• SPARC enhances MSC regenerative capacity and migration, improving their therapeutic potential for diabetes.
• SPARC-MSC transplantation reduces hyperglycemia and improves glucose tolerance in diabetic mice and canine models.
• SPARC promotes β-cell regeneration and insulin secretion via increased intracellular ATP and Ca2+ influx.
• Transcriptomic and proteomic analyses reveal enrichment in calcium binding and cell migration pathways, supporting the mechanism.