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Departamento de Planejamento Alimentar e Nutrição, Faculdade de Engenharia de Alimentos and * Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • fructose • insulin receptor • insulin receptor substrate-1 • phosphatidylinositol 3-kinase • phosphotyrosine phosphatase • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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, Rosen 1987
). The insulin receptor
(IR)3
ß-subunit, which contains an intrinsic tyrosine kinase, undergoes
tyrosyl autophosphorylation and is activated in response to insulin
binding to the extracellular 
-subunit (Kasuga et al. 1982
). Subsequent steps in insulin signal transduction are
mediated via the phosphorylation of specific intracellular proteins,
including insulin receptor substrate-1 (IRS-1) (Sun et al. 1991
). In peptide motifs with the sequence Tyr-Met-x-Met (YMXM)
or Tyr-x-x-Met (YXXM), tyrosine phosphorylated IRS-1 serves as a
docking protein that interacts with signaling proteins containing
src homology-2 (SH2) domains, including the 85-kDa subunit
of phosphatidylinositol 3-kinase (PI 3-kinase), phosphotyrosine
phosphatase (SHP2) and other SH2-containing proteins (White 1997
).
An impairment of insulin action (insulin resistance) is involved
in many diseases, including noninsulin-dependent diabetes, obesity,
hypertension and cardiovascular disease (O’Doherty et al. 1997
). The rats fed a high fructose diet provide an animal
model of insulin resistance associated with hyperinsulinemia,
hypertriglyceridemia (Sleder et al. 1980
, Tobey et al. 1982
, Zavaroni et al. 1980
and 1982
) and
hypertension (Thorburn et al. 1989
). Although fructose
in the diet alters the activity of several enzymes and regulates
hepatic carbohydrate metabolism, leading to hepatic insulin resistance
(Blakely et al. 1981
, Tuovinen and Bender 1975
), the mechanisms by which an excess of fructose produces
these effects are unknown. The phosphorylation of the IR and IRS-1, as
well as their association with PI 3-kinase and SHP2 "in vivo," has
not been examined in insulin resistance induced by a high fructose
diet. In this study, we investigated the levels of insulin-induced
IR and IRS-1 tyrosine phosphorylation and the association of the latter
with PI 3-kinase and SHP2 in the liver and muscle of fructose-fed
rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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The reagents for SDS-PAGE and immunoblotting were from Bio-Rad (Richmond, CA). Tris, phenylmethylsulfonylfluoride (PSMF), aprotinin, dithiothreitol (DTT), Triton X-100, Tween 20 and glycerol were from Sigma Chemical (St. Louis, MO). Protein A-Sepharose 6 MB was from Pharmacia (Uppsala, Sweden), [125I]protein A was from Amersham (Aylesbury, UK) and nitrocellulose paper (Hybond ECL, 0.45 µm) was from Schleicher & Schuell (Keene, NH). Human recombinant insulin (Humulin R) was from Biobrás (Belo Horizonte, Brazil) and sodium thiopental was from Cristália (Itapira, Brazil). Antibodies against phosphotyrosine, IR, IRS-1 and SHP2 were from Santa Cruz Technology (Santa Cruz, CA), and antibodies against the p85 subunit of PI 3-kinase were from Upstate Biotechnology (Lake Placid, NY). The fructose was kindly provided by Vepê Indústria Alimentícia Ltda (São Bernardo dos Campos, Brazil)
General protocol.
Male Wistar-Hannover rats (~120 g) from the University’s Central
Animal Breeding Center were randomly distributed into two diet groups
(control and high fructose) for the subsequent 28 d. The control
diet was a nonpurified diet (Nuvilab–Nuvital, Curitiba, Brazil)
containing cornstarch (527 g/kg diet), corn oil (35 g/kg diet), beef
and fish flours (220 g/kg diet), sodium (3 g/kg diet) and potassium (10
g/kg diet). The high fructose semipurified diet contained fructose (624
g/kg diet), soybean oil (50 g/kg diet), casein (223 g/kg diet), sodium
(1.0 g/kg diet) and potassium (3.6 g/kg diet). The fiber and mineral
and vitamin mixtures used in the experimental diets met the criteria
specified by the AIN (Reeves et al. 1993
). The rats had
free access to food and tap water, were maintained under standard
conditions (20–22°C and a 12-h light:dark cycle) and were weighed
weekly to record their body weight gain. Different groups of rats were
used for tissue sampling and the biochemical assays. The experiments
were approved by the Faculty’s Committee for Animal Experimentation
and the general guidelines established by the Declaration of Helsinki (1964) for laboratory animals were followed throughout the study.
