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Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Address all correspondence and requests for reprints to: Dr. Nils Welsh, Department of Medical Cell Biology, Biomedical Center, P.O. Box 571, S-751 23 Uppsala, Sweden. E-mail: nils.welsh{at}medcellbiol.uu.se
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Introduction |
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The long-term inhibitory effects of FFA on islet ß-cell function were first characterized by Zhou and Grill (7). It was observed that FFA induced inhibitory actions on islet glucose-induced insulin secretion and biosynthesis after a 48-h exposure period. Similar observations were made in an in vivo model in which a lipid emulsion was infused into rats (6). Inhibition of insulin release induced by long term FFA exposure was explained in terms of a glucose-fatty acid cycle (8), i.e. that addition of FFA leads to inhibition of glucose metabolism via a lowered pyruvate dehydrogenase activity (9) and an increased activity of carnitine palmitoyl transferase I (10). Other reports have suggested that inhibitory actions of palmitate are due to build-up of long chain fatty acyl-coenzyme A (acyl-CoA) thioesters, leading to enhanced activity of hexokinase and phosphofructokinase (11, 12), decreased activity of GLUT2 and glucokinase (13), increased oxidation of FFA (14), or activation of the ATP-sensitive K+ channel (15).
It has been well known for some 40 yr now that FFA act as weak
uncouplers of mitochondrial respiration. FFA uncoupling is associated
with a decrease in mitochondrial membrane potential (
), enhanced
state 4 respiration, lower ATP generation, and mitochondrial swelling
(16). Although this effect of FFA has been observed in a wide variety
of cells (17), FFA-induced uncoupling in insulin-producing cells has,
to our knowledge, not yet been addressed. It was therefore the aim of
the present investigation to study the in vitro effects of
FFA on ß-cell mitochondrial function and morphology, and our findings
suggest that palmitate induces partial mitochondrial uncoupling.
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Materials and Methods |
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Islet insulin release and content
For determination of insulin release after culture for 48 h
with or without palmitate, islets were incubated in groups of 10 in 100
µl Krebs-Ringer bicarbonate buffer supplemented with 10
mM HEPES (KRBH). The incubation was carried out at 37 C for
60 min in the presence of 1.7 or 17 mM glucose. Insulin
release to the incubation buffer was determined according to the method
of Heding (14). Islets were then recovered, sonicated in 200 µl
H2O, and subsequently used for DNA and insulin content
determinations (19, 20).
Islet respiration
Islet respiration was measured by the Cartesian diver technique
modified according to the method of Hellerström (21). Islets in
groups of 5–10 were placed in a Cartesian diver, which is a glass
capillary open at the top with an internal volume of approximately 10
µl, and were allowed to respire in ambient air for 60 min at 37 C in
a 10 mM HEPES-buffered Krebs-Ringer solution (pH 7.4) in
which the NaHCO3 had been replaced with an equimolar amount
of NaCl. The buffer contained 1.7 mM glucose. The glucose
concentration was then increased to 17 mM by forcing a side
drop to fuse with the islet-containing buffer, and the incubation was
continued for another 60 min. Throughout the incubation periods the
equilibrium pressure, i.e. an externally applied pressure,
which makes the diver float at a specific point, was measured on a
manometer. Oxygen uptake was expressed as nanoliters of O2
per islet/h.
ATP contents
For determination of ATP contents, islets cultured for 48 h
with or without palmitate were rapidly washed with cold PBS and then
sonicated briefly in 50 µl ice-cold 5% (vol/vol) perchloric acid
containing 2 mM EDTA. The samples were neutralized by
adding 2 M NaOH. After dilution with 0.1 M
Tris-acetate buffer supplemented with 2 mM EDTA, ATP
reagent was added (Bio-Orbit, Turku, Finland), and determinations were
performed using bioluminescence. ATP contents were calculated against
an ATP standard curve.
