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, which allow lactate and acetate to pass cell membranes, may be potential targets for diagnostics and drugs. Lactate metabolism can be assessed indirectly and directly using MR and PET imaging.

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). Equilibrating action of monocarboxylate transporters between lactate producing and consuming tissues allows lactate to act as a volume transmitter that can mediate metabolic signals through the nervous tissue (Bergersen et al., 2012 and 2015).

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 reversible reaction where pyruvate is formed from L-lactate while NAD⁺ is reduced to NADH, or 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. Kidneys maintain pyruvate/lactate ratio in circulation by converting lactate into pyruvate.

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, and ketone bodies. Transporter subtypes show somewhat different affinities towards the substrates, and their expression is organ-specific. MCT1 expression is ubiquitous, except that it is suppressed in pancreatic β- and α-cells; lactate generally overrides glucose in regulating energy substrate partitioning, and in β-cells this would interfere with glucose sensing and lead to hypoglycaemia (Zhao et al., 2001; Brooks, 2020).

Lactate metabolism

The brain

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). Lactate is released from astrocytes via monocarboxylate transporters MCT1 and MCT4, high-capacity cation channel, and pannexins. Lactate exerts metabolic effects and activates signalling cascades via MCT2 and HCAR1 on neurons (Magistretti and Allaman, 2018).

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). Rat brain studies with L-3-[¹¹C]lactate suggest that insulin increases lactate uptake (Temma et al., 2018).

¹³C-NMR with L-3-[¹³C]lactate have been used to study lactate metabolism in the rat brain (Bouzier et al., 2000; Duarte et al., 2015) and glioma (Terpstra et all., 1998).

Skeletal muscle

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.

Intracellular lactate releases O₂ from myoglobin (Adepu et al., 2022).

Myocardial muscle

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.

PET with L-3-[¹¹C]lactate could be used to assess myocardial L-lactate metabolism under conditions of net lactate extraction (Herrero et al., 2007b).

Liver and kidney

In postabsorbtive state liver and kidneys consume L-lactate, converting it mainly to glucose (gluconeogenesis). In human kidneys, 95% of filtrated lactate is reabsorption by sodium-coupled monocarboxylate transporters SMCT1 and SMCT2, expressed at the apical side of the proximal tubules; lactate is then either used in gluconeogenesis or recirculated back to blood via MCT1 (Gündel et al., 2022). 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

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).

Blood cells

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.

Lactate in blood plasma

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.

PET radiopharmaceuticals

Lactate has been labelled with C-11 in the 1- (carboxylic) and 3-position (Bjurling et al., 1990). 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-2 or 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., 2007b; Temma et al., 2018). During PET scan most of the ¹¹C label will be attached to other metabolites of the TCA cycle.

Lactate has also been labelled with F-18. When label is inserted in C-2 position ([¹⁸F]-2-fluoropropionate), the molecule is transported into cells but the transport could not be inhibited with MCT1 inhibitor like lactate, and is therefore not suitable as a lactate radiotracer for PET imaging. When lactate is labelled in C-3 position ([¹⁸F]-3-fluoro-2-hydroxypropionate), the molecule is transported into cells by MCT1 like lactate, as the transport can be inhibited. (Van Hée et al., 2017).

L-1-[¹¹C]lactate

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

The main label-carrying metabolite in rat blood is [¹¹C]CO₂, when L-lactate is labelled in C-1 position (van Hall et al, 2009; Wyss et al, 2011).

L-3-[¹¹C]lactate

Herrero et al (2007b) 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 (k_mono 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.

In non-fasted, fasted, and insulin pretreated rats the appearance of labelled metabolites was too fast to allow full quantification of lactate metabolism (Temma et al., 2018). Instead, SUV at 10 min after injection was used. In the brain SUV was higher in the insulin pretreated rats.

Labelled metabolites in plasma

In the dog study (Herrero et al, 2007b), 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.

In a rat study (Temma et al., 2018), more than half of radioactivity in the plasma was due to metabolites already 2 min after L-3-[¹¹C]lactate administration in fasted rats. [¹¹C]glucose was the main metabolite, followed by [¹¹C]alanine, and [¹¹C]CO₂. This suggests that in fasted rats gluconeogenesis and redistribution of glucose is very rapid, and the role of lactate as energy source is low. Insulin pretreatment inhibited gluconeogenesis, seen as somewhat lower concentration of [¹¹C]glucose in plasma. No [¹¹C]pyruvate was detected.

While [¹¹C]glucose, as the main metabolite, hampers the quantification in L-3-[¹¹C]lactate PET, similarly [¹¹C]lactate is a problem when trying to quantitate [¹¹C]glucose PET data (Herrero et al., 2007a).

[¹⁸F]fluorolactate

The racemic mixture of [¹⁸F]-3-fluoro-2-hydroxypropionate ([¹⁸F]fluorolactate, [¹⁸F]-FLac) is taken up by cancer cells cells in vitro and tumours in vivo (Van Hée et al., 2017; Wang et al., 2018). [¹⁸F]-FLac, and its enantiomeric form [¹⁸F]-S-fluorolactate ([¹⁸F]-S-FL), could be used to monitor MCT1-dependent lactate transport and inhibition (Van Hée et al., 2017; Braga et al., 2020). In vitro assay suggested that [¹⁸F]-FLac could be metabolized by LDH to [¹⁸F]-3-fluoropyruvate (Van Hée et al., 2017). Low levels of radioactivity in bone after 1 h of ¹⁸F]-S-FL administration indicates a low level of defluorination of the radiotracer (Braga et al., 2020).

See also:

• Glucose
• Pyruvate
• Acetate
• Mitochondria
• Monocarboxylate transporters

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Tags: Lactate, Glucose, Glycolysis

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Updated at: 2023-01-25
Created at: 2015-05-28
Written by: Vesa Oikonen