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Methods |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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Control and fructose-fed rats in the fed state were anesthetized intraperitoneally (i.p.) with sodium thiopental (80 mg/kg body weight) and used as soon as they were fully anesthetized (loss of pedal and corneal reflexes). The abdominal cavity was opened, the portal vein exposed, and 10-5 mol/L insulin was injected. Within 30 s, the liver sample was removed, minced coarsely and homogenized immediately in 10 vol of solubilization buffer (10 mL/L Triton-X 100, 100 mmol/L Tris, pH 7.4, 100 mmol/L sodium pyrophosphate, 100 mmol/L sodium fluoride, 10 mmol/L EDTA, 10 mmol/L sodium vanadate, 2 mmol/L PSMF and 0.1 g of aprotinin/L) at 4°C, using a Polytron PTA 20S generator (model PT 10/35, Brinkmann Instruments, Westbury, NY) operated at maximum speed for 20 s.
Approximately 90 s after the insulin injection, hindlimb muscle samples were excised and homogenized as described above. The tissue extracts were centrifuged at 16,000 x g at 4°C for 20 min to remove insoluble material and the supernatants were used in immunoprecipitation experiments.
Protein analysis by immunoblotting.
For immunoprecipitations, the supernatants were incubated with
antibodies against IR or IRS-1 at 4°C overnight, followed by the
addition of protein A-Sepharose 6 MB. The immunoprecipitated
proteins were treated with Laemmli buffer (Laemmli 1970
)
containing 100 mmol/L DTT, heated in a boiling water bath for 4 min and
subjected to SDS-PAGE (6% bis-acrylamide) in a Bio-Rad minigel
apparatus (Mini-Protean, Bio-Rad). The electrotransfer of proteins from
the gels to nitrocellulose membranes was performed for 90 min at 120 V
(constant) in a Bio-Rad miniature transfer apparatus (Mini-Protean)
as described by Towbin et al. (1979)
, but with 0.02%
SDS added to the transfer buffer to enhance the elution of
high-molecular-mass proteins. Nonspecific protein binding to the
nitrocellulose was reduced by preincubating the filter for 2 h at
22°C in blocking buffer (50 g/L nonfat dry milk, 10 mmol/L Tris, 150
mmol/L NaCl and 0.5 mL/L Tween 20). The nitrocellulose blots were
incubated for 4 h at 22°C with antibodies against
phosphotyrosine, IR, IRS-1, the p85 subunit of PI 3-kinase or SHP2
diluted in blocking buffer (30 g/L nonfat dry milk, 10 mmol/L Tris, 150
mmol/L NaCl and 0.02% Tween 20) followed by washing for 30 min in
blocking buffer without milk. The blots were then incubated with 2
µCi of [125I]protein A (1.11 TBq/g) in
10 mL of blocking buffer (10 g/L nonfat dry milk) for 1 h at
22°C and washed again as described above. [125I]Protein
A bound to the antibodies was detected by autoradiography using
preflashed Kodak XAR film (Eastman Kodak, Rochester, NY) with Cronex
Lightning Plus intensifying screens (DuPont, Wilmington, DE) at
-80°C for 12–48 h. Band intensities were quantitated by optical
densitometry of the developed autoradiographs.
Other assays.
Serum triacylglycerol, cholesterol and insulin concentrations were determined in 9-wk-old fructose-fed and control rats after 4 wk of diet treatment. The rats were deprived of food for 6 h and then anesthetized with sodium thiopental (80 mg/kg body weight, i.p.) after which blood samples were collected by cardiac puncture. Serum triacylglycerol and cholesterol concentrations were determined by the glycerol phosphate oxidase and cholesterol oxidase methods, respectively, using commercial kits (Labtest Diagnóstica, Lagoa Santa, Brazil), and serum insulin was determined by double-antibody RIA using a rat-specific kit (Diagnostic Products, Los Angeles, CA).
