Renal glycogen handling in diabetes: A narrative review of diabetic kidney disease pathogenesis

ABSTRACT Kidney disease is a major microvascular complication of diabetes, affecting approximately 40% of individuals with diabetes, and is a leading cause of end‐stage renal disease. Besides the functional consequences of hyperglycemia; hemodynamic alterations are well understood. Activation of the sorbitol and hexosamine pathways, formation of advanced glycated products, and prevailing oxidative stress in the background of diabetic hyperglycemia are determinants of diabetic kidney disease (DKD) and its progression. The contribution of ectopic glycogen deposition remains unexplored. Glycogen metabolism in the kidneys is well regulated under physiological conditions, yet chronic hyperglycemia disrupts this balance across podocytes, tubular cells, and the glomerulus. Abnormal glycogen buildup has been observed in experimental diabetes models and human biopsy samples. GSK3β inactivation and mTORC1 upregulation emerge as central regulators. Metformin and SGLT2 inhibitors alter renal glycogen flow via AMPK‐dependent pathways, a potential avenue for therapeutic exploration. The significance of observational studies needs to be further explored for the potential involvement of glycogen buildup in the pathogenesis of DKD. This narrative review aims to provide a comprehensive understanding of glycogen metabolism, examine the dysregulation of key enzymes and signaling pathways, collate available evidence from animal and clinical studies and propose hypothesis that glycogen accumulation may have an additive role in the progression of DKD.