![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
*
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 and
Department of Animal Sciences, University of Illinois, Urbana, IL 61801
2To whom correspondence should be addressed. E-mail: nshay1{at}nd.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
KEY WORDS: • zinc • insulin • insulin signaling • glucose transport.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. The first
contribution to insulin-stimulated glucose transport is enhanced
translocation of glucose transporters from intracellular compartments
to the plasma membrane (2)
. The translocation of these
glucose transporters is the final step in a complex process of vesicle
trafficking. This translocation caused by insulin is believed to be
carried out by a metabolic signaling pathway, which includes the
insulin receptor
(IR),3
the insulin receptor substrate (IRS) proteins (3)
,
phosphoinositide 3-kinase (PI 3-K), protein kinase C (PKC) isoforms
(4
5
6)
and Akt (or protein kinase B) (7)
.
Recently, Akt was shown to promote glucose transporter (GLUT) 4
translocation, but not GLUT 1 (7)
. Sharma et al.
(8)
found that the translocation of GLUT4, caused by
insulin, was independent of IRS-1 in 3T3-L1 adipocytes. Although
tremendous advances have been made in delineating the
insulin-signaling pathway, many details are still poorly
understood.
Zinc is required for the function of many intracellular proteins,
including enzymes, transcription factors and proteins involved in DNA
replication. Zinc has an effect on epidermal growth factor
(EGF)-stimulated intracellular signaling, stimulating tyrosine
phosphorylation of the EGF receptor (9)
. Zinc also has
been reported to have insulin-like effects as well. Zinc
potentiates the mitogenic signaling of insulin (10)
and
activates extracellular-signal–regulated kinases 1 and 2
(11)
. Coulston and Dandona (12)
first
reported that zinc promoted lipogenesis of rat epididymal adipocytes,
and this function is insulin-like. Also, May and Contoreggi
(13)
found that zinc had another insulin-like
function, i.e., increasing glucose transport into rat epididymal
adipocytes. Clinical research shows evidence of a correlation between
zinc deficiency and diabetes (14)
. May and Contoreggi
(13)
proposed both direct effects of zinc on intracellular
events and indirect effects related to the generation of
H2O2. Since then, the
intracellular signaling events have not been well investigated. To our
knowledge, only one report exploring the relationship between zinc and
insulin-signaling pathway exists (15)
. In that report,
zinc stimulated glucose transport into rat adipocytes through a
postinsulin receptor mechanism. Nevertheless, the relationship between
zinc and the insulin-signaling pathway remains unclear. To
determine which intracellular events are activated by zinc to stimulate
glucose transport, we examined the effects of zinc on the members of
insulin metabolic signaling pathway in 3T3-L1 preadipocytes and
adipocytes.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
3T3-L1 fibroblasts were purchased from American Type Culture Collection (ATCC, Rockville, MD). Zinc chloride was from Fisher Scientific (Pittsburgh, PA). Cytochalasin B, cytochalasin D, 3-isobutyl-1-methyl-xanthine (IBMX), dexamethasone, Dulbecco’s PBS (DPBS), wortmannin, H7 and 2-deoxy-D-glucose were from Sigma Chemical (St Louis, MO). Tritiated (1,2-3H) 2-deoxy-D-glucose was from ICN (Costa Mesa, CA). Bovine insulin was from Gibco Life Technologies (Gaithersburg, MD). Protein A–coated agarose beads, anti-insulin receptor ß (IR-ß) subunit antibody, and anti-IRS-1 antibody were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-IRS-2 antibody was purchased from Upstate Biotechnology (Lake Placid, NY). Mouse anti-phosphotyrosine antibody PY 20 was from Transduction Laboratories (San Diego, CA). Anti-Akt and anti-phospho-Akt (Ser 473) were from New England Biolabs (Beverly, MA). The enhanced chemiluminescence (ECL) detection system was from Amersham Pharmacia (Buckinghamshire, UK).
Cell culture and induction of differentiation.
