Expression and Distribution of Lactate/Monocarboxylate Transporter Isoforms in Pancreatic Islets and the Exocrine Pancreas
Chao Zhao,
Marieangela C. Wilson,
Franz Schuit,
Andrew P. Halestrap, and
Guy A. Rutter
From the Department of Biochemistry (C.Z., M.C.W., A.P.H., G.A.R.),
School of Medical Sciences, University Walk, University of Bristol, Bristol,
U.K; and the Molecular Pharmacology Unit (F.S.), Diabetes Research Centre,
Vrije Universiteit Brussel, Brussels, Belgium.
Address correspondence and reprint requests to Dr. Guy A. Rutter, Department
of Biochemistry, School of Medical Sciences, University Walk, University of
Bristol, Bristol BS8 1TD, U.K. E-mail:
g.a.rutter{at}bris.ac.uk
.
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ABSTRACT
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Transport of lactate across the plasma membrane of pancreatic islet
ß-cells is slow, as described by Sekine et al. (J Biol Chem
269:4895-4902, 1994), which is a feature that may be important for normal
nutrient-induced insulin secretion. Although eight members of the
monocarboxylate transporter (MCT) family have now been identified, the
expression of these isoforms within the exocrine and endocrine pancreas has
not been explored in detail. Using immunocytochemical analysis of pancreatic
sections fixed in situ, we demonstrated three phenomena. First,
immunoreactivity of the commonly expressed lactate transporter isoform MCT1 is
near zero in both
- and ß-cells but is abundant in the pancreatic
acinar cell plasma membrane. No MCT2 or MCT4 was detected in any pancreatic
cell type. Second, Western analysis of purified ß- and
nonß-cell membranes revealed undetectable levels of MCT1 and MCT4.
In derived ß-cell lines, MCT1 was absent from MIN6 cells and present in
low amounts in INS-1 cell membranes and at high levels in RINm5F cells. MCT4
was weakly expressed in MIN6 ß-cells. Third, CD147, an MCT-associated
chaperone protein, which is closely colocalized with MCT1 on acinar cell
membranes, was absent from islet cell membranes. CD147 was also largely absent
from MIN6 and INS-1 cells but abundant in RINm5F cells. Low expression of
MCT1, MCT2, and MCT4 contributes to the enzymatic configuration of
ß-cells, which is poised to ensure glucose oxidation and the generation
of metabolic signals and may also be important for glucose sensing in islet
nonß-cells. MCT overexpression throughout the islet could
contribute to deranged hormone secretion in some forms of type 2 diabetes.
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INTRODUCTION
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Glucose-stimulated insulin secretion involves glycolytic breakdown of the
sugar and its oxidation within mitochondria
(1). This leads to an increase
in the concentration of intracellular free MgATP
(2,3),
causing the closure of ATP-sensitive K+ channels
(4), Ca2+ influx,
and the activation of exocytosis. Well-differentiated ß-cell lines and
purified primary ß-cells are able to oxidize a remarkably high proportion
(>80%) of glucose carbon to CO2 and H2O
(5,6).
We have previously reported that islet ß-cells contain very low levels of
lactate dehydrogenase (LDH) and lactate (monocarboxylate) transporter (MCT)
activity. Recently, eight isoforms of MCT, each predicted to be an integral
membrane protein with 12 well-conserved transmembrane-spanning regions, have
been identified and cloned (7).
MCT1 and MCT4 are closely associated with the monotopic membrane protein CD147
(8,9).
This protein is a widely distributed member of the immunoglobulin superfamily
(10,11)
and appears to act as a chaper-one that is essential for the correct targeting
of MCT1 and MCT4 to the plasma membrane.
