Hyperglycemia differentially regulates osteoblast and osteoclast autophagy via AMPK/mTOR/p70 S6K signaling in diabetic osteoporosis

Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mTOR/p70 S6K signaling axis in bone cell function. In vivo, diabetes reduced AMPK phosphorylation, enhanced mTOR/p70 S6K activation, and diminished Autophagy in rat femoral tissue. In vitro, HG exerted cell-type-specific effects via the AMPK signaling pathway: in osteoblasts, HG inhibited AMPK phosphorylation, activated mTOR/p70 S6K, suppressed Autophagy, and impaired mineralization as well as Alkaline Phosphatase (ALP) activity; conversely, in osteoclasts, HG enhanced Autophagy through the inverse regulatory pathway and accelerated osteoclast differentiation and bone resorption. Collectively, these findings illustrate that hyperglycemia disrupts bone homeostasis via cell-type-specific regulation of AMPK, suggesting that AMPK-mediated Autophagy serves as a potential critical therapeutic target for diabetes-related bone diseases.