Palmitate Re-Directs Glucose Utilization in Type 2 Diabetic Hearts, Improving Function: A Metabolomic-Fluxomic Study

Abstract

Hyperglycemia and hyperlipidemia are two main traits of type-2 diabetes (T2DM). T2DM patients may develop a cardiomyopathy, and the excess in nutrients greatly contributes to systolic and diastolic dysfunction. The Randle cycle postulates that fatty acid (FA) utilization further impairs glucose utilization, impeding its oxidation. Yet recent evidence suggests that, when acutely infused, FAs such as palmitate (Palm) actually help in maintaining function in T2DM hearts stressed with high glucose and catecholamines. Thus, under conditions of sustained stress, lipids may be necessary to maintain function in stressed T2DM hearts. Using a novel procedure for translating metabolomics into metabolic fluxes, here we tested whether Palm is able to redirect the glucose fluxome in T2DM hearts, contributing to a better utilization/oxidation of glucose. We found that Palm, without inhibiting glycolysis, led to a 50% increase in glucose oxidation via the pentose phosphate [PP] pathway. Palm presence shifted the control of the glycolytic flux from phosphofructokinase to glucose uptake, glucose 6-phosphate dehydrogenase and glycogenolysis. Palm-induced remodeling of the glucose fluxome decreased the intracellular levels of glucose by 17-fold, owing to reduced uptake at maintained utilization. Moreover, it augmented the content of reduced GSH, via higher NADPH generation through the PP pathway. Our study provides a mechanistic explanation to the in vitro observation that FAs such as Palm are necessary for the T2DM hearts to maintain function when in presence of hyperglycemia and/or increased workload, by remodeling glucose utilization leading to a higher supply of reducing equivalents to the heart. Present findings suggest that in T2DM subjects the Randle cycle may apply to some but not all pathophysiological contexts.