Cells were grown in Dulbecco’s modified Eagle medium (DMEM) plus 10% fetal bovine serum (FBS) and antibiotic-antimycotics in 5% CO2/95% air at 37°C. To induce the differentiation of fibroblasts into adipocytes, confluent fibroblasts were incubated with DMEM plus 10% FBS, antibiotic-antimycotics, 1000 µg/L insulin, 0.5 mmol/L IBMX and 1 µmol/L dexamethasone for 3 d. Cells were then switched to DMEM plus 10% FBS, antibiotic-antimycotics and 1000 µg/L insulin for 3 d. After this treatment, cells were then switched to normal growth medium, and medium was changed at least every 3 d. After differentiation, at least 85% of the cells demonstrated the phenotype of adipocytes. Cell viability for all cellular treatments, including zinc and cell inhibitors, was monitored by trypan blue stain exclusion. No treatments used in this report affected cell viability.
Glucose transport assay.
Cells were plated into gelatin-coated 24-well plates. The confluent fibroblasts and differentiated adipocytes were rinsed once with PBS and switched to serum-free medium for 3 h at 37°C in 5% CO2/95% air. Cells were then rinsed three times with DPBS with 1.0 g/L bovine serum albumin (BSA) (pH 7.4). The cells were incubated in 250 µL DPBS with or without zinc or insulin for 30 min at 37°C. Cells were then washed three times with DPBS; then, 250 µL DPBS with 100 µmol/L 2-deoxy-D-glucose/2-deoxy-D-[1.2-3H] glucose (final concentration of 3H was 37 Bq/µL) was added into each well and incubated in the presence or absence of 20 µmol/L cytochalasin B at 37°C for 10 min. After incubation, the cells were quickly rinsed three times with ice-cold PBS (Sigma Chemical, pH 7.4). Cells were then solubilized with 0.4 mL 0.1% SDS. Radioactive 2-deoxy-glucose uptake was measured using liquid scintillation counting. Data were analyzed using ANOVA, with P < 0.05 set as an indicator of difference. When ANOVA indicated that significant differences existed, post-hoc differences between values were determined using Tukey’s test.
In the experiments exploring the effects of protein kinase inhibitors, cells were incubated with an inhibitor for the last 30 min of a trial in DPBS (1.0 g/L BSA) at 37°C. To examine the role of actin filaments, cells were incubated with 2 µmol/L cytochalasin D in serum-free medium for 3 h; during the last 30 min, cells were incubated with 200 µmol/L ZnCl2 or 14 nmol/L insulin. Cells were then washed 3 times with DPBS with 1.0 g/L BSA, and glucose uptake was measured as described above.
Immunoprecipitation.
Cells were grown in 100-mm diameter dishes. Near-confluent 3T3-L1 fibroblasts and differentiated adipocytes were rinsed with and incubated in serum-free medium at 37°C for 6 h. Cells were then treated with 70 nmol/L insulin for 5 or 10 min, and 200 µmol/L ZnCl2 for 5, 10 and 20 min at 37°C. Cells were then rinsed twice with ice-cold PBS and lysed in 200 µL lysis buffer [1% (v/v) Nonidet P-40, 50 mmol/L Tris, 100 mmol/L NaCl, 50 mmol/L NaF, 2 mmol/L sodium orthovandate, 10 mmol/L sodium pyrophosphate, 2.5 mmol/L benzamidine, 1 mmol/L phenylmethylsulfonyl fluoride, 10 mg/L aprotinin, 10 mg/L leupeptin and 10 mg/L pepstatin A, pH 7.4) on ice for 30 min. Cell lysates were then centrifuged at 13,000 x g at 4°C for 10 min, and the supernatant was incubated on a rotator with protein A-coated agarose beads (Santa Cruz Biotechnology) and a specific antibody at 4°C overnight. The immunoprecipitated complexes were washed 3 times with lysis buffer, resuspended in sample loading buffer, boiled for 5 min and subjected to electrophoresis and Western-blot analysis.
Western-blot analysis.
