Quantification of lactate metabolism with [11C]lactate
The available repertoire of PET radiotracers enables quantification of glucose, fatty acid, and amino-acid metabolism. In addition to these, lactate (2-hydroxypropanoate) is an important substrate for most tissues, including heart and brain, and altered lactate metabolism has been associated with insulin resistance and cancer. Furthermore, monocarboxylate transporters (Halestrap, 2013), which allow lactate and acetate to pass cell membranes, may be potential targets for diagnostics and drugs. L-lactate functions as a signalling molecule: binding to hydroxycarboxylic acid receptor 1 (HCA1, GPR81) reduces cAMP concentration; HCA1 is highly expressed in adipose tissue, where it downregulates lipolysis and increases storage functions (Ahmed et al., 2009, 2010). L-lactate functions as signalling molecule also in the brain (Lauritzen et al., 2014; Morland et al., 2015; Mosienko et al., 2015). Lactate metabolism can be assessed indirectly and directly using MR and PET imaging.
Biochemistry of lactate
Lactate exists in the body as two stereoisomers, L-lactate and D-lactate. Lactic acid is not present at physiological pH.
L-lactate dehydrogenase (LDH) catalyses reactions where L-lactate is formed from pyruvate while NADH is oxidized to NAD+, and vice versa. Cellular L-lactate production is required for regenerating cytosolic NAD+ to sustain glycolysis, consuming H+ in the process. Glucose (via glycolysis) and L-alanine are the main sources of pyruvate. L-lactate can be concerted back to glucose via gluconeogenesis. Oxidative decarboxylation of pyruvate to acetyl-CoA and CO2 is irreversible reaction, catalysed by pyruvate dehydrogenase (PDH) complex in the mitochondria. Acetate (from acetyl-CoA) is then consumed in the tricarboxylic acid (TCA) cycle forming CO2.
D-lactate is endogenously formed from methylglyoxal through glyoxylase system and as byproduct of glycolysis. Some foods (sour milk products, apples, tomatoes) are also sources of D-lactate. D-lactate is efficiently removed from the body via oxidation to pyruvate, and the concentrations of D-lactate are small compared to L-lactate.
Lactate transport across plasma membranes requires either proton-coupled (MCTs, SLC16 family) or sodium-coupled monocarboxylate transporters (SMCTs, SLC5 family). Non-ionic diffusion accounts for only about 5% of total lactate transport across erythrocyte membranes (De Bruijne et al, 1983). These transporter families also transport other substrates than lactate such as pyruvate, acetate, acetoacetate, and β-hydroxybutyrate. Transporter subtypes show somewhat different affinities towards the substrates, and their expression is organ-specific.
The brain shows normally a small net release of L-lactate. During intense physical exercise and increased blood lactate levels the brain starts to extract more L-lactate than it releases. Most of the extracted L-lactate is oxidised; at rest L-lactate accounts for about 8% of cerebral energy requirements, but during intense exercise it may increase to 60%. In the brain, astrocytes mainly consume glucose, releasing lactate, which is the main fuel for the neurons (Magistretti and Allaman, 2015).
In rat cerebral cortex using L-1-[11C]lactate and [18F]FDG, it was shown that lactate is readily oxidized in brain activity dependent manner. Increasing plasma lactate concentration resulted in the reduction of cerebral glucose utilization (Wyss et al, 2011).
Muscle can switch quickly from a net lactate producer to a net lactate consumer, depending on the plasma lactate concentration. Resting skeletal muscle in postabsorbtive state releases more L-lactate than is taken up, providing about 40% of the total L-lactate released into circulation. L-lactate concentration is higher in the muscle tissue than in the blood (3 mM vs 1.4 mM, respectively). During exercise, L-lactate release and extraction are both increased. Low and moderate exercise does not increase L-lactate concentration in the plasma; the work rate where lactate concentration starts to rise is referred to as the lactate threshold. As plasma lactate levels increase, the non-exercising muscles take up more lactate than they release.
During rest, heart muscle extracts more L-lactate than it releases. Most but not all of the extracted L-lactate is oxidized. L-lactate uptake correlates positively with plasma lactate concentration, and negatively with concentration of free fatty acids.
Liver and kidney
In postabsorbtive state liver and kidneys consume L-lactate, converting it mainly to glucose (gluconeogenesis). Insulin decreases lactate uptake and glucose production. Lactate uptake is increased during exercise in the liver.
The gut may be a substantial L-lactate net producer, but the liver extracts most of it before it can reach the main circulation.
