The SGLT2 Inhibitor Canagliflozin Promotes β-Cell Regeneration and Restores and Stabilises β-Cell Identity in a Polygenic Model of Severe Early-Onset Type 2 Diabetes

Abstract

Childhood obesity has led to an increase in type 2 diabetes (T2D) among youth, with adolescent-onset T2D showing a rapid decline in β-cell function compared to adult-onset cases. While the disease progression is more aggressive in early life, treatment can lead to recovery or remission more often at younger ages. SGLT2i have proven multiple health benefits when prescribed to adults with T2D but may have a greater potential in improving insulin production and β-cell mass in youth. In our study, TallyHO mice, which develop severe early-onset T2D, were treated with canagliflozin (cana) while on a 10-week diet. Results showed a significant reduction in blood glucose levels and improved β-cell function, indicated by higher C-peptide, islet insulin content, and HOMA-B index compared to untreated mice. Cana treatment restored the islet area and β to α-cell ratio, while also decreasing apoptosis. Notably, cana promoted the transient appearance of endocrine bihormonal cells and small clusters of insulin-positive cells, suggesting a possible transdifferentiation process and β-cell neogenesis. Furthermore, cana stabilised β-cell phenotype, restoring the expression of key identity markers while reducing abnormal cell types and the dedifferentiation to precursors and mesenchymal cells. These findings suggest that canagliflozin can promote the regeneration of pancreatic islets and mitigate β-cell dedifferentiation in the early onset of β-cell deficiency.