The effect of fructose on the ability of insulin to stimulate glucose
disposal was estimated by the intravenous insulin tolerance test (ITT).
The ITT was determined in control and fructose-fed rats after14 h
of food deprivation. The rats were anesthetized with thiopental (80
mg/kg body weight, i.p.); tail blood samples were drawn before insulin
(10-5 mol/L) injection (0 or basal) and at 4, 8, 12 and 16
min after hormone administration. The blood samples collected before
insulin infusion were used to determine the basal glucose
concentrations. Serum glucose concentrations were determined by the
glucose oxidase method using a commercial kit (Labtest
Diagnóstica). The rate constant for plasma glucose disappearance
(Kitt) was calculated using the formula
0.693/t1/2. The plasma glucose t1/2 was
calculated by the slope of the least-squares analysis of the plasma
glucose concentrations during the linear decay phase (Bonora et al. 1989
).
Statistical analysis.
The results are presented as means ± SEM for the number of rats (n) per experimental condition. The experiments were always performed by analyzing samples from fructose-fed rats in parallel with a control group. Student’s t test for unpaired analyses was used for comparisons. The level of significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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After 28 d of treatment, the body weights did not differ between
groups. The food intake was 20 ± 2 g/d for rats fed the high
fructose diet and 23 ± 1.5 g/d for those fed the control diet.
Serum triacylglycerol concentrations were significantly higher in the
fructose group than in the controls (Table 1
). The basal serum glucose, cholesterol and insulin concentrations did
not differ between groups after 4 wk of diet treatment. The glucose
disappearance rate (Kitt) during the
ITT was significantly lower in fructose-fed rats than in control
rats, demonstrating a moderate state of insulin resistance.
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There were no differences in the insulin receptor and IRS-1 protein
levels (Fig. 1A, E
) in the liver of control and fructose-fed rats, as determined by
immunoblotting with anti-IR and anti-IRS-1 antibodies. However,
after stimulation with insulin, samples previously immunoprecipitated
with anti-IR antibody and immunoblotted with antiphosphotyrosine
(anti-PY) antibody showed IR autophosphorylation that was reduced to 71
± 2% of the control values (P < 0.05) in
fructose-fed rats (Fig. 1C
).
|
), the
insulin-induced IRS-1 phosphorylation in the fructose-fed group
was reduced to 70 ± 6% (P < 0.05) of the
control group value.
After stimulation with insulin, the intensity of the band with
the expected molecular weight of the regulatory subunit of PI 3-kinase
(85 kDa) was greater in anti-IRS-1 antibody immunoprecipitates of the
liver samples from both groups of rats compared with the basal bands.
This observation was consistent with a stable association between IRS-1
and PI 3-kinase. However, comparison of the bands stimulated by insulin
revealed that the association between IRS-1 and PI 3-kinase was
slightly reduced (84 ± 3% of control; P < 0.05)
in the liver of fructose-fed rats compared with the control group
(Fig. 1I
).
When the same blots containing liver samples previously
immunoprecipitated with anti-IRS-1 antibody were incubated subsequently
with antibodies directed against SHP2 (Fig. 1L
), an
immunoreactive band was seen in the basal state of control and
fructose-fed rats. The intensity of this band increased after
insulin stimulation, indicating a stable association of IRS-1 with SHP2
in both groups of rats. However, comparison of the
insulin-stimulated bands revealed that the amount of SHP2
associated with IRS-1 in the liver of fructose-fed rats was 79
± 5% that of the controls (P < 0.05).
Tyrosine phosphorylation of IR and IRS-1, and IRS-1 association with PI 3-kinase or SHP2 in skeletal muscle of fructose-fed rats.
As in liver, the fructose diet did not affect the IR and IRS-1 protein
levels in rat skeletal muscle (Fig. 1B, F
). However, in
contrast to liver, stimulation with insulin did not alter the extent of
phosphorylation of the IR in the fructose-fed rats compared with
the control group (Fig. 1D
). Insulin-induced IRS-1
phosphorylation in fructose-fed rats was reduced to 76 ± 5%
(P < 0.05) of the control group (Fig. 1H
).
