Cyclic AMP suppresses the inhibition of glycolysis by alternative oxidizable substrates in the heart.

Abstract

In normoxic conditions, myocardial glucose utilization is inhibited when alternative oxidizable substrates are available. In this work we show that this inhibition is relieved in the presence of cAMP, and we studied the mechanism of this effect. Working rat hearts were perfused with 5.5 mM glucose alone (controls) or together with 5 mM lactate, 5 mM beta-hydroxybutyrate, or 1 mM palmitate. The effects of 0.1 mM chlorophenylthio-cAMP (CPT-cAMP), a cAMP analogue, were studied in each group. Glucose uptake, flux through 6-phosphofructo-1-kinase, and pyruvate dehydrogenase activity were inhibited in hearts perfused with alternative substrates, and addition of CPT-cAMP completely relieved the inhibition. The mechanism by which CPT-cAMP induced a preferential utilization of glucose was related to an increased glucose uptake and glycolysis, and to an activation of phosphorylase, pyruvate dehydrogenase, and 6-phosphofructo-2-kinase, the enzyme responsible for the synthesis of fructose 2,6-bisphosphate, the well-known stimulator of 6-phosphofructo-1-kinase. In vitro phosphorylation of 6-phosphofructo-2-kinase by cAMP-dependent protein kinase increased the Vmax of the enzyme and decreased its sensitivity to the inhibitor citrate. Therefore, in hearts perfused with various oxidizable substrates, cAMP induces a preferential utilization of glucose by a concerted stimulation of glucose transport, glycolysis, glycogen breakdown, and glucose oxidation.

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

“…By reducing the content of this protein, alternative pathways that activate PFK‐2 via phosphorylation would have less of an effect on glycolytic flux under fasting conditions. For example, β‐adrenergic activation preferentially increases glucose metabolism48 via PKA‐mediated phosphorylation of PFK‐2 and a concurrent increase in the calcium‐mediated activation of pyruvate dehydrogenase in the mitochondria 16, 49. Thus, the decrease in PFK‐2 content would ensure that periods of high sympathetic activity and fasting do not cause dangerously low blood glucose levels.…”

“…The kinase activity of the enzyme is activated by insulin and adrenergic signaling via phosphorylation, thus allowing the heart to normally alter its substrate selection depending on discrete external cues 14, 15. For example, protein kinase A (PKA)–mediated phosphorylation of PFK‐2 is sufficient to increase glucose use, even in the presence of lipids 16. However, we have found that PFK‐2 is unresponsive to β‐adrenergic pathway agonists in a diabetic model 8.…”

Glucose for the Heart

“…42 The concentration of this effector increases when glycolytic flux is stimulated and decreases when the heart oxidizes competing substrates. [42][43][44] GAPDH catalyzes the transformation, by oxidation and phosphorylation, of glyceraldehyde 3-phosphate into 1,3-diphosphoglycerate. As is the case with most dehydrogenases, GAPDH is inhibited by high concentrations of NADH and protons.…”

“…58 As already stated, fatty acids inhibit glucose oxidation more than glycolysis and glycolysis more than glucose uptake. 44,59 Glucose becomes the main substrate for oxidative metabolism of the heart when fatty acid levels are low and when the concentrations of glucose and insulin are high, as in the postprandial state. 7 We have already mentioned that glucose decreases rates of long-chain fatty acid oxidation, 60 most likely at the level of CPT-1 through the production of malonyl-CoA by ACC.…”

Myo-Myo: Yes, papa. Eating sugar? No, papa!

“…Although betablockers seem to be an obvious choice to restrict insulinsensitive glucose transporter 4 (GLUT4)-related transport, they have also been demonstrated to paradoxically decrease FFA oxidation in favor of glucose oxidation and increased FDG uptake. On the other hand, Ca 2+ -dependent intracellular adenosine 3′,5′-monophosphate (cAMP) upregulation facilitates intramyocardial glucose transport by sarcolemmal recruitment of glucose transporters [25,26] and may also stimulate glycogen breakdown (via phosphorylase activation) and glucose consumption, with consequent increase in myocardial glucose uptake.…”