Perspective

https://doi.org/10.1038/s42255-020-0243-4

Lactate: the ugly duckling of energy metabolism

Joshua D. Rabinowitz   1 ✉ and Sven Enerbäck   2 ✉

Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactoba-
cilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals.
Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and isch-
aemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate’s reputation as a deleterious
waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circu-
lating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds,
circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate
and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This
reconceptualization of lactate as a fuel—analogous to how Hans Christian Andersen’s ugly duckling is actually a beautiful
swan—has the potential to reshape the field of energy metabolism.

C
arbohydrates account for approximately half the caloric
intake in humans. Most are eaten as starch, which is broken
down into glucose in the small intestinal lumen. Glucose is
then absorbed into the portal circulation and passed to the liver.
The liver takes up a portion of dietary glucose and stores it as gly-
cogen for future release during fasting. The remainder is distributed
throughout the body for use as fuel. Some of this glucose is con-
verted into lactate, and glucose and lactate are the two most abun-
dant circulating carbon carriers in mammals.
The classic view: glucose as fuel, lactate as waste
Energy can be derived from glucose through two processes: fermen-
tation and respiration. Both begin with catabolism of glucose via
glycolysis into two molecules of pyruvate, with associated produc-
tion of two ATP and two NADH molecules. The NADH is made at
the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) step in
the middle of glycolysis. During fermentation, the NADH is used to
reduce pyruvate to lactate, which is then excreted. This process results
in a net yield of two ATP and two lactate molecules per glucose, with-
out consuming any oxygen. In respiration, the NADH electrons and
pyruvate generated by glycolysis are shuttled into the mitochondria,
where they are consumed and subsequently produce copious usable
energy (approximately 25 ATP molecules per glucose).
The ability to ferment glucose into lactate reflects that two lac-
tic acid molecules contain the same atoms as one glucose molecule
(Fig. 1a). Thus, although the chemical bonds are rearranged, lactic
acid is half of glucose.
Pyruvate, in contrast, is more oxidized than either glucose or
lactate. Specifically, each lactate molecule carries two more hydro-
gen atoms than pyruvate. These two hydrogen atoms consist of
two protons and two electrons. To convert either glucose or lactate
into pyruvate, these electrons must be disposed of, in a process that
requires transporting the electrons, which are stored in NADH, into
mitochondria. Although direct lactate import into the mitochon-
drial matrix is a possibility1, there are two better-established routes
to transport the electrons: the malate–aspartate and glycerol phos-
phate shuttles2–4 (Fig. 1b).
When oxygen is available, NADH’s electrons can be quickly
used by the electron-transport chain in the mitochondria, thereby
yielding valuable energy. When oxygen is not available, however,
mitochondria can no longer effectively clear electrons. Thus, under
anaerobic conditions, fermentation is the only metabolic option.
Even when oxygen is available, ATP production by oxidative phos-
phorylation can be limited by the oxygen uptake rate. Thus, under
high-demand conditions, such as intense exercise, fermentation
provides a way to accelerate energy generation. Accordingly, when
muscle is pushed beyond the aerobic threshold, such as during a
short sprint or toward the end of a long hard run, lactate is released
as metabolic waste5 (Fig. 1b).
Lactate excretion by cultured cells
Lactate production does not occur in only oxygen-limited muscle.
Most cultured mammalian cells produce copious lactate even when
oxygen is abundant. Such aerobic glycolysis was initially noted by
Warburg nearly a century ago, and rapid lactate production was
the first molecular phenotype associated with cancer6. This obser-
vation led to the hypothesis that cancer is a disease of defective
mitochondria7. But although mitochondrial defects occasionally
occur in cancer, they are not a major cause8–10. Instead, fermenta-
tion is a common feature of mammalian cells in culture, includ-
ing non-cancerous cells, such as proliferating T cells and even
non-growing cells, such as quiescent fibroblasts11,12.
The reasons why cultured cells avidly ferment glucose remain
incompletely understood, but media formulation plays a role.
Classical tissue medium contains serum growth factors, supraphysi-
ologic glucose and no lactate13. In such conditions, glucose is the
only available carbohydrate fuel. Moreover, both glucose availabil-
ity and lactate secretion are unconstrained, and glucose is refreshed
and lactate is removed every time the culture medium is changed.
These factors, together with growth-factor signals that trigger glu-
cose uptake14, favour avid glucose fermentation. The release of lac-
tate by both cells in vitro and stressed muscle in vivo supports the
paradigm of glucose as fuel and lactate as waste.
An emerging possibility: glucose as specific fuel, lactate as
universal fuel
Mammals evolved under different metabolic pressures from cells in
culture, including a frequent risk of starvation. Because lactate is

