Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Abstract

BackgroundThe healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK‐2) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK‐2 content, activity, and cardiac metabolism.Methods and ResultsStreptozotocin‐induced diabetes mellitus, high‐fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK‐2 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK‐2 degradation. Both type 1 diabetes mellitus and a high‐fat diet induced a significant decrease in cardiac PFK‐2 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK‐2, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK‐2 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse‐1, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK‐2 is rapidly degraded via both proteasomal‐ and chaperone‐mediated autophagy.ConclusionsThe loss of PFK‐2 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.

Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway

“…GK mainly expressed in hepatocytes had effects on regulating blood glucose level in vivo [ 38 ]. Previous study also found that the ability of glucose metabolism in T2DM was reduced when the syntheses of PFK and PK were decreased [ 39 ]. In this work, owing to the amelioration of the insulin signaling pathway, PEPCK, FBPase, G6Pase, and GP activities were notably decreased, while prominent increased activities of GK, PFK, PK, and GS were detected after treatment.…”

Metabolic Coordination of Physiological and Pathological Cardiac Remodeling

“… 322 , 325 These metabolic changes seem to be the product of higher circulating fatty acids and ketone bodies, increased fatty acid transport, decreased insulin sensitivity, downregulation of glucose transporters, elevated levels of PDK4, higher malonyl-CoA decarboxylase activity, and lower acetyl CoA carboxylase and PFK activities. 20 , 322 , 326 – 329 Associated with the metabolic phenotype of the diabetic heart are metabolic inflexibility, lipotoxicity (eg, accumulation of triacylglycerols, diacylglycerols, ceramide, long chain acyl CoAs, acylcarnitines), glucotoxicity, mitochondrial dysfunction, and cardiac insulin resistance. 20 , 330 , 331 …”

Recent advances in understanding glucose transport and glucose disposal

“…This facilitates the metabolism of glucose, taken up by GLUT4, through glycolysis. In our own work, we have found that PFK-2 content is regulated by insulin signaling and that it is constitutively decreased in mouse models of diabetes 27 . Regulation of PFK-2 content by insulin may serve as a mechanism to decrease cardiac glucose uptake and metabolism during fasting, but, in the context of diabetes, a chronic decrease in PFK-2 may contribute to metabolic inflexibility.…”