mice showed altered bone metabolome with enrichment in amino acid transport and tryptophan catabolism.
• Female mice exhibited changes in nucleic acid metabolism, and both sexes displayed reduced expression of key metabolic and cellular pathways.
• A positive correlation was found between bone metabolome and RNA sequencing data in male mice.

Conclusions:

• Canagliflozin impacts bone metabolism primarily through induced "glucose restriction," affecting bone cell proliferation and differentiation.
• SGLT2i treatment elicits sex-specific skeletal responses.
• These findings highlight the importance of considering sex differences in clinical applications of SGLT2i impacting substrate availability.