Fig. 9.
Illustration of how lactatemia affects blood (glucose) and peripheral glucose uptake as well as the production, uptake and oxidation of FFA, giving rise to metabolic inflexibility in muscle. Lactate is the inevitable consequence of glycolysis,18 the minimal muscle lactate (L) to pyruvate (P) ratio (L/P) being 10 and rising to an L/P of >100 when glycolytic flux is high.57 Lactate is the favored oxidizable substrate and provides product inhibition of glucose and FFA oxidation. As the products of glycolysis, lactate and pyruvate provide negative feedback inhibition of glucose disposal (blue dashed lines). Also, as the predominant mitochondrial substrate, lactate gives rise to acetyl-coenzyme A (CoA), and in turn malonyl-CoA. Acetyl-CoA inhibits β-ketothiolase and, hence, β-oxidation, while malonyl-CoA inhibits mitochondrial FFA-derivative uptake via CPT1 (T).199 Moreover, lactate is the main gluconeogenic precursor raising glucose production and blood (glucose) (red lines). Via GPR81 binding, lactate inhibits lipolysis in WAT (T), depressing circulating FFA.96,104 This model explains the paradoxical presence of lactatemia in high-intensity exercise and insulin-resistant states with limited ability to oxidize fat (green lines). Modified from.76 CPT1 = carnitine palmitoyl transporter-1; FAT = fatty acid translocator comprised of CD36 and FABPc; FFA = free fatty acid; GLUT = glucose transporter; m = mitochondrial; Malonyl = CoA formed from exported TCA citrate controlled by the interactions of malonyl-CoA decarboxylase (MCD) and acetyl-CoA carboxylase (ACC); MCT = monocarboxylate transporter; mPC = mitochondrial pyruvate transporter; PDH = pyruvate dehydrogenase; s = sarcolemmal; T = inhibition; WAT = white adipose tissue. Not shown is fatty acyl-Co (FA-CoA) that will accumulate if FFAs are taken up by myocytes, but blocked from mitochondrial entry by the effect of malonyl-CoA on CPT1. Accumulated intracellular FA-CoA will give rise to intramyocellular triglyceride (IMTG) and the formulation of LC-FA, DAG, and ceramides via inhibition of PI3 Kinase (PI3-K) and reducing GLUT4 translocation; from Ref. 23 with permission.