5,5'6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol-carbocyanine
iodide (JC-1) and dichlorofluoroscein (DCFH) fluorescence
For determination of JC-1 (Molecular Probes, Inc.
Europe, Leiden, The Netherlands) fluorescence, islets in groups of 100
were either precultured for 24 h with or without palmitate or used
directly. In these experiments, palmitate was dissolved in ethanol, and
all groups received the same amount of vehicle (2%, vol/vol). The
islets were then incubated for 20 min at room temperature in the same
culture medium as that used during the preculture with the additional
supplementation of 10 µg/ml JC-1 (solubilized in
N,N-dimethylformamide; 1%, vol/vol). This was
followed by trypsin digestion (0.5%, wt/vol) for 8 min at 37 C. The
dispersed cells were resuspended in KRBH containing 5 mM
glucose, and aliquots (100 µl) of the cell suspensions were applied
to a 96-well plate. After preincubation for 20 min at 37 C, the
fluorescence was determined using a Perkin-Elmer LS-5B
luminescence spectrometer (Norwalk, CT) with excitation wavelength at
490 nm and emission wavelength at 590 nm. In other experiments,
different concentrations of palmitate and carbonyl cyanide
p-(trifluoromethoxy)phenylhydrazone (FCCP) were added, and
the fluorescence was followed for an additional 60–90 min.
Fluorescence was corrected by subtracting parallel blanks and expressed
per µg DNA, which was recovered in each well (20).
For determination of DCFH oxidation, dispersed islet cells were preincubated for 20 min at 37 C in KRBH supplemented with 5 mM glucose and 10 µM DCFH diacetate (DCFH-DA; Acros Organics, Geel, Belgium). The fluorescence was determined (time zero) with excitation wavelength at 505 nm and emission wavelength at 535 nm (22). To some groups 0.2 mM palmitate was added at time zero. Determinations were performed every 20 min during 80 min at 37 C. Fluorescence was corrected by subtracting parallel blanks and expressed per µg DNA, which was recovered in each well.
Nitrite determination
For nitrite determinations, islets were cultured for 24 h
in groups of 50 in 500 µl culture medium with or without 0.32
mM sodium palmitate or with 50 U/ml interleukin-1ß
(provided by Dr. Klaus Bendtzen, Rigshospitalet, Copenhagen, Denmark).
Blanks with or without sodium palmitate were run in parallel. Nitrite
levels in culture medium samples (two, 80 µl each) were determined
with the Greiss reagent as previously described (23).
Electron microscopy
Electron microscopy was essentially performed as previously
described (24). Groups of 100 islets from two different preparations
were cultured with or without 0.32 mM palmitate for 24
h, fixed in 2.5% (vol/vol) glutaraldehyde, and embedded in Epon 812.
Ultrathin sections were contrasted with uranyl acetate and lead
citrate. Electron microscopy was carried out with a Hitachi H-7100
transmission electron microscope at an accelerating voltage of 75 kV.
In the morphometric analysis only islet ß-cells were taken into
account. They were identified by the typical structure of their
secretory granules. Measurements were made on 64 individual ß-cells
from 9 islets not treated with palmitate and 49 individual ß-cells
from 8 islets treated with palmitate. For each individual ß-cell
profile in the tissue sections, the area, the number of mitochondria
and the total mitochondrial section area were determined. All electron
microscopic photographs were analyzed blindly with respect to
treatment.
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Results |
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),
which gives a quantitative estimate of (25). This effect was
observed at 0.1 mM palmitate and reached its maximum at 0.2
mM palmitate (Fig. 1). The uncoupler FCCP promoted a rapid
and pronounced loss of JC-1 fluorescence (Fig. 1). The FCCP effect was
maximal at 1 µg/ml and only partial (
20%) at 0.1 µg/ml (Fig. 2). Culture for 24 h in the presence
of 0.2 mM palmitate induced a 24% decrease in JC-1
fluorescence in the presence of 28 mM glucose (Fig. 3). At 2.8 mM glucose,
however, there was only a nonsignificant trend for lower JC-1
fluorescence in response to palmitate.