Cell lysates or immunoprecipitated complexes were subjected to SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose membrane (Bio-Rad Laboratories, Hercules, CA). The membrane was blocked in TBS-0.1% Tween 20 containing 50 g/L nonfat dry milk for 1 h at room temperature. Detection of specific proteins was carried out by incubation with the primary antibody at 4°C overnight in TBS-0.1% Tween-20 containing 50 g/L nonfat dry milk or BSA. Blots were then incubated with horseradish peroxidase–labeled secondary antibody (1:2000). The immunolabeled bands were visualized on Kodak O-MAT film (Rochester, NY) with an ECL detection system using the manufacturer’s suggested protocol.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Zinc chloride enhanced glucose transport (P < 0.05)
in the absence of insulin. Insulin and ZnCl2 also
had a similar effect on the differentiated 3T3-L1 adipocytes; however,
the effect on the differentiated adipocytes was greater than that on
fibroblasts (Fig. 2
). When zinc was included in the incubation medium, glucose uptake
increased (P < 0.05) in a dose-dependent fashion
with or without insulin in the medium. Other experiments showed that
calcium and magnesium did not enhance glucose transport (data not
shown).
|
|
). Treatment with wortmannin (Fig. 4
) decreased (P < 0.05) basal glucose transport into
3T3-L1 fibroblasts and adipocytes. Wortmannin totally abolished
(P < 0.05) the insulin- and
ZnCl2-induced increases in glucose transport.
Unlike wortmannin, the PKC inhibitor H7 did not decrease basal glucose
transport (Fig. 5
), whereas it decreased (P < 0.05) glucose transport
into 3T3-L1 adipocytes (but not fibroblasts) induced by
ZnCl2.
|
|
|
). Insulin increased tyrosine phosphorylation of the IR-ß subunit on
both 3T3-L1 fibroblasts and adipocytes. Treatment with
ZnCl2 also produced an insulin-like effect,
but the extent was lower than that of insulin. Next in the pathway,
IRS-1 and –2 were investigated. In the same experiments in which zinc
was observed to stimulate phosphorylation of the IR-ß subunit, IRS
proteins were immunoprecipitated with the anti-phosphotyrosine
PY-20 antibody and immunoblotted with anti-IRS antibodies. Neither
IRS-1 nor IRS-2 increased tyrosine phosphorylation after zinc treatment
(data not shown). Both IRS-1 and -2 were tested in five independent
experiments; in every case, insulin stimulated IRS tyrosine
phosphorylation, whereas zinc did not. Normally, the activation of PI
3-kinase caused by insulin is via the association of
tyrosine-phosphorylated IRS proteins with the p85 subunit of PI
3-kinase. The IRS proteins were studied in a second way. After
treatment with insulin and/or zinc, cell lysates were
immunoprecipitated with anti-IRS-1 antibody and immunoblotted with an
antibody to the p85 subunit of PI 3-kinase. When PI 3-kinase is
detected by immunoblot, an association of PI 3-kinase with IRS-1 is
presumed. Only insulin caused this kind of association, whereas zinc
had no effect. Five separate trials were conducted, with each trial
including a variety of incubation times (data not shown). Although
insulin treatment always resulted in PI 3-kinase being detected, zinc
did not produce a similar result. We conclude that IRS-1 and IRS-2 may
not be important in the increase in glucose transport induced by zinc,
even when the IR phosphorylation was stimulated by the same treatment.
|
). To determine whether Akt phosphorylation can be carried out by other
divalent cations, CaCl2 and
MgCl2 were tested. When either 10 mmol/L
CaCl2 or 2 mmol/L MgCl2 was
tested, neither noticeably increased Ser 473 phosphorylation of Akt as
had been observed for zinc. We do not rule out the possibility that Ca
or Mg may affect Akt phosphorylation to some slight degree (Fig. 8
). However, if there is some slight effect of Ca or Mg, it appears that
it is much less than the effect of zinc. The phosphorylation of Akt is
usually dependent on PI 3-kinase (16)
. To determine
whether PI 3-kinase plays a critical role in zinc-potentiated Akt
action, wortmannin was again used. Treatment with wortmannin alone did
not affect the phosphorylation of Akt on serine 473 in either
preadipocytes or adipocytes, whereas the inhibition of PI 3-kinase with
100 nmol/L wortmannin totally blocked the ability of zinc to increase
the activity of Akt (Fig. 9
). Therefore, the present data indicate that PI 3-kinase appears to be a
key intracellular signaling mediator in the activation of Akt by zinc,
rather than zinc acting on Akt directly.