The tissue distribution of MCTs 1-4 has been studied quite extensively at
both the protein and mRNA level and is both complex and to some extent species
dependent (7). MCT1 (the only
form in erythrocytes and probably also gut cells) is present in the majority
of tissues, whereas MCT4 predominates in those cells requiring high rates of
lactic acid efflux, such as white muscle fibers and white blood cells
(12). Thus, MCT1 is the major
isoform present in red muscle fibers whereas MCT4 predominates in white fibers
(13). The distribution of MCT2
is more restricted and is expressed in liver, heart, kidney, testis, and the
brain. Expression of MCT2 is also species dependent, particularly in the liver
and heart. In hamsters, MCT2 is the major isoform in the liver and is present
in the heart. In the rat, no MCT2 is found in the heart and MCT1 is present at
higher levels than MCT2 in the liver
(14,15).
In humans, little MCT2 is found in any tissue
(12). MCT3 expression appears
to be exclusive to the basolateral surface of retinal pigment epithelial cells
(7). Distribution of the other
MCT isoforms has only been explored at the mRNA level because no suitable
antibodies are currently available. It is also unknown whether these higher
MCT isoforms transport lactate, because this has only been demonstrated
directly for MCT1-MCT4 (7).
Isoforms 5-8 are more distantly related members of the MCT family
(7). Indeed, we have currently
been unable to demonstrate lactate or pyruvate transport activity for isoforms
5, 6, and 8 after expression of the recombinant proteins (the activity of MCT7
is unexplored). Within the whole pancreas, the only MCT isoforms detected by
Northern analysis are MCT7 and MCT8
(12), but neither the pattern
of expression of the MCT isoforms and CD147 nor their presence at the protein
level has been explored within the endocrine pancreas. Using heterologous
expression in Xenopus oocytes, detailed characterization of the
kinetics and substrate/inhibitor specificity has been performed for MCT1,
MCT2, and MCT4 in which Km values for L-lactate are
respectively 4, 0.7, and 28 mmol/l
(16,17,18).
In our earlier studies, islet ß-cells were reported to express
somewhat lower levels of LDH and lactate transport activities than islet
non-ß-cells, whereas both cell types contained dramatically lower levels
of these activities compared with nonislet tissue, including liver
(5). Subsequent quantification
of LDH and mitochondrial glycerol phosphate dehydrogenase (mGPDH) activity in
islet non-ß-cells (19)
has suggested that the difference in the LDH and mGPDH activities of islet
ß- and non-ß-cells may be smaller than earlier estimates
(5). Stable overexpression of
LDH-A activity perturbs glucose-stimulated insulin secretion in MIN6
ß-cells (20) and
interferes with oxidative glucose metabolism and ATP generation after acute
infection of cells with LDH-Aexpressing adenoviral vectors
(21). Furthermore, increases
in LDH activity in the islets of rodents rendered diabetic by 95%
pancreatectomy (22) are
associated with impaired glucose-stimulated insulin secretion. Finally,
co-overexpression of LDH and MCT activities confers sensitivity to lactate of
insulin secretion in islets
(23).
The present study was undertaken to assess, using immunocytochemistry, the
intraislet expression of LDH and MCT and CD147 activities and to compare this
with the level of these proteins in the exocrine pancreas and in other rat
tissues. The use of in situ fixation of the pancreas, which reduces problems
of degradation of mRNA and protein, has allowed us to compare MCT and CD147
levels simultaneously within the islet and nonendocrine pancreas. The findings
confirm that the common MCT isoforms are essentially absent from islets but
indicate that both MCT1 and CD147 are abundant on the acinar cell plasma
membrane. The role of this pattern of transporter expression in glucose
sensing by islet cells is discussed.
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RESEARCH DESIGN AND METHODS
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Tissue preparation. Male Wistar rats weighing 220-250 g were
supplied by B & K Universals (Bristol, U.K.) and housed in the Bristol
Medical School animal house with free access to standard pellets and water.