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). Islets cultured with palmitate,
however, did not respond to an increased glucose concentration (Table 1). Indeed, the insulin release from islets cultured at 11 and 28
mM glucose with palmitate was significantly lower than that
of corresponding control islets. There were no significant differences
between the different groups at 1.7 mM glucose. The DNA
contents of islets cultured for 48 h in the presence of palmitate
and at different glucose concentrations were similar to those of islets
cultured without palmitate (results not shown). The insulin contents of
control islets cultured at 2.8, 11, and 28 mM glucose were
917 ± 65, 1217 ± 170, and 1516 ± 278 ng/10 islets,
respectively. Corresponding values for palmitate-cultured islets were
614 ± 181, 742 ± 144, and 670 ± 142 ng/10 islets
(n = 5–7). Thus, islets cultured with palmitate contained less
insulin than corresponding control islets after culture at 11.1 and 28
mM glucose (P < 0.01 at 11 mM
glucose and P < 0.05 at 28 mM glucose, by
Student’s paired t test). There was, however, no
significant decrease after culture at 2.8 mM glucose.
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). Islets cultured in the presence of
palmitate did not respond to KIC or glucose with increased insulin
release. However, there was a small increase in the insulin release in
response to KCl in the palmitate-cultured islets.
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contributes to the loss of glucose-sensitive insulin release, we
performed short term insulin release experiments in the presence of 0.1
µg/ml FCCP, a concentration that decreased by approximately
20%. It was found that the insulin release from control islets was
132 ± 22 ng/µg DNA at 2.8 mM glucose and 572
± 78 ng/µg DNA at 28 mM glucose (n = 8). The
corresponding results for islets incubated in the presence of FCCP were
119 ± 25 and 392 ± 70 ng insulin/µg DNA, respectively
(n = 8). Thus, FCCP induced a 31% decrease in the glucose-induced
insulin release (P < 0.05, by Student’s paired
t test).
Effects of palmitate on islet ATP contents and oxygen uptake
High glucose culture induced a slight increase in ATP in control
islets, an effect that was not seen in palmitate cultured islets (Table 3). Indeed, the ATP content of palmitate
islets cultured at 28 mM glucose was significantly lower
than that of corresponding control islets (Table 3). In 11 and 2.8
mM glucose-cultured islets, there was a slight trend of
lower and higher ATP contents in response to palmitate, respectively
(Table 3).
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). The islet oxygen uptake at 1.7
mM glucose was markedly higher in palmitate-cultured islets
than in control islets (Table 3). Addition of a high glucose
concentration did not further increase the oxygen consumption rate of
the palmitate-cultured islets (Table 3).
Effects of palmitate on islet cell reactive oxygen species (ROS)
and nitric oxide (NO) generation
DCFH-DA produces a fluorescent signal after intracellular
oxidation by ROS such as hydrogen peroxide and the hydroxyl radical.
The generation of ROS was higher in islet cells exposed to palmitate
for 24 h than in corresponding controls (Fig. 3). The acute
addition of palmitate to control or palmitate-cultured islets did not
enhance ROS production (Fig. 3). Islets exposed to palmitate for
24 h did not produce more nitrite, which is the stable end product
of NO, than controls (0.12 ± 0.08 pmol nitrite/islet·h for
controls and 0.18 ± 0.06 pmol nitrite/islet·h for
palmitate-exposed islets; n = 6). However, increased nitrite
production was observed in response to interleukin-1ß (0.64 ±
0.11 pmol nitrite/islet·h; P < 0.01 vs.
controls, by Student’s paired t test), which is a well
known activator of iNOS in rat islet cells (21).
Effects of palmitate on ß-cell mitochondrial morphology
The ultrastructural analysis showed a normal mitochondrial
morphology of ß-cells in both control and palmitate-treated islets.
