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Decreased Insulin Signaling Causes Loss of PFK‐2 and Impaired Glycolysis in the Heart

The heart has a dynamic capacity to orchestrate energy production with contractile demand. Normally, beta‐adrenergic signaling works through the cAMP‐dependent protein kinase (PKA) pathway to coordinate moment‐to‐moment changes in both contraction and metabolism. The main metabolic target of PKA is phosphofructose kinase‐2 (PFK‐2), which generates fructose‐2,6‐bisphosphate in response to PKA mediated phosphorylation. This metabolite is a potent allosteric activator of PFK‐1 and serves to increase glycolysis. We have previously found that PFK‐2 is unresponsive to PKA activation in the diabetic heart and we hypothesize that this may contribute to metabolic inflexibility. Despite the central role of PFK‐2 in cardiac metabolism it is unknown how its content and activity changes in either the healthy or diabetic heart. We have recently found that in the absence of insulin signaling there is a decrease in cardiac PFK‐2 content. This is true in types 1 and 2 diabetic models and with fasted animals, suggesting turnover of PFK‐2 is a normal glucose‐sparing response. Functionally, metabolomics studies have revealed that the loss of PFK‐2 is accompanied by an increase in glycolytic products upstream of PFK‐1, and a decrease of products downstream of PFK‐1. Ongoing mechanistic studies in primary adult mouse cardiomyocytes have identified that PFK‐2 levels are regulated by multiple means. In the absence of insulin PFK‐2 is rapidly degraded by both proteasomal and chaperone mediated autophagy mechanisms. Thus, the loss of PFK‐2 content as a result of reduced insulin signaling impairs its ability to dynamically regulate glycolysis. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a potential pathological impairment in diabetes.