The animals were deeply anesthetized by an intraperitoneal injection of sodium
pentobarbital and then perfused via the ascending aorta, first with 150 ml
ice-cold normal saline followed by 300 ml Zambonis fixative solution (4%
paraformaldehyde, picric acid in phosphate-buffered saline [PBS], and PBS 0.1
mol/l, pH 7.4). Pieces of tissue from the pancreas were immediately dissected
out and immersed in the same fixative for 2 h and moved into 30% sucrose
solution overnight before cryostat sectioning. The tissue was embedded in
Bright Cryo-M-Bed (Bright Instrument, Huntingdon, U.K.) and frozen in
isopentane/liquid nitrogen. Cryostat sections were cut at a thickness of 5 or
8 µm and mounted on poly-L-lysinecoated glass slides (BDH, London)
and air-dried for 1 h at room temperature. The sections were used for
immunostaining immediately or stored at -70° C for up to 8 weeks.
Antibodies. Polyclonal anti-peptide COOH-terminal antibodies to
human MCT1 (cross-reacts with MCT1 from most species [M.Z., A.P.H.,
unpublished observations]), Chinese hamster ovary MCT1 (cross-reacts with rat
but not human MCT1) (24),
human MCT4 (cross-reacts with rat MCT4)
(12), rat MCT2
(15), and rat CD147
(9) were raised in rabbits and
affinity purified as described previously.
Crude plasma membrane preparations from liver tissue homogenate and cell
lines were performed as described
(9,25).
Samples were separated by SDS-PAGE and analyzed by Western blotting using the
antibodies described and enhanced chemiluminescence detection
(15,24).
Immunohistochemistry. Tissue sections were rinsed with PBS and
permeabilized with 0.3% Triton X-100, then incubated in 10% swine serum (for
MCTs) or 1% skim milk powder in PBS for 1 h. Incubation of the primary
antibodies was performed at 4°C overnight. Briefly, sections were covered
in a moist chamber with one of the following antibody solutions: rabbit
anti-MCT1 at a dilution of 1:100, anti-MCT2 at 1:100, anti-MCT4 at 1:100,
mouse monoclonal antibody against CD147 at 1:10, guinea pig anti-insulin at
1:500 (Dako), or rabbit anti-glucagon at 1:100 (ICN). The sections were then
rinsed in PBS for 10 min three times and then incubated with fluorescein
isothiocyanate (FITC)-, tetramethyl-rhodamine isothiocyanate (TRITC)-, or
indocarbocyanine (Cy3)- conjugated secondary antibodies against IgG of the
species from which the corresponding primary antibodies were generated. These
were obtained from various suppliers including Sigma, Dako, and Jacksons.
Confocal microscopy. Specific immunoreactivities were revealed by
laser scanning confocal microscopy. Confocal images were acquired using TCS NT
software on an upright Leica IRBE confocal microscope equipped with an
Argron/Krypton laser and using a x 63 oil immersion lens.
Islet cell purification. Purified rat ß- and non-ß-cells
were obtained as described previously
(26). Briefly, pancreatic
islets were collagenase isolated from male Wistar rats. Dissociated islet
cells were flow sorted on the basis of light scatter and FAD+ fluorescence
into ß-cells (purity >90%) and non-ß-cells (70-80%
-cells,
5-10% ß-cells, and 10-15% other cells) using a FAC-Star Plus (Becton
Dickinson, Mountain View, CA) cell sorter. Freshly isolated cells were washed
in PBS, frozen in liquid nitrogen, and stored at -80°C before
immunoblotting.
COS7 cell culture and transfection. Cells were cultured and
transfected with CD147 as described previously
(9).
Statistics. Data are presented as the means ± SE for the
number of observations given in parentheses.
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RESULTS
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Immunolocalization of MCT isoforms in pancreatic sections.
Immunofluorescence confocal microscopy revealed the presence of MCT1 but not
other MCT isoforms in exocrine pancreatic cells, at a level equal to or
greater than that in skeletal muscle
(12). In contrast, within the
islet, neither MCT1 nor other MCT isoforms could be detected in
insulin-containing ß-cells (Fig. 1
AF). Weak reactivity to MCT1 was apparent in the
cytosolic compartment of glucagon-containing
-cells using the anti-rat
polyclonal antibody (Fig. 1 D and
I). This staining, which displayed a punctate
distribution, was also observed with an anti-human MCT1 antibody that
cross-reacts with rat MCT1 (data not shown). Therefore, this signal in
-cells would seem most likely caused by nonspecific staining of an
abundant non-MCT protein present in secretory vesicles.

