Comorbidity of osteoporosis and Alzheimer’s disease: Is `AKT `-ing on cellular glucose uptake the missing link?

Osteoporosis and Alzheimer’s disease (AD) are both degenerative diseases. Osteoporosis often proceeds cognitive deficits, and multiple studies have revealed common triggers that lead to energy deficits in brain and bone. Risk factors for osteoporosis and AD, such as obesity, type 2 diabetes, aging, chemotherapy, vitamin deficiency, alcohol abuse, and apolipoprotein Eε4 and/or Il-6 gene variants, reduce cellular glucose uptake, and protective factors, such as estrogen, insulin, exercise, mammalian target of rapamycin inhibitors, hydrogen sulfide, and most phytochemicals, increase uptake. Glucose uptake is a fine-tuned process that depends on an abundance of glucose transporters (Gluts) on the cell surface. Gluts are stored in vesicles under the plasma membrane, and protective factors cause these vesicles to fuse with the membrane, resulting in presentation of Gluts on the cell surface. This translocation depends mainly on AKT kinase signaling and can be affected by a range of factors. Reduced AKT kinase signaling results in intracellular glucose deprivation, which causes endoplasmic reticulum stress and iron depletion, leading to activation of HIF-1α, the transcription factor necessary for higher Glut expression.