Adipose tissue is a net producer of L-lactate, especially after glucose or insulin challenge. In diabetic and obese subjects the lactate production by adipose tissue is higher than in lean subjects with normal insulin sensitivity in the basal state, but the insulin-induced increase in lactate production is attenuated.
Lactate stimulates TGF-β2 expression in adipocytes; TGF-β2 improves glucose tolerance and insulin sensitivity, increases fatty acid uptake and oxidation, and stimulates glucose uptake in skeletal muscle, heart, and brown adipose tissue (Takahashi et al., 2019).
White blood cells, platelets, and erythrocytes are net producers of L-lactate. Erythrocytes lack the mitochondria and can produce ATP only by the non-oxidative glycolytic pathway, with L-lactate as the end product. Lactate transport of erythrocytes varies between species, being high in humans and dogs.
L-Lactate concentration is healthy subjects is generally less than 2 mM, but during physical exercise can increase to 10 mM. Fasting plasma lactate concentration is higher in patients with type 1 and type 2 diabetes and in obese subjects (hyperlactatemia) compared to subjects who are lean or have normal insulin sensitivity, mainly caused by increased lactate production in adipose tissue. Glucose challenge and insulin increase plasma lactate concentration, but less so in insulin resistant subjects.
"Lactic acidosis" is diagnosed when plasma L-lactate concentration is > 5 mM and blood pH is < 7.35. Systemic acidosis is not caused by excessive lactate production, although it is often accompanied by hyperlactatemia.
D-lactate concentrations in plasma and urine are higher in diabetic than in normal subjects because of increased production of methylglyoxal.
Lactate has been labelled in the 1- (carboxylic) and 3-position. If L-lactate is labelled in the C-1 position (L-1-[11C]lactate), the 11C label is released as [11C]CO2 already when pyruvate is converted to acetyl-CoA by PDH complex in mitochondria (Wyss et al., 2011). But if L-lactate is labelled in the C-3 position (L-3-[11C]lactate), the 11C label follows acetyl-CoA into the TCA cycle, where it finally is released as [11C]CO2 (Herrero et al., 2007). During PET scan most of the 11C label will be attached to other metabolites of the TCA cycle.
Wyss et al (2011) used L-1-[11C]lactate to study L-lactate oxidation in the brain of rats, using beta-probe system instead of PET. Data was analysed using a one-tissue compartmental model including parameter for vascular volume. Uptake rate of L-lactate can then be calculated as the product of K1 and plasma lactate concentration. Rate constant k2 represents the back-diffusion of labelled lactate to blood and the release of [11C]CO2. It can be assumed that LDH, not PDH, is the rate-limiting step for the release of [11C]CO2 in the rat brain (Wyss et al., 2011).
Labelled metabolites in plasma
Herrero et al (2007) showed in a dog study that under conditions of net lactate extraction, L-3-[11C]lactate depicts myocardial metabolism of exogenous lactate and that measurements of lactate metabolism are feasible with PET using monoexponential clearance analysis (kmono representing L-lactate oxidation), or applying compartmental model with two compartments (vascular and extravascular/cytosolic) with four rate constants and vascular volume fixed to 0.08, providing estimates of L-lactate extraction, back-diffusion, and oxidation.
Labelled metabolites in plasma
In the dog study (Herrero et al, 2007), the fraction of parent radiotracer (including some labelled pyruvate which could not be separated from lactate in the applied method) stayed on a relatively high level (about 40%) because of lactate back-diffusion. The fractions of neutral metabolites (mainly glucose, possibly glycerol) and [11C]CO2 increased by time, while the fraction of basic metabolites (mainly alanine, possibly other amino acids) was relatively stable (usually less than 10%) during the 60 min study. Interventions had high impact on the plasma fractions.
Adeva-Andany M, López-Ojén M, Funcasta-Calderón R, Ameneiros-Rodríguez E, Donapetry-García C, Vila-Altesor M, Rodríguez-Seijas J. Comprehensive review on lactate metabolism in human health. Mitochondrion 2014; 17: 76-100. doi: 10.1016/j.mito.2014.05.007.
Bjurling P, Långström B. Synthesis of 1- and 3-11C-labelled L-lactic acid using multi-enzyme catalysis. J Label Compd Radiopharm. 1990; 28(4): 427-432. doi: 10.1002/jlcr.2580280409.
De Bruijne AW, Vreeburg H, Van Steveninck J. Kinetic analysis of L-lactate transport in human erythrocytes via the monocarboxylate-specific carrier system. Biochim Biophys Acta 1983; 732: 562-568. doi: 10.1016/0005-2736(83)90232-8.