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FIG. 1. Distribution of MCT1, MCT2, and MCT4 in the pancreas. Confocal
microscopic immunohistochemical images of rat pancreatic islets. A:
Shows the bright field image of an islet. B is the same islet as
A stained with rat MCT1, whereas in C the MCT1 antibody was
preabsorbed with MCT1 peptide against which the antibody was raised.
D is another example of MCT1 staining of a smaller islet. E
and F are serial sections of the same region of the pancreas, stained
with anti-MCT2 and anti-MCT4 antibody, respectively. G to I
are serial consecutive sections of pancreas immunostained for insulin,
glucagon, and MCT1, respectively. The apparent cytosolic staining of glucagon+
cells in slide I was nonspecific (see RESULTS). For other details,
see RESEARCH DESIGN AND METHODS. Scale bar = 50 µm.
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Western analysis of MCT isoforms in purified islets and derived
ß-lines. Western analysis of either total cellular protein with
anti-rat MCT1 antibody or cell membranes with antibodies against MCT1 or MCT4
failed to detect any band at the predicted molecular mass (43 kDa)
(7)
(Fig. 2A). These data
confirm the absence of MCT protein in both islet ß- and non-ß-cells.
Similarly, the highly differentiated and glucose-responsive mouse ß-cell
line, MIN6 (27), did not
express detectable MCT1 immunoreactivity
(Fig. 2B), whereas
weak reactivity at 43 kDa was apparent in this cell line, corresponding to
MCT4 (Fig. 2B).
Another relatively responsive ß-cell line, INS-1
(28), expressed low but
detectable MCT1 reactivity (but not MCT4). Finally, the poorly
glucose-responsive and highly glycolytic RINm5F line
(5,29)
expressed MCT1 at high levels (Fig.
2B). A closely parallel pattern of expression of CD147, a
chaperone for MCT1 and MCT4
(9), was also observed in these
lines with levels increasing in the order MIN6 < INS-1 < RINm5F
(Fig. 2C).

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FIG. 2. Western analysis of MCT and CD147 expression in primary islet -
and ß-cells and derived ß-cell lines. A: MCT1 in
fluorescence-activated cell sorter-purified islet ß- and non-ß-cells
(5 µg total cellular protein) with polyclonal antibodies raised to rat
(rMCT1) or human (hMCT1 and hMCT4) sequences (5 µg membranes). RBL, rat
retinoblastoma cells; He, HeLa cells (human). The band of Mr
60 kDa represents nonspecific binding not removed by preabsorbing the
antibody with peptide. B: MCT1 and MCT4 expression in membranes of
derived ß-cell lines, I, INS-1; M, MIN6; R, RINm5F; or L, rat liver
membranes. Relative intensities of MCT-1 expression (arbitrary units) were L,
230,000; INS-1, 29,000; MIN6, undetectable; RINm5F 125,000; and HeLa, 172,000.
C: CD147/CD147 expression in: F, rat epididymal fat pads; I, INS-1
cells; M, MIN6 cells; R, RINm5F; and He, HeLa cells; Co, untransfected or Co+,
Cos7 cells transfected with cDNA encoding CD147. Note that multiple bands
represent differential glycosylation, which varies between cell types
(9).
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Immunolocalization of CD147 in pancreatic sections. Given the
parallelism between the expression of MCT1 and CD147 in ß-cell lines, we
next examined the expression of the protein in pancreatic sections. CD147
displayed a close spatial colocalization with MCT1 immunoreactivity being
present at highest levels in the plasma membrane of acinar cells
(Fig. 3). The remarkably
similar distribution of these two proteins is demonstrated by the overlay
images of Fig. 3A, B, D, and
E. In contrast, weak cytosolic staining was apparent
throughout the islet (Fig. 3B and
E), though CD147 was essentially absent from the plasma
membrane of all islet cells (observed in both large and small islets;
Fig. 3), and from islet-cell
membranes examined by Western blotting (data not shown). However, some CD147
staining was apparent in the cytosol of all islet cells.