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. 2Department of Medical Biochemistry and Cell Biology, Institute
1

of Biomedicine, University of Gothenburg, Gothenburg, Sweden. ✉e-mail: joshr@princeton.edu; sven.enerback@medgen.gu.se

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NATure MeTABoLIsm
a b
O H
H OH
HO H
O O
H OH
H3C H3C
H OH OH
OH
CH2OH OH O Glycerol
Glucose 2 Lactic acids 2 Pyruvic acids
C, O 6 6 6
H 12 12 8 Pyruvate
Fig. 1 | Lactate—waste and fuel. a, Lactate is half of glucose, whereas pyruvate is more oxidized. b, Lactate as waste. Glycolytic flux from glucose to
pyruvate generates NADH from NAD at the GAPDH reaction. NADH’s electrons can be transported into mitochondria via the malate–aspartate or
glycerol phosphate shuttles, regenerating cytosolic NAD. Alternatively, NADH can be used by LDH to reduce pyruvate to lactate, which is secreted as
waste. c, Lactate as fuel. The reactions are the same, but the direction of LDH flux is reversed. The resulting extra NADH electrons are transported into
mitochondria. GAP, glyceraldehyde 3-phosphate.
energy rich, mammals do not excrete it. Indeed, CO2 is the only
carbonaceous waste that we excrete in substantial quantities. The
full oxidation of dietary carbon to CO2 maximizes the extraction of
usable energy from food. How is this achieved?
The two most abundant circulating carbon metabolites are glu-
cose (5 mM) and lactate (1 mM). Glucose and lactate can be inter-
converted by the processes of glycolysis and gluconeogenesis. One
logical way to coordinate these processes is as follows: (1) most cells
extract energy from carbohydrate by taking up glucose and fully
oxidizing it to CO2; (2) cells facing particularly urgent energy needs
take up extra glucose and release some lactate as waste—in addition,
as shown by Gerty and Cori, fasting muscle releases glycogen stores
as lactate15; and (3) the liver ‘cleans up’ this lactate, reconverting it
to glucose. In this scenario, lactate is valuable only as a substrate for
generating glucose.
The above strategy yields clear expectations regarding mamma-
lian metabolic flux: tissue glucose consumption should far exceed
lactate consumption, and the whole-body lactate production rate
should approximately equal the lactate use by the liver and kidneys
to support gluconeogenesis.
The relevant metabolic fluxes can be measured from two per-
spectives: arterial–venous differences in metabolite concentration
and isotope tracing. Differences in arterial–venous metabolite con-
centrations reveal the net production or consumption of a metabo-
lite across a vascular bed. In some cases, such as the renal artery and
vein, the vascular bed aligns relatively neatly with a single organ
(the kidney). In other cases, such as the femoral artery and vein, the
vascular bed drains multiple tissue types (skin, adipose, bone and
various types of muscle) whose activities may offset one another.
With this caveat, such measurements generally conform to the
above expectations regarding metabolic flux16,17.
Isotope-tracing measurements, however, paint a different pic-
ture. At pseudo–steady state, the total flux of a metabolite from
tissues into the bloodstream is balanced with the total tissue con-
sumption of the metabolite, thereby defining the metabolite’s ‘cir-
culatory turnover flux’. For non-perturbative isotope infusions,
circulatory turnover flux is synonymous with the ‘rate of appear-