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Perry et al.
(17)
and Fukamachi et al. (18)
found that
zinc suppresses apoptosis through inhibition of caspase-3 activity and
an increase in the Bcl/Bax ratio, respectively. Thus, evidence is
accumulating that zinc may be involved in certain intracellular signal
transduction events. The present data show that zinc promotes glucose
transport into cells through the PI 3-kinase signal transduction
pathway. Because PI 3-kinase plays a critical role in insulin
signaling, zinc may be exerting an insulin-like function by
affecting phosphorylation or dephosphorylation of one or more
components of the insulin pathway.
Zinc has insulin-like functions in lipogenesis (12)
,
glucose transport (13
,15)
and leptin production in humans
(19)
. 3T3-L1 fibroblasts predominantly express
insulin-insensitive GLUT1, whereas 3T3-L1 adipocytes express more
of the insulin-responsive GLUT4. Generally, most of the experiments
presented in this report confirm that zinc has a greater effect on
glucose transport in the 3T3-L1 adipocytes than in the preadipocyte
fibroblast form. We consider it important to recognize that when we
used a range of doses for zinc, the effect of zinc was dose dependent,
and significant differences were observed between zinc-free and
zinc concentrations as low as 20 or 50 µmol/L. Considering
that normal serum concentration for zinc may be 
15
µmol/L, we consider significant effects seen at 20 or 50
µmol/L to be physiologic in nature rather than pharmacologic. Due to
the nature of immunoblot experiments, it is more difficult to test a
large number of conditions, including various zinc concentrations.
Generally, zinc was tested at 0 or 200 µmol/L in these
experiments. On the basis of the results of the glucose uptake
experiments shown in Figures 1
and 2
, we consider it likely that
zinc-induced phosphorylation of Akt or the IR was responding to
zinc in a similar manner, and dose-dependent effects of zinc on
phosphorylation would be expected if dose-response studies on Akt
and the IR were to be conducted.
The IR-ß subunit is a tyrosine kinase and is activated through
autophosphorylation when insulin binds to its receptor on the cell
membrane (20)
. Like insulin, zinc also increases tyrosine
phosphorylation of the IR-ß subunit (Fig. 6)
. This result is
consistent with the findings that zinc causes tyrosine phosphorylation
of the EGF receptor, which is also a tyrosine kinase (9)
.
In 1989, Ezaki (15)
found that zinc did not increase
tyrosine phosphorylation of the insulin receptor, which led to the
conclusion that zinc affects glucose transport by a postinsulin
receptor mechanism in rat adipocytes. However, Ezaki tested the effect
of zinc on tyrosine phosphorylation of the IR only at 30 min. We
examined and found an insulin-like effect at just 5 and 10 min
after insulin treatment. Other data (not shown) indicate that
phosphorylation of the IR returns to baseline at between 10 and 20 min.
Although zinc enhances tyrosine phosphorylation of the IR, this is not
conclusive evidence that this event is necessary for zinc-enhanced
glucose transport.
The IRS-1 and -2 proteins play a critical role in insulin action.
Homozygous IRS-1 gene knockout mice exhibit a mild insulin resistance,
but do not develop diabetes (21)
. Disruption of the IRS-2
gene results in decreased insulin production, insulin resistance and
diabetes (22)
. However, several reports suggest that
IRS-1, -2 and -3 may not be required for GLUT4 translocation and
insulin-stimulated glucose transport (8
,23
,24)
. We
report here that zinc did not cause the association of IRS-1 and PI
3-kinase p85 subunit, even when glucose transport was enhanced (data
not shown). We suggest that the interaction between the IR and IRS
proteins may not be necessary for insulin- and zinc-induced glucose
transport.