No signs of disrupted mitochondrial cristae or other disturbances were
seen. The area of the individual ß-cell profiles in the tissue
sections was 31.6 ± 2.2 µm2 in control islets and
36.2 ± 2.1 µm2 in islets exposed to palmitate
(P > 0.05), which indicates that there was no
significant difference in the size and form of the cells between the
two experimental groups. The total mitochondrial section area in the
individual ß-cell profiles was 1.6 ± 0.2 µm2 in
islets incubated without palmitate and 2.1 ± 0.2
µm2 in islets incubated with palmitate (P
> 0.05). The frequency distribution for this area showed for both
groups no significant deviation from the normal Gaussian distribution,
and no specific subpopulation of ß-cells with diverging mitochondrial
content was found. The number of mitochondria per individual ß-cell
profile was 14.9 ± 1.4 in control and 16.2 ± 1.5 in
palmitate-treated islets (P > 0.05). From the primary
measurements, the average section area per mitochondrium was 0.104
± 0.003 µm2 in the absence and 0.134 ± 0.007
µm2 in the presence of palmitate (P <
0.001, by Student’s unpaired t test). Thus, the section
area was 29% greater in the ß-cells exposed to palmitate. Assuming a
spherical shape of the mitochondria, this would correspond to a 46%
greater mitochondrial volume.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and increased mitochondrial volume, all signs typical of
uncoupling (16). Somewhat unexpectedly, there was only a weak trend of
lower ATP contents after culture at 11 mM glucose. However,
as we did not determine ADP and AMP levels, it is possible that a
palmitate-induced lowering of ATP was partially counteracted by an
increase in the total ATP-ADP-AMP pool. Interestingly, uncoupling was
not observed in short term experiments, which is in line with previous
findings showing that ß-cell function is initially stimulated by
exposure to FFA (6). Stimulation of ß-cell function by FFA has among
other explanations been ascribed to the oxidation of FFA leading to
increased generation of ATP (26). Indeed, we presently observed a
modest increase in in response to an acute palmitate challenge.
This dual role of FFA as both an uncoupler and a substrate for
mitochondrial oxidation has long confounded investigations dealing with
FFA-induced uncoupling. However, in a recent study (27), a
nonmetabolizable FFA was used to demonstrate that uncoupling occurs in
liver cells independently of its mitochondrial oxidation. The opposite
situation can be achieved by using a short chain FFA, such as
octanoate, which is known not to induce uncoupling. Long-term
supplementation of octanoate to insulin-producing cells potentiates,
rather than inhibits, glucose-stimulated insulin release (28). In line
with this, our results with rat islet cells suggest that palmitate acts
as an uncoupler also in the insulin-producing cell and that this effect
predominates over the nutrient effect when the FFA is present for
24–48 h. Although the palmitate-induced decrease in was modest,
it is likely that it contributes to the loss of insulin release, as a
similar decrease in induced by FCCP affected the glucose-induced
insulin release negatively. Thus, it is probable that FFA-induced
uncoupling accounts at least in part for the loss of glucose-sensitive
insulin release. Other sites at which FFA and their CoA esters could interfere with glucose-induced insulin release are at the level of glucose phosphorylation and the ATP-sensitive K+ channel (13, 15). The present findings that the glucokinase-independent nutrient KIC did not stimulate insulin release in palmitate-cultured islets support the idea that mitochondrial events contribute to the poor insulin release of these cells. Moreover, it is possible to interpret the weak response to KCl to indicate that the secretory defect could involve an enhanced opening of the ATP-sensitive K+ channel, either by a lowering of the ATP/ADP ratio or by a direct effect of long chain acyl-CoA on the channel. The insulin release data are, however, not easily interpreted, because the increased basal insulin release of the palmitate-cultured islets could have masked the effects of KIC and KCl. In addition, it is not clear whether the high basal release of insulin is due to the increased hexokinase/glucokinase ratio or to passive leakage of insulin as a result of the beginning of palmitate-induced lipotoxicity.