ance’, ‘rate of disappearance’ and, in the fasted state, the ‘endogenous
production rate’. It can be measured by infusing an isotope-labelled
metabolite and monitoring its dilution by endogenous production
and the diet. Such measurements have commonly been made since
the 1970s (refs. 18–21). The fasted circulatory turnover flux of lactate
has consistently been shown, in both rodents and humans, to be
approximately twice that of glucose on a molar basis, and thus is
Nature Metabolism | VOL 2 | July 2020 | 566–571 | www.nature.com/natmetab
Perspective
c
Lactate-producing cell Lactate-consuming cell
Glucose Glucose
×2 ×2
GAP Malate– GAP Malate–
aspartate aspartate
GAPDH shuttle GAPDH shuttle
Glycerol
NADH phosphate NADH phosphate
shuttle shuttle
Lactate Pyruvate Lactate
LDH LDH
equivalent on a carbon-atom basis (because two lactates are equal to
one glucose). The straightforward interpretation of these measure-
ments is that pyruvate generated by glycolysis rarely flows within a
cell directly into the tricarboxylic acid (TCA) cycle but instead is
converted to lactate and released into the bloodstream. This process
requires lactate dehydrogenase (LDH) and monocarboxylic trans-
porter (MCT) activity.
Rapid production of circulating lactate must be offset by compa-
rably rapid consumption (Fig. 1c). Recent work has examined the
fate of infused 13C-labelled lactate, finding that it is a major fuel in
the TCA cycle. Specifically, [13C]lactate labels TCA intermediates in
every tissue of the body, even in tumors22,23. With the exception of
the brain, tissue TCA labelling from lactate is typically greater than
that from infused [13C]glucose.
A challenge in interpreting these isotope-tracer studies is that
lactate can be converted into glucose, and glucose can be converted
into lactate. Thus, infusion of either metabolite also labels the
other. The relative contributions of circulating glucose and lactate
to tissue TCA-cycle metabolism can be deconvoluted mathemati-
cally. Such analysis has shown that, in agreement with textbook
knowledge, the brain directly oxidizes glucose as its primary fuel.
Especially in the fasted state, however, the main route through
which glucose labels the TCA cycle in the other major organs is via
circulating lactate22.
How can these observations be reconciled with the arterial–
venous measurements, which show modest net lactate consumption
or production across most vascular beds? One possibility is that tis-
sue pyruvate is rapidly exchanged for circulating lactate, but with
only modest net flux of three-carbon (3C) units. This possibility is
biochemically reasonable, because MCTs exchange one carboxylic
acid for another more rapidly than they catalyse net excretion or
uptake24
The more radical possibility is that, at the cellular level, glucose
uptake may be dissociated from carbohydrate burning, and lactate
may serve as a universal carbohydrate fuel.
Uncoupling of glycolysis and TCA
In the absence of lactate, glycolysis must operate in lockstep with
the TCA cycle, such that every glycolysis-produced NADH and
pyruvate is cleared by mitochondrial metabolism. Correspondingly,
cells would need to break down glucose via glycolysis to generate
energy from carbohydrate. Lactate’s fundamental role is to uncouple
these pathways25 (Fig. 2). Interestingly, pancreatic alpha and beta
cells, whose function is to secrete glucagon and insulin in response
567
Perspective NATure MeTABoLIsm