Deuticke B, Rickert I, Beyer E. Stereoselective, SH-dependent transfer of lactate in mammalian erythrocytes. Biochim Biophys Acta 1978; 507: 137-155. doi: 10.1016/0005-2736(78)90381-4.
Dienel GA. Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab. 2012; 32: 1107-1138. doi: 10.1038/jcbfm.2011.175.
Drandarov K, Schubiger PA, Westera G. Automated no-carrier-added synthesis of [1-11C]-labeled d- and l-enantiomers of lactic acid. Appl Radiat Isot. 2006; 64(12): 1613-1622. doi: 10.1016/j.apradiso.2006.05.013.
Drandarov K, Wyss M, Westera G, Schubiger PA, Buck A. 1-[11C]-D- and L-lactic acid, potential markers of neuronal lactate metabolism. Eur J Nucl Med Mol Imaging 2005; 32(Suppl 1): S267.
Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008; 10(1): 193-199. doi: 10.1208/s12248-008-9022-y.
Goodwin ML, Gladden LB, Nijsten MWN, Jones KB. Lactate and cancer: revisiting the Warburg effect in an era of lactate shuttling. Front Nutr. 2015; 1:27. doi: 10.3389/fnut.2014.00027.
Halestrap AP. The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med. 2013; 34(2-3): 337-349. doi: 10.1016/j.mam.2012.05.003.
van Hall G. Lactate kinetics in human tissues at rest and during exercise. Acta Physiol. 2010; 199: 499-508. doi: 10.1111/j.1748-1716.2010.02122.x.
Herrero P, Dence CS, Coggan AR, Kisrieva-Ware Z, Eisenbeis P, Gropler RJ. L-3-11C-lactate as a PET tracer of myocardial lactate metabolism: a feasibility study. J Nucl Med. 2007; 48(12): 2046-2055. doi: 10.2967/jnumed.107.044503.
Herrero P, Kisrieva-Ware Z, Dence CS, Patterson B, Coggan AR, Han DH, Ishii Y, Eisenbeis P, Gropler RJ. PET measurements of myocardial glucose metabolism with 1-11C-glucose and kinetic modeling. J Nucl Med. 2007; 48(6): 955-964. doi: 10.2967/jnumed.106.037598.
Knudsen GM, Paulson OB, Hertz MM. Kinetic analysis of the blood-brain barrier transport of lactate and its influence by hypercapnia. J Cereb Blood Flow Metab. 1991; 11: 581-586. doi: 10.1038/jcbfm.1991.107.
Magistretti PJ, Allaman I. A Cellular perspective on brain energy metabolism and functional imaging. Neuron 2015; 86: 883-901. doi: 10.1016/j.neuron.2015.03.035.
Rogatzki MJ, Ferguson BS, Goodwin ML, Gladden LB. Lactate is always the end product of glycolysis. Front Neurosci. 2015; 9: 22. doi: 10.3389/fnins.2015.00022.
Sampol D, Ostrofet E, Jobin ML, Raffard G, Sanchez S, Bouchaud V, Franconi JM, Bonvento G, Bouzier-Sore AK. Glucose and lactate metabolism in the awake and stimulated rat: a 13C-NMR study. Front Neuroenergetics 2013;5:5. doi: 10.3389/fnene.2013.00005.
Smith D, Pernet A, Hallet WA, Bingham E, Marsden PK, Amiel SA. Lactate: a preferred fuel for human brain metabolism in vivo. J Cereb Blood Flow Metab. 2003; 23: 658-664. doi: 10.1097/01.WCB.0000063991.19746.11.
Tyson RL, Gallagher C, Sutherland GR. 13C-Labeled substrates and the cerebral metabolic compartmentalization of acetate and lactate. Brain Res. 2003; 992: 43-52. doi: 10.1016/j.brainres.2003.08.027.
Wahl P, Yue Z, Zinner C, Bloch W, Mester J. A mathematical model for lactate transport to red blood cells. J Physiol Sci. 2011; 61: 93-102. doi: 10.1007/s12576-010-0125-8.
Wyss MT, Jolivet R, Buck A, Magistretti PJ, Weber B. In vivo evidence for lactate as a neuronal energy source. J Neurosci. 2011; 31(20): 7477-7485. doi: 10.1523/JNEUROSCI.0415-11.2011.
Updated at: 2019-02-22
Created at: 2015-05-28
Written by: Vesa Oikonen