FFA are thought to act as protonophores, which move from the outer to the inner lipid layer of the inner mitochondrial membrane in the protonized form and flip-flop back in the anionic form, leading to acidification of the matrix and loss of membrane potential (16). Flip-flopping of long chain FFA, but not of short chain FFA, occurs spontaneously when the fatty acid is protonized, but not when it is unprotonized (29). Thus, FFA will not affect conductance over artificial phospholipid bilayers that lack membrane proteins, as specific proteins are required for the uniport of amphiphilic anions. It has been demonstrated that at least four proteins facilitate the unilateral transport of the anionic fatty acid, namely the mammalian uncoupling protein (UCP) (30), the potato and tomato plant uncoupling mitochondrial protein (31), the ATP/ADP translocator (32), and the glutamate/aspartate transporter (33). Elegant studies have demonstrated that the presence of these proteins in lipid bilayers leads to uptake of amphiphilic anions, and that if the substrate (FFA) can associate with H+ at physiological pH, a proton flux is created, whereas with dissociated substrates (long chain alkylsulfonates) no proton flux is induced (30).
It is not clear which carrier translocates palmitate across the
mitochondrial inner membrane in the insulin-producing cell. One
possible candidate is the ATP/ADP translocator, which is differentially
expressed in ß-cells in response to different ß-cell toxins and
metabolic stimuli (34). A second possibility is the mammalian UCP-2,
which is also expressed in pancreatic islets (35). We have presently
observed that acute addition of palmitate (<2 h) does not induce
uncoupling. This might indicate that a gradual build-up of FFA, fatty
acyl-CoA thioesters, and triglycerides (36) leads to an altered gene
expression, which precedes the uncoupling effect. Indeed, FFA have
recently been shown to increase the expression of UCP-2 messenger RNA
in islet cells (37). Therefore, it is tempting to speculate that
palmitate-induced gene expression and uncoupling occur to decrease
intracellular stores of triglycerides. Interestingly, it has recently
been demonstrated that fatty acyl-CoA thioesters are ligands of the
hepatic nuclear factor-4
and that specific fatty acids are ligands
of peroxisome proliferator-activated receptor- (38, 39). These
transcription factors are known to control the expression of genes that
code for several metabolic enzymes (39, 40). Thus, it is possible that
prolonged exposure to high levels of FFA promotes hepatic nuclear
factor-4 or peroxisome proliferator-activated receptor-
activation and thereby alters gene transcription of metabolic enzymes,
possibly UCP-2, leading to uncoupling. This hypothesis could also
explain why a decrease in ATP contents and was only observed
after culture at 28 mM glucose. Hypothetically, the
combination of high glucose and palmitate might synergize in the
induction of UCPs, because glucose, by increasing malonyl-CoA contents
(41), slows down FFA oxidation and thereby increases cellular contents
of fatty acyl-CoA thioester and triglycerides.
It appears that FFA-induced regulated uncoupling plays an important role in processes such as ripening of fruit (31), heat production in brown fat and skeletal muscle (42), and enhanced hydrolysis and oxidation of lipids in white fat (35). Our findings suggest that the insulin-producing cell also responds to FFA by uncoupling. Whether this is a physiological response with the purpose of decreasing insulin release or only a way to diminish intracellular stores of triglycerides remains to be established. However, it is easily envisaged that FFA-induced ß-cell uncoupling in vivo would worsen the condition of a type 2 diabetic patient. Moreover, if the insulin-producing cell is exposed to high levels of both FFA and glucose for prolonged periods of time, it is conceivable that ROS-induced damage is inflicted. It is known that state 4 respiration is associated with enhanced ROS production (43), which is in line with our present findings. It is also noteworthy that insulin-producing cells have a low antioxidative capacity (44), which would predispose them to damage induced by prolonged regulated uncoupling.
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Acknowledgments |
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Footnotes |
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Received November 5, 1998.
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References |
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