a b
Traditional Redox buffering

Pyruvate
Glucose Lactate Glucose Lactate MCT
GLUT MCT GLUT MCT

Glucose Glucose
Lactate Lactate
NAD NAD

LDH LDH

NADH NADH
Pyruvate Pyruvate

TCA TCA

Fig. 2 | Redox buffering by circulating lactate and pyruvate. a, Traditional perspective. Glycolytic flux exceeds pyruvate and lactate exchange between
the cell and the circulation. Intracellular metabolic reactions (glycolytic flux and transport of NADH’s electrons into mitochondria) determine the cellular
NADH/NAD ratio and thereby the cellular lactate/pyruvate ratio. b, Redox buffering perspective. Exchange in pyruvate and lactate between cells and the
circulation is more rapid than glycolysis. These MCT-catalysed exchange reactions determine the cellular lactate/pyruvate ratio and thereby the cellular
NADH/NAD ratio. In cases in which excessive NADH begins to build up, net uptake of pyruvate and excretion of lactate alleviates the redox imbalance.
GLUT, glucose transporter.

to circulating glucose levels, lack MCTs and therefore have tight gly-
colysis–TCA coupling26,27. Most mammalian cells, however, express
both LDH and MCTs and therefore can independently run glycoly-
sis and the TCA cycle.
How extensive is such uncoupling? Given the modest net lactate
exchange across major vascular beds, this depends on the extent
of lactate by exchange within vascular beds. Such exchange might
occur between different tissues sharing the same vascular supply or
between cell types within a tissue. For example, in the kidney, lactate
uptake by the gluconeogenic cortex may be offset by lactate produc-
tion by the glycolytic medulla28. Or, within the leg, a subset of highly
glycolytic cells might rapidly ferment circulating glucose to circu-
lating lactate, while other cells consume circulating lactate as their
carbohydrate fuel. For example, adipocytes have been suggested to
be highly glycolytic and to secrete copious lactate29–33.
In agreement with glucose use being relatively restricted, fluoro-
deoxyglucose positron emission tomography (PET) imaging stud-
ies show intense glucose uptake in the brain, tumours and areas of
inflammation, but little uptake in many other parts of the body34.
Although this finding partially reflects PET imaging studies being
conducted in fasted resting individuals, the PET data align with
glucose-transporter expression, which is strongest in the brain and
activated immune cells.
In contrast to the restricted expression of glucose transporters,
which renders glucose uptake a key gating step in metabolism, the
nearly universal expression of MCTs makes lactate freely available
to all cells of the body.
Use of lactate as the primary circulating carbohydrate energy
source advantageously reserves glucose for particularly vital systems
(such as the brain and immune system) and for biochemical func-
tions that cannot be readily achieved by using other substrates (gly-
cogen storage, glycosylation, NADPH and ribose generation by the
pentose-phosphate pathway). By dissociating these processes from
the housekeeping function of aerobic ATP generation from carbo-
hydrate, glucose use can be regulated in tune with more advanced
organismal needs. For example, in lymphocytes, glucose entry is
coordinately regulated with activation and proliferation. Exclusion
of glucose in the quiescent state may help prevent autoimmunity
and cancer35.
In contrast, lactate rapidly exchanges throughout the body. This
advantagenously tends to minimize local lactate build-up. When
lactate does accumulate, this accumulation often reflects underlying
pathology, such as acute inflammation or inadequate perfusion36,37.
Such accumulation can be read out to drive proper physiological
responses, such as inflammation resolution through favouring the
development of regulatory T cells38, a propensity that can backfire
in the case of cancer by suppressing anticancer immune responses39.
Redox robustness
Both lactate and pyruvate circulate, and lactate is approximately 20
times more abundant in the bloodstream. MCTs can transport both
lactate and pyruvate, and one can be exchanged for the other. Once
inside cells, pyruvate and lactate are rapidly interconverted via the
action of LDH. The direction of net LDH flux depends on the reac-
tion quotient (Q) relative to the equilibrium constant (Keq) of LDH,
as shown in the following equation:
Q ¼ ½lactate½NAD=½pyruvate½NADH
with square brackets indicating concentration, and Q > Keq imply-
ing lactate consumption. Both lactate consumption and glycolysis
require NAD as a substrate. Because GAPDH’s Michaelis constant
for NAD is lower than LDH’s, glycolysis has priority for NAD40,41.
On the basis of the LDH reaction approaching equilibrium, the
cellular lactate-to-pyruvate ratio has often been used as a proxy for
the cytosolic NADH-to-NAD ratio42–44. If most cytosolic NADH,
pyruvate and lactate were from glycolysis, then intracellular met-
abolic reactions would indeed control, via NADH, the balance
between cellular lactate and pyruvate (Fig. 2a). Given the rapidity
of the pyruvate–lactate exchange between cells and the circulation,
however, causality may flow in the other direction. Specifically, the
abundance of lactate and pyruvate in the circulation may deter-
mine their intracellular concentrations, which in turn may deter-
mine the cellular NADH-to-NAD ratio. In this case, the MCT–LDH
reaction sequence would function to align every cell’s cytosolic
NAD-to-NADH ratio to the systemic pyruvate-to-lactate ratio,
thus effectively buffering NAD and NADH in each cell against the
whole-body pyruvate–lactate pool (Fig. 2b).

