Insulin safeguards apoptotic fate of mesenchymal stem cells to sustain long-term therapeutic efficacy in type 2 diabetes

Abstract Type 2 diabetes mellitus (T2DM) remains a major global health challenge, and although mesenchymal stem cell (MSC)-based therapy has shown promise in targeting its core pathological features, its translational potential is limited by unstable efficacy, including limited therapeutic durability and marked variability associated with baseline insulin secretion and β-cell reserve. Here, using db/db mice and diet-induced obese mice as complementary T2DM models, we investigated whether combining umbilical cord MSCs (UCMSCs) with insulin could improve therapeutic stability and explored the underlying mechanisms. UCMSC monotherapy improved glucose tolerance and insulin sensitivity in the short term but failed to maintain prolonged efficacy, whereas UCMSC-insulin combination therapy achieved more stable glycemic control and more effectively alleviated hepatic steatosis and dyslipidemia over a relatively long term, as well as alleviating renal complications. Mechanistically, insulin promoted early MSC apoptosis under high-glucose conditions, thereby increasing apoptotic vesicle (apoV) production while also remodeling molecular cargo of apoVs and enhancing their immunomodulatory activity, as reflected by enhanced macrophage reprogramming toward an anti-inflammatory phenotype. Exogenous supplementation with UCMSC-derived apoVs produced prolonged therapeutic efficacy comparable to that of the UCMSC-insulin combination in db/db mice. In diet-induced obese mice, insulin-primed MSC-derived apoV treatment stably improved glucose homeostasis. Together, these findings identify insulin as a key modulator that stabilizes MSC-based therapy in T2DM by safeguarding MSC apoptotic fate and improving both the production and functional competence of MSC-derived apoVs, while also highlighting apoVs as a promising cell-free alternative for targeting T2DM.