As expected, in both groups, the 85-kDa subunit of PI 3-kinase was
present in the IRS-1 immunoprecipitates after exposure to insulin. A
comparison of the bands revealed a significant reduction in the
fructose group to 84 ± 4% (P < 0.05) of the
control rats (Fig. 1J
).
When the blots from these experiments were incubated with antibody
directed against SHP2, immunoreactivity was detected in the basal state
of both groups. After insulin stimulation, the intensity of this 66-kDa
band increased in both groups of rats. However, comparison of the bands
stimulated by insulin revealed that the amounts of SHP2 associated with
IRS-1 did not differ in the muscle of both groups (Fig. 1M
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSMethodsRESULTSDISCUSSIONREFERENCES |
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, Iimura et al. 1995
,
Thorburn et al. 1989
, Tobey et al. 1982
,
Zavaroni et al. 1980
and 1982
). Our results showed a
state of moderate insulin resistance in the fructose-fed rats, as
demonstrated by the reduced glucose disappearance rate after insulin
infusion and the greater serum triacylglycerol concentration. The
discrepancies between the metabolic serum glucose and insulin
concentrations in our study, compared with previous reports
(Sleder et al. 1980
, Tobey et al. 1982
),
may be related to the duration of the fructose feeding and the lipid
content of the diets (Sleder et al. 1980
,
Zavaroni et al. 1982
).
Despite the normal number of insulin receptors in the liver and muscle
of fructose-fed rats, there was a 29% reduction in insulin
receptor autophosphorylation in the liver after stimulation with
insulin "in vivo." The decrease observed here may be of biological
importance because a reduction in receptor phosphorylation has been
correlated with insulin resistance in different animal models
(Carvalho et al. 1996
, Saad et al. 1993
and 1997
). Our results differed from those of Deutsch et al. (1993)
, who reported no change in insulin receptor kinase
activity in fructose-fed rats. In that study, the insulin receptors
were purified from liver samples and the kinase assay was performed
"in vitro" using an exogenous phosphoacceptor (Shepherd et al. 1998
). This difference likely reflected the amount and mode
of feeding, as well as variations in assay conditions.
There was a significant reduction in the level of hepatic and muscle
IRS-1 tyrosine phosphorylation, followed by a reduction in IRS-1/PI
3-kinase association in liver and muscle. In previous studies of
fructose-fed rats, a reduced ability of insulin to suppress hepatic
glucose production has been implicated as one of the elements of
insulin resistance (Thorburn et al. 1989
, Tobey et al. 1982
). The IRS-1/PI 3-kinase association induced by
insulin is necessary, and in some cases sufficient to elicit many of
the insulin effects on glucose and lipid metabolism. The lipid products
of PI 3-kinase act as both membrane anchors and allosteric regulators,
serving to locate and activate downstream enzymes and their protein
substrates (Shepherd et al. 1998
). Glucose 6-phosphatase
is a key enzyme of glucose homeostasis because it catalyzes the
ultimate reaction of both glycogenolysis and gluconeogenesis. Insulin
may regulate this enzyme through competitive inhibition of the
microsomal glucose-6-phosphatase by phosphatidylinositol
3,4,5-trisphosphate (PIP3), the main lipid
product of PI 3-kinase (Mithieux et al. 1998
). As shown
previously, rats fed a high fructose diet for 4 or 12 wk had increased
liver glucose-6-phosphatase levels (Tuovinen and Bender 1975
). Phosphoenolpyruvate carboxykinase (PEPCK) is another
regulatory enzyme in gluconeogenesis. Inhibitors of PI 3-kinase block
the effects of insulin on PEPCK gene transcription in liver cells
(Sutherland et al. 1995
), suggesting that the control of
PEPCK by insulin is mediated by PI 3-kinase. PEPCK activity is greater
in animals fed high fructose diets (Blakely et al. 1981
). Together with our results, these findings suggest that a
reduction in the IRS-1/PI 3-kinase association in the liver of rats fed
a high fructose diet can reduce the effects of insulin on
glucose-6-phosphatase activities and PEPCK expression. In addition, a
correlation between PI 3-kinase activity and glycogen metabolism has
been described (Van Weeren et al. 1998
). Indeed, a
reduction in the hepatic glycogen concentration has been reported in
this model (Rawana et al. 1993
, Thorburn et al. 1989
). Glycogen synthase 3-kinase (GS3K) is an enzyme that
regulates glycogen synthesis through the inactivation of glycogen
synthase by phosphorylation. One of the downstream effectors of
PIP3 lipid signaling is the serine-threonine protein
kinase B (PKB or Akt) (Shepherd et al. 1998
). PKB
activation is necessary and sufficient for insulin-induced GS3K
inactivation (Van Weeren et al. 1998
). Thus, the
reduction in IRS-1/PI 3-kinase association in the liver of
fructose-fed rats may have a role in their insulin resistance.