568 Nature Metabolism | VOL 2 | July 2020 | 566–571 | www.nature.com/natmetab

NATure MeTABoLIsm
Glucose
Glycogen
Fig. 3 | Whole-body lactate homeostasis. At the tissue level, lactate exchange with the circulation allows for independent operation of glycolysis and
the TCA cycle. At the organismal level, however, lactate production (largely via glycolysis) and consumption (largely via the TCA cycle) must balance to
maintain lactate homeostasis. Some tissues, such as kidney and muscle, both produce and consume circulating lactate.
Similar redox equilibration can also occur across compartments
of a cell. Mitochondria are notable for lacking MCT transporters on
their inner membranes, thereby excluding lactate, and instead using
mitochondrial pyruvate carriers to import pyruvate. However, per-
oxisomes express MCT2, which may buffer their NAD and NADH
pools with the cytosol45.
Redox buffering is based on cells (or compartments) with
excess NADH taking in pyruvate and excreting lactate (Fig. 2b).
Importantly, whereas glycolysis terminating in lactate is redox
neutral, uptake of pyruvate and excretion of lactate results in a net
dumping of electrons. Physiologically, the kidneys clear lactate elec-
trons, releasing pyruvate and thereby helping to maintain an appro-
priately oxidized circulating lactate-to-pyruvate ratio17.
Direct support for the ability of circulating pyruvate and lac-
tate to control tissue NADH-to-NAD ratio comes from the
Mootha laboratory, which has recently developed an engineered
enzyme that uses molecular oxygen to irreversibly convert circu-
lating lactate to pyruvate. Administration of this enzyme to mice
with lactate and NADH build-up due to genetic mitochondrial
deficiency resulted, as desired, in a more oxidized circulating
lactate-to-pyruvate ratio. Importantly, although the enzyme was
localized to the bloodstream, both the brain and heart showed
a decreased NADH-to-NAD ratio46. Thus, lactate–pyruvate
exchange renders tissue redox maintenance robust by equilibrat-
ing redox status across the organism.
Regulation of lactate homeostasis
Compared with some other important fuel molecules such as fatty
acids, lactate is notable for tight homeostasis of its serum concen-
trations, and elevated serum lactate is a serious medical condition
known as lactic acidosis. How are circulating lactate levels regu-
lated? Lactate’s entry and exit from cells are governed by MCTs
1–4 (Slc16a1, Slc16a7, Slc16a3 and Slc16a4). Both the expression
and activity of these proteins can potentially be regulated to con-
trol lactate localization in the body. MCT flux, however, is fast, and
therefore lactate is typically well mixed between tissues and the cir-
culation. Accordingly, regulation of lactate concentration occurs
substantially at the level of the whole-body lactate pool. Because
lactate is always much more abundant in the circulation than pyru-
vate, lactate homeostasis depends on controlling the total pool size
of these 3C carboxylic acids.
To maintain tight concentration homeostasis, overall production
and consumption of lactate must be synchronized. The main route
of 3C-compound production is glycolysis. The major consumption
route is via the TCA cycle. Thus, whereas lactate decouples glycoly-
Nature Metabolism | VOL 2 | July 2020 | 566–571 | www.nature.com/natmetab
Perspective
Blood lactate
Glycolysis Tissue TCA
CO2
lactate
sis and the TCA cycle at the cellular level, glycolysis and the TCA
cycle must be balanced at the whole-body level (Fig. 3). TCA entry
via pyruvate carboxylase generates a four-carbon compound, which
can be reconverted into 3C compounds via malic enzyme or phos-
phoenolpyruvate carboxykinase47. In contrast, TCA entry via PDH
generates a two-carbon unit in the form of acetyl-CoA, which in
mammals cannot be reconverted into 3C units (Fig. 4). Thus, the
PDH reaction irreversibly clears lactate. Therefore, the whole-body
balance between glycolysis and PDH flux is likely to be the key
determinant of lactate levels.
PDH is a multimeric enzyme whose catalytic activity is regu-
lated by the phosphorylation status of the E1a subunit and by