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FIG. 3. Colocalization of MCT1 and CD147 in the pancreas. Two examples of
colocalization of MCT1 and CD147 protein in rat pancreas. A to
C and B to D represent two sections containing
islets ( in AC) of different dimensions. Sections were
incubated with anti-MCT1 (A, D from rabbit) and CD147 (B, E
mouse monoclonal) antibodies and revealed with cy3 and FITC-conjugated
secondary antibodies. C and F are overlays of A and
B, and D and E, respectively. Scale bar = 50
µm.
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DISCUSSION
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We describe here the distribution of MCT isoforms and CD147 within the
pancreas. We show that no MCT isoform known to transport lactate/pyruvate is
expressed at the protein level on the plasma membranes or internal membrane of
any rat islet cell type analyzed in situ. In contrast, MCT1 was expressed
strongly at the plasma membrane of acinar cells, but no staining of
intracellular membranes was apparent. These data argue against a mitochondrial
location of MCT1, contrary to the proposal of others
(30). Indeed, we have not
detected any MCT1 associated with mitochondria in any cell type or in isolated
mitochondrial preparations (M.W., A.P.H., unpublished data). Furthermore, the
plasma membrane preparation used here (Fig.
2) contained mitochondrial membranes because the adenine
nucleotide translocase (ANT), an exclusively inner mitochondrial membrane
protein, could be readily detected using specific anti-ANT antibodies (M.Z.,
A.P.H., unpublished data). Our current findings complement direct measurements
of lactate transport into islet cells
(5), which indicated that rates
of transport are extremely low in both ß- and islet non-ß-cells.
Whether other members of the MCT family are expressed in islet cells remains
to be established because appropriate antibodies are currently not available.
However, if they are present it seems unlikely that they will transport
lactate. Interestingly, low levels of MCT4 were expressed in derived MIN6
cells and MCT1 in INS-1 cells, whereas high levels of MCT1 were present in
RINm5F cells (Fig.
2B). These data are also consistent with direct activity
measurements
(5,20)
and may reflect adaptations of the immortalized cell lines for growth and
division that involve enhanced rates of glycolysis.
Consistent with the low levels of MCT immunoreactivity in both islet
ß- and non-ß-cells, our own in situ immunocytochemical studies
(C.Z., G.A.R, unpublished data) suggest that the difference in mGPDH levels
between islet ß- and non-ß-cells may be smaller than previously
measured (5), probably
reflecting contamination of the non-ß-cell fraction in these studies with
nonendocrine cells. Indeed, more highly purified preparations reveal smaller
differences (
2-fold when expressed per unit mass of protein) between
mGPDH and LDH expression in ß- and in non-ß-cells
(19). Thus, the ratio of
LDH:mGPDH may be similar in ß- and islet non-ß-cells (but
dramatically lower than other cell types)
(5), which is consistent with
the important role of the glycerol phosphate shuttle in these cells.
Supporting this view, LDH immunoreactivity was not significantly different in
islet ß- and non-ß-cells, as observed in the immunocytochemical
studies of Jonas et al. (22).
Furthermore, these workers demonstrated that in a model of diabetes (partial
pancreatectomy), LDH-A was overexpressed thoughout the islet, consistent with
the inhibitory effects of LDH-A overexpression on glucose-stimulated insulin
secretion
(20,21).
All these data fit well with the recent findings that KATP channel
(31) and sulphonyl-urea
receptor-1 immunoreactivity
(32) are present in islet
- and somatostatin-secreting cells, and the demonstration of
tolbutamide and diazoxide-sensitive K+ currents in
-TC
glucagon-secreting cells (33).
