Akt2 regulates autophagy and osteogenesis in diabetic osteoporosis via PI3K/AKT/mTOR signaling axis.

Abstract

Adipose-derived stem cells (ASCs) are crucial seed cells for bone defect repair. In diabetic osteoporosis (DOP), however, their osteogenic potential is impaired. This study found that ASCs from a pre-clinical DOP model, established in C57BL/6 J mice using a high-fat/high-sucrose diet combined with streptozotocin-induced insulin deficiency, exhibited suppressed osteogenic differentiation and impaired autophagy flux. This was accompanied by hyperactivation of the PI3K/AKT/mTOR signaling, particularly elevated AKT2 phosphorylation. Transcriptomic analysis confirmed enrichment of related pathways. Mechanistically, Akt2 overexpression suppressed osteogenesis and autophagy, while its knockdown restored both. Crucially, implanting shAkt2-treated DOP-ASCs into calvarial defects of DOP mice enhanced bone regeneration, improving bone volume, trabecular number, and collagen deposition. These findings identify Akt2 as a key regulator of ASC dysfunction in DOP and demonstrate that its targeted inhibition rescues osteogenic potential, offering a promising therapeutic strategy for diabetic osteoporotic bone repair.