Glycogen Accumulation and Its Influence on Metabolite Dynamics in Diabetic Myocardium

Abstract

The incidence rates of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and their associated health risks continue to rise. Diabetes is associated with myocardial glycogen accumulation and increased rates of cardiac dysfunction, though the underlying mechanisms vary between T1D and T2D. Despite this, the mechanical and metabolic effects of glycogen accumulation in the myocardium remain unexplored. This study investigates the hypothesized barrier effects of glycogen on cardiomyocyte metabolites. Left-ventricular samples from streptozotocin-induced T1D rats were imaged using transmission electron microscopy (TEM) to quantify mitochondrial, myofibril, and glycogen structures within cardiomyocytes. A 115% increase in glycogen area fraction was confirmed, accompanied by a 19.8% decrease in myofibril area fraction. To assess the functional and metabolic impacts of glycogen, finite element models of cardiomyocytes were created, simulating conditions with and without glycogen. Computational simulations of mitochondrial respiration and reaction-diffusion mechanisms were conducted on these finite element mesh models to evaluate glycogen's effects on metabolite diffusion and steady-state concentrations. Our simulations revealed that increased glycogen levels in diabetic cardiomyocytes led to significant increases in ATP, phosphocreatine (PCr), and inorganic phosphate (Pi), with a corresponding decrease in ADP. Additionally, glycogen amplified the spatial variability of PCr and Pi concentrations in diabetic cells, but not in control cells.