Caveolin-1 deficiency improved glucose metabolism via modulation of β-cell autophagy in high-fat diet-fed mice.

Lipotoxicity caused β-cell mass decrease and impaired β-cell function in type 2 diabetes mellitus. We previously reported that caveolin-1 (Cav-1) deficiency protected pancreatic β cells against palmitate (PA)-induced apoptosis and dysfunction in both NIT-1 cells and isolated islets. In this study, we firstly established inducible β-cell-specific Cav-1 KO mice model. Next, we investigated whether Cav-1 depletion in vitro or in vivo affected β-cell function and survival through the regulation of autophagy under lipotoxicity. Our results showed that Cav-1 depletion exhibited increased islets size, improved insulin resistance and glucose tolerance in lipid stressing conditions. In addition, KO of Cav-1 also increased β-cell viability through suppression of gene expression of pro-apoptotic molecules (BIM, BID, SMAC, Apaf, Caspase9, Caspase3, AIF, and EndoG). Mechanism studies revealed that Cav-1 depletion protected β cells from PA-induced apoptosis through p38 MAPK signaling pathway. Meanwhile, we also found that Cav-1 depletion enhanced autophagy through elevated expression of Beclin-1 and Lc3b, and increased degradation of p62 protein. Further investigation indicated that mechanistic target of rapamycin (mTOR) signaling pathway was participated in the regulation of PA-induced autophagy. Taking together, our data suggested that Cav-1 depletion ameliorated PA-induced glucose metabolism abnormality, increased cell viability, and improved β-cell apoptosis through the enhancement of autophagy. Our findings would provide valuable clues for developing novel treatments based on Cav-1 inhibition against diabetes under lipotoxicity.