Taken together, this would seem to be strong evidence to support the view that
each of these cell types is capable of sensing changes in blood glucose (and
other nutrient) concentrations via metabolic coupling mechanisms involving the
enhanced oxidation of pyruvate derived from glucose. However, the mechanisms
by which the two cell types then respond differently (with either enhanced
[ß-] or diminished [
-] hormone secretion) are unknown.
The importance of low LDH-A levels for glucose-induced insulin secretion in
the ß-cell type has been directly demonstrated
(20,21).
Importantly, overexpression of LDH interferes with mitochondrial metabolism of
glucose and insulin secretion, most profoundly at submaximal but
suprathreshold glucose concentrations
(21). Although not examined
here, it seems possible that MCT overexpression may exert a similar inhibitory
effect on insulin release and could synergize with the effect of increased LDH
levels under some circumstances.
Therefore, a further intriguing question is whether low LDH and MCT levels
are also important for normal glucose-mediated inhibition of secretion in
other islet neuroendocrine cells types (
,
, polypeptide P). If
this is the case, then alterations (increases) in LDH-A and MCT levels in
-cells could potentially contribute to the diabetic phenotype by
decreasing the inhibition of glucagon release by elevated glucose. At the same
time, it is also likely that low levels of LDH-A and MCT, and perhaps CD147,
are important to prevent the inappropriate activation of insulin, glucagon,
and other islet hormones release by lactate
(23).
CD147 and MCT1 in the exocrine pancreas. The striking parallelism in
the level of expression and close subcellular colocalization of CD147 and MCT1
that we report here lends further support to the view that CD147 expression is
important for correct targeting of MCT1 to the plasma membrane
(9). The expression of MCT1 in
acinar cells is expected given the widespread occurrence of this isoform
(7). While MCT2 and MCT4
protein were not detected in acinar cells, we cannot exclude the possibility
that higher MCT isoforms may be present, which is consistent with the presence
of MCT7 and MCT8 mRNA in the pancreas
(34).
Conclusion. Our data indicate that low plasma membrane lactate
transport activity, previously described for purified ß-cells and other
islet cells in transport assays
(5), can be correlated at the
molecular level with the expression of undetectable levels of MCT protein in
these cells. Thus, islet cells appear at present to be unique in mammals in
not expressing the apparently ubiquitous MCT1 isoform present in all other
tissues and cell types so far examined.
Because MCT1 expression is regulated in skeletal muscle during chronic
stimulation (13), it will be
important to show whether changes in MCT expression can also occur in the
islet during altered nutritional regimes or disease states. In particular,
derangement of MCT or CD147 gene expression might contribute to modifications
in insulin secretion in some forms of type 2 diabetes
(23), as previously reported
for LDH activity
(21,22).
Given the large excess of lactate transport activity in most tissues
(7), inhibitors of islet cell
lactate transport, or of MCT gene expression, could provide a novel
therapeutic target for this disease.
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ACKNOWLEDGMENTS
|
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This study was supported by grants from the Medical Research Council U.K.
(MRC) (G.A.R., A.P.H.), Diabetes U.K. (formerly the British Diabetes
Association), the Wellcome Trust, the Biotechnology and Biological Sciences
Research Council, and the European Union (G.A.R.). Work in A.P.H.'s lab was
supported by grants from the MRC, British Heart Foundation, and the Wellcome
Trust.
We thank Xin Fang and Dr. Sally Lawson (Physiology, Bristol) for expert
advice on the preparation of pancreatic sections. We also thank Alan Leard and
Dr. Mark Jepson of the Bristol MRC Imaging Facility for assistance with
imaging experiments.
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FOOTNOTES
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ANT, adenine nucleotide translocase; LDH, lactate dehydrogenase; MCT,
monocarboxylate transporter; mGPDH, mitochondrial glycerol phosphate
dehydrogenase; MRC, Medical Research Council; PBS, phosphate-buffered
saline.
Received for publication August 7, 2000
and accepted in revised form October 11, 2000
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