Cardiac Metabolism

The heart is a highly oxidative organ: over 90% of its energy is produced by mitochondrial respiration. Cardiomyocytes are packed with mitochondria containing all enzymes for beta-oxidation and oxidative phosphorylation. The heart can utilise any fuel — fatty acids, glucose, lactate, ketone bodies, and amino acids — depending on availability and conditions. Fatty acids are preferred under fasting conditions because the myocardium is highly oxidative and fat yields more ATP per molecule (105 ATP per palmitate vs 32 per glucose).

Fuel selection is governed by substrate availability, oxygen availability, hormones (especially insulin and glucagon), and workload. In the fed state, insulin rises → GLUT4 translocates to the membrane (increased glucose uptake) → ACC enzyme is activated → Malonyl-CoA accumulates → CPT is inhibited → fatty acid entry into mitochondria is blocked → carbohydrate metabolism dominates. In the fasted state, low insulin → reduced GLUT4 → hormone-sensitive lipase activated → free fatty acids released from stored TAGs → Acyl-CoA enters mitochondria via CPT (uninhibited) → beta-oxidation → Acetyl-CoA → inhibits PDH → reduces glucose metabolism. Malonyl-CoA produced by ACC is a key fuel-switching regulator.

In type 2 diabetes, impaired insulin signalling reduces GLUT4 availability and glucose uptake; the heart increases fatty acid oxidation. This is problematic because diabetic patients face high ischaemic risk (hyperlipidaemia/hypercholesterolaemia), and ischaemic tissue demands increased carbohydrate metabolism — which is impaired by insulin resistance.

During ischaemia, insufficient O2 → ATP falls → AMP rises → AMPK is activated → ACC activity falls → Malonyl-CoA falls → CPT is activated → initial increase in beta-oxidation. But insufficient O2 cannot sustain beta-oxidation → Acetyl-CoA drops → PDH inhibition relieved → glucose enters mitochondria → but without O2, the citric acid cycle fails → anaerobic glycolysis increases → lactic acid accumulates → acidosis. Overall: both substrate pathways are compromised. AMPK activation by exercise, adiponectin, or metformin is cardioprotective — it increases glucose uptake, GLUT4, and fat oxidation while suppressing lipogenic gene expression.