NADH48,49. High phosphorylation, mediated by pyruvate dehydro-
genase kinases (PDK 1–4), impairs mitochondrial pyruvate clear-
ance and thereby promotes cellular lactate excretion and systemic
3C-compound accumulation. NADH activates PDK and thereby
inhibits PDH, thus contributing to the elevated circulating lactate in
patients with impaired mitochondrial activity or respiration.
Future perspectives
Given that 3C compounds are mainly produced by glycolysis (Fig.
4), mechanisms of lactate homeostasis may substantially overlap
with those for glucose homeostasis. In insulin resistance, circulat-
ing lactate may play a critical role as an energy substrate in cells
that are carbon limited because of deficient insulin-mediated glu-
cose uptake. Whether interindividual differences in lactate handling
contribute to diabetes pathogenesis or robustness to diabetic com-
plications is an important topic for future study.
Control of lactate clearance ties into the well-studied regulatory
biology of PDK. Despite PDK’s importance, manifested by the exis-
tence of four different kinase isozymes, its physiological purpose
remains unclear. One likely role is redox homeostasis, promot-
ing lactate export instead of catabolism when NADH builds up.
Another possibility is that, during starvation, PDK serves to shut
off PDH to preserve 3C units50. Conversion of these 3C units into
glucose would then preserve the availability of glucose for the brain
and immune system.
Given the particularly tight control of circulating lactate levels,
a novel regulatory system for lactate homeostasis is likely to exist.
Lactate can potentially be cleared by urinary excretion in addition
to PDH. Renal lactate loss is typically prevented by urinary reab-
sorption via the sodium/lactate co-transporters Slc5a12 and Slc5A8
(ref. 51). Whether these enzymes are sometimes downregulated to
release lactate is unclear. Circulating lactate can also enter the faeces
and thereby feed the microbiome52. A quantitative understanding
569
Perspective
Glycogen Glucose
Glycolysis makes 3C units
3C (lactate)
PDH clears 3C units
2C (Acetyl-CoA)
4C Citrate
Fig. 4 | Production and consumption of 3C units. At the organismal level,
3C-unit production (largely via glycolysis) and consumption (largely
via PDH) must balance to maintain lactate homeostasis. Bidirectional
connections indicate that the metabolites can interconvert (typically with
energy input, for example, via glycolysis or gluconeogenesis).
of the importance and regulation of microbiome-mediated lactate
clearance merits further investigation.
Major metabolic enzymes and transporters, including glycolytic
enzymes, MCTs, LDH, mitochondrial pyruvate carriers and PDH,
are also potential targets for novel regulatory circuits controlling
lactate homeostasis. Such circuits would presumably involve lactate
sensors such as G-protein-coupled receptor 81 (ref. 53). Given the
role of lactate as a universal fuel, the elucidation of such a system—
for ensuring a beautiful but not overcrowded ‘pool of swans’—has
the potential to reshape understanding of mammalian metabolism
and disease treatment.
Received: 23 April 2020; Accepted: 16 June 2020;
Published online: 20 July 2020
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Perspective
Acknowledgements
S.E. is supported by the Swedish Research Council (2019-00773, 2018-02537), The Knut
and Alice Wallenberg Foundation, Sahlgrenska’s University Hospital (LUA-ALF) and
Novo Nordisk Foundation. J.D.R. is supported by NIH Pioneer award 1DP1DK113643,
Diabetes Research Center grant P30 DK019525 and Pfizer, Inc.
Author contributions
J.R. and S.E. equally conceived the idea, selected content and wrote the manuscript.
Competing interests
J.D.R. is a cofounder and stockholder in VL54 and Raze Therapeutics, and an advisor
and stockholder in Agios Pharmaceuticals, Kadmon Pharmaceuticals, Bantam
Pharmaceuticals, Colorado Research Partners, Rafael Pharmaceuticals and L.E.A.F.
Pharmaceuticals. S.E. declares no competing interests.
Additional information
Correspondence should be addressed to J.D.R. or S.E.
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