Regulation of the blood glucose concentration is one of the most
important physiologic functions of insulin. An important aspect of this
process is the ability of insulin to stimulate the translocation of
GLUT4 from an intracellular pool to the plasma membrane, thus
increasing the rate of glucose uptake in insulin-responsive
tissues, including muscle and adipose tissue (Gould and Holman 1993
). Although the molecular mechanism that regulates the
intracellular trafficking of GLUT4-containing vesicles is not yet
completely known, several effector molecules have recently been
identified, including the well-documented targeting and/or
activation of PI 3-kinase involved in GLUT4 translocation
(Shepherd et al. 1998
). In addition to the reduced
glucose disappearance rate (Kitt), the
association of IRS-1/PI 3-kinase in muscle samples was reduced in rats
fed a high fructose diet. These observations suggest that there are
probably alterations in the PI 3-kinase–dependent pathways for glucose
transport translocation.
IRS-1 contains >30 potential serine/threonine phosphorylation sites in
motifs recognized by various kinases such as serine-threonine
protein kinase C (PKC), mitogen activating protein kinases, and cyclic
AMP- and cyclic GMP-dependent protein kinases (Fea and Roth 1997
, Mothe and Obberghen 1996
, Sun et al. 1991
). The phosphorylation of IRS-1 on serine/threonine
residues has an inhibitory effect on insulin signaling. The enhanced
synthesis of triacylglycerol observed in rats fed a high fructose diet
is associated with an increase in 1,2-sn-diacylglycerol and
an increased expression of one isoenzyme of PKC in these rats
(Donnelly et al. 1994
). Thus, an increase in PKC
activity may play an important role in altering the phosphorylation
level of the IRS-1.
As with the activation of PI 3-kinase, the association of SHP2 with
IRS-1 may activate this phosphatase (Ugi et al. 1996
).
SHP2 may modulate postreceptor signaling by dephosphorylating the
phosphotyrosyl forms of cellular proteins that are substrates for the
insulin receptor (White and Kahn 1994
). Recent data
suggest that SHP2 plays a role in insulin-stimulated mitogenesis
and also indicate that this phosphatase is necessary for the
insulin-stimulated expression of GLUT1 (Hausdorff et al. 1995
). SHP2 can also dephosphorylate IRS-1 (Kuhné et al. 1994
, Yamauchi et al. 1995
), although
this has not been observed uniformly (Milarski and Saltiel 1994
, Noguchi et al. 1996
). Our results showed
that the association of IRS-1/SHP2 after insulin stimulation was
reduced in the liver of fructose-fed rats, suggesting that an
alteration in this association does not account for the reduction in
IRS-1 phosphorylation in these rats.
In summary, a reduction in the phosphorylation of IRS-1 in the liver and muscle of fructose-fed rats led to a reduction in IRS-1/PI 3-kinase association. These changes may help to explain some aspects of insulin resistance in this animal model.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DTT, dithiothreitol; GS3K, glycogen synthase 3-kinase; i.p., intraperitoneal; IR, insulin receptor; IRS-1, insulin receptor substrate-1; ITT, insulin tolerance test; PEPCK, phosphoenolpyruvate carboxykinase; PI 3-kinase, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-triphosphate; PKB, serine-threonine kinase B; PKC, serine-threonine kinase C; PSMF, phenylmethylsylfonylfluoride; SH2, src homology-2; SHP2, phosphotyrosine phosphatase.
Manuscript received August 30, 1999. Initial review completed October 11, 1999. Revision accepted February 16, 2000.
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