Glycogen dynamics in podocytes: metabolic adaptations from glucose overload to deprivation

Podocytes are key components of the glomerular filtration barrier and rely heavily on glucose metabolism to sustain energy-demanding functions. Glycogen serves as an energy reserve in classical glycogen-storing tissues, but its regulation and functional significance in podocytes under conditions of variable glucose availability remain poorly understood. The present study addresses this gap. We found that human podocytes dynamically reprogram glycogen metabolism in response to glucose availability. Under high-glucose conditions, podocytes accumulated glycogen in a time-dependent manner, accompanied by a reduction in the activity of key glycolytic enzymes, including hexokinase, pyruvate kinase, and lactate dehydrogenase. Glycogen synthase (GYS) activity was unchanged, consistent with the lack of alterations in inhibitory Ser641 phosphorylation. Glycogen phosphorylase (PYG) activity was suppressed, supporting net glycogen accumulation. In contrast, during glucose deprivation (0G), glycogen stores were rapidly mobilized within 24 h. At this stage, GYS activity was unchanged despite an increase in inhibitory phosphorylation, whereas PYG activity decreased. Glycolytic enzyme activity increased under 0G conditions, reflecting a compensatory response to glucose limitation. The pharmacological inhibition of GYS revealed cross-regulation between the synthetic and degradative pathways of glycogen metabolism, suggesting unidirectional regulation of glycogen turnover in podocytes. These findings highlight glycogen as a central, regulated energy reserve in podocytes and demonstrate their metabolic flexibility in response to changing glucose availability. Understanding these mechanisms provides insights into podocyte adaptation under stress conditions and offers potential therapeutic strategies that target glycogen metabolism in glomerular diseases that are associated with metabolic imbalance, such as diabetic kidney disease.