Actin filament rearrangement is important for GLUT4 translocation to
the plasma membrane (25)
. Tsakiridis et al.
(26)
reported the recruitment of GLUT4, PI 3-kinase
subunits and GLUT4-containing vesicles to a reorganized actin network.
Although cytochalasin D does not have an effect on basal glucose
transport, we showed that cytochalasin D inhibits zinc-induced
glucose transport into cells (Fig. 3)
. Thus, the induction of transport
caused by zinc is likely dependent on reorganization of the actin
filament network, and that the last step of insulin- or
zinc-induced glucose transport is a common one.
Phosphoinositide 3-kinase has been demonstrated to play a key role in
insulin-stimulated glucose uptake (27)
. To investigate
the role of PI 3-kinase in zinc-induced glucose transport,
wortmannin, the potent mammalian PI 3-kinase inhibitor was used to
block the phospholipid-mediated signaling pathway. Wortmannin can
totally abrogate the effect of insulin on glucose transport into rat
adipocytes (28)
. Expression of the dominant-negative
PI 3-kinase p85 subunit mutant completely blocks insulin-induced
GLUT4 translocation (1)
. Constitutively active PI 3-kinase
has an effect on GLUT4 translocation similar to insulin’s action in
adipocytes (29)
. Consistent with this, our experiments
showed that wortmannin decreases basal glucose transport of 3T3-L1
cells and also blocks insulin-induced glucose transport. Wortmannin
inhibited zinc-induced glucose transport as well (Fig. 4)
. Because
it has been reported that the 50% inhibitory concentration of
wortmannin on mammalian PI 3-kinases is in the nanomolar range
(30)
, and wortmannin concentrations >100 nmol/L
may inhibit some isoforms of PI 4-kinases (31)
and
phospholipase A2 (32)
, we used
concentrations of wortmannin in this experiment that would specifically
inhibit PI 3-kinase. This result suggests to us that the zinc effect
requires PI 3-kinase to enhance glucose transport. Our result is
consistent with the findings of Kim et al. (33)
that zinc
can activate PI 3-kinase. Regarding GLUT4 translocation, the specific
subcellular site of PI 3-kinase activation is of importance. This is
why insulin can stimulate GLUT4 translocation through targeting PI
3-kinase to GLUT4 vesicles, whereas platelet-derived growth factor
activation of PI 3-kinase has a lesser effect on glucose transport
(34)
. In the insulin pathway, it is most typically thought
that PI 3-kinase is activated by the association of its p85 subunit and
IRS proteins (35)
. However, IRS proteins are not necessary
in insulin-induced glucose transport, probably because IRS proteins
do not target PI 3-kinase to the proper intracellular location. For
enhancement of glucose transport, the association with other
intracellular factors likely activates PI 3-kinase. Imamura et al.
(36)
reported that Gq/
11 protein plays an important
role in the activation of catalytic subunits of PI 3-kinase for
insulin-induced glucose transport in 3T3-L1 adipocytes. Other
evidence suggests ways that zinc may activate PI 3-kinase without IRS
involvement, i.e., May and Contoreggi (13)
observed that
treatment of zinc (from 250 µmol/L to 1 mmol/L) causes the
production of H2O2 in rat
epididymal adipocytes, and
H2O2 can activate focal
adhesion kinase (FAK) (37)
. FAK can activate the PI
3-kinase-Akt pathway (38)
. We can advance at least one
hypothesis for future testing, i.e., that PI 3-kinase is activated in
part through the H2O2/FAK
pathway and then delivered to GLUT4-containing vesicles. There is also
the possibility of G-protein activation of PI 3-kinase after zinc
treatment. Some proteins, including ARNO, bind to the product of PI
3-kinase, PI (3,4,5)-P3, and regulate ARF6, which
is involved in membrane ruffling and insulin-stimulated actin
filament reorganization (39)
. Therefore, we suggest that
like insulin, zinc mediates actin reorganization through PI 3-kinase,
and finally stimulates glucose transport.
The PI 3-kinase downstream targets, PKC-ß2, and atypical PKC family
members PKC-
and -
, are involved in insulin-stimulated GLUT4
translocation. Braiman et al. (4)
found that the specific
PKC-ß2 inhibitor LY379196 blocks insulin-induced glucose
transport in rat skeletal muscle, and wortmannin inhibits the
activation of PKC-ß2 by insulin. On the other hand, PKC- and
PKC- can be activated by insulin, and transfection studies with
constitutively active and dominant-negative mutants demonstrate
that these two PKC family members are involved in GLUT4 translocation
in rat adipocytes (6
,40)
. The general PKC inhibitor, H7,
did not inhibit insulin-induced glucose transport in 3T3-L1
adipocytes (Fig. 5)
. This lack of inhibition may be due to the fact
that although insulin acts mainly through PKC- and PKC-, zinc
partially induces glucose uptake through PKC ß2.
Because there are at least two intermediaries downstream from PI
3-kinase involved in glucose transport, PKC proteins and Akt/protein
kinase B (7)
, another hypothesis would suggest that Akt is
responsible for the major contribution to zinc-induced glucose
transport. Our study clearly demonstrates that zinc causes
phosphorylation of Akt serine 473 in 3T3-L1 cells, and other divalent
cations, such as calcium and magnesium, do not have a similar effect,
if any at all (Figs. 7
, 8)
. Consistent with our results, Kim et al.
(33)
also detected Akt serine 473 phosphorylation after
treatment with 100 µmol/L zinc in Swiss 3T3 cells. We
provide direct evidence that the activation of Akt caused by zinc is PI
3-kinase dependent (Fig. 9)
, and this mechanism of Akt activation is
the same as that induced by insulin and other growth factors
(7)
. Recently, accumulated evidence has shown the
relationship between Akt and GLUT4 translocation. Constitutively active
Akt stimulates glucose transport by the translocation of GLUT4 to
plasma membrane (41)
. Kupriyanova and Kandror
(42)
demonstrated that Akt-2 associated with
GLUT4-containing vesicles and phosphorylated vesicular proteins. The
activation of Akt by zinc in this study suggests that Akt is important
for zinc-stimulated glucose transport, but it will be necessary to
examine the effect of a dominant-negative Akt mutant to confirm a
role for Akt.
In conclusion, we have established that zinc exerts an insulin-like effect in 3T3-L1 cells, which is more pronounced in the 3T3 L1 adipocytes. We measured this effect as a stimulation of glucose transport and demonstrated that zinc affects components of the insulin intracellular signaling pathway. Zinc stimulates the tyrosine phosphorylation of IR-ß subunit and activates the PI 3-kinase pathway and Akt. IRS proteins appear not to participate in zinc’s effect on glucose transport. From these results, we propose that zinc deficiency may indeed affect optimal function of the insulin-signaling pathway. How or whether zinc is involved in the development of insulin resistance is an important question; better understanding of the signaling pathway may ultimately help answer these questions.
|
FOOTNOTES |
|---|
3 Abbreviations used: BSA, bovine serum albumin; DMEM, Dulbecco’s modified Eagle medium: DPBS, Dulbecco’s PBS; ECL, enhanced chemiluminesce; EGF, epidermal growth factor; FAK, focal adhesion kinase; FBS, fetal bovine serum; GLUT, glucose transporter; IBMX, 3-isobutyl-1-methyl-xanthine; IR-ß, insulin receptor ß subunit; IRS, insulin receptor substrate; MAP kinase, mitogen-activated protein kinase; PI 3-kinase, phosphoinositide 3-kinase; PKC, protein kinase C.
Manuscript received October 31, 2000. Initial review completed December 13, 2000. Revision accepted February 5, 2001.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.
Haruta T., Morris A. J., Rose D. W., Nelson J. G., Mueckler M., Olefsky J. M. Insulin-stimulated GLUT4 translocation is mediated by a divergent intracellular signaling pathway. J. Biol. Chem. 1995;270:27991-27994
2.
Cushman S. W., Wardzala L. J. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J. Biol. Chem. 1980;255:4758-4762
3.
Quon M. J., Butte A. J., Zarnowski M. J., Sesti G., Cushman S. W., Taylor S. I. Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. J. Biol. Chem. 1994;269:27920-27924
4. Braiman L., Sheffi-Friedman L., Bak A., Tennenbaum T., Sampson S. R. Tyrosine phosphorylation of specific protein kinase C isoenzymes participates in insulin stimulation of glucose transport in primary cultures of rat skeletal muscle. Diabetes 1999;48:1922-1929[Abstract]
5.
Bandyopadhyay G., Standaert M. L., Zhao L., Yu B., Avignon A., Galloway L., Karnom P., Moscat J., Farese R. V. Activation of protein kinase C (alpha, beta, and zeta) by insulin in 3T3–L1 cells: transfection studies suggest a role for PKC-zeta in glucose transport. J. Biol. Chem. 1997;272:2551-2558
6.
Kotani K., Ogawa W., Matsumoto M., Kitamura T., Sakaue H., Hino Y., Miyake K., Sano W., Akimoto K., Ohno S., Kasuga M. Requirement of atypical protein kinase C-lambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3–L1 adipocytes. Mol. Cell. Biol. 1998;18:6971-6982
7. Coffer P. J., Jin J., Woodgett J. R. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem. J. 1998;335:1-13
8. Sharma P. M., Egawa K., Gustafson T. A., Martin J. L., Olefsky J. M. Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3–L1 adipocytes. Mol. Cell. Biol. 1997;17:7386-7397[Abstract]
9.
Wu W., Graves L. M., Jaspers I., Devlin R. B., Reed W., Samet J. M. Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals. Am. J. Physiol. 1999;277:L924-L931
10. Kiss Z., Crilly K. S., Tomono M. Bombesin and zinc enhance the synergistic mitogenic effects of insulin and phosphocholine by a MAP kinase-dependent mechanism in Swiss 3T3 cells. FEBS Lett 1997;415:71-74[Medline]
11. Park J. A., Koh J. Y. Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. J. Neurochem. 1999;73:450-456[Medline]
12. Coulston L., Dandona P. Insulin-like effect of zinc on adipocytes. Diabetes 1980;29:665-667[Abstract]
13.
May J. M., Contoreggi C. S. The mechanism of the insulin-like effects of ionic zinc. J. Biol. Chem. 1982;257:4362-4368
14. Ripa S., Ripa R. Zinc and diabetes mellitus. Minerva Med 1995;86:415-421[Medline]
15.
Ezaki O. IIb group metal ions (Zn2+, Cd2+, Hg2+) stimulate glucose transport activity by post-insulin receptor kinase mechanism in rat adipocytes. J. Biol. Chem. 1989;264:16118-16122
16.
Datta K., Bellacosa A., Chan T. O., Tsichlis P. N. Akt is a direct target of the phosphatidylinositide 3-kinase. Activation by growth factors, v-src and v-Ha-src, in sf9 and mammalian cells. J. Biol. Chem. 1996;271:30835-30839
17.
Perry D. K., Smyth M. J., Stennicke H. R., Salvesen G. S., Duriez P., Poirier G. G., Hannun Y. A. Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis. J. Biol. Chem. 1997;272:18530-18533
18. Fukamachi Y., Karasaki Y., Sugiura T., Itoh H., Abe T., Yamamura K., Higashi K. Zinc suppresses apoptosis of U937 cells induced by hydrogen peroxide through an increase of the Bcl-2/Bax ratio. Biochem. Biophys. Res. Commun. 1998;246:364-369[Medline]
19. Chen M. D., Song Y. M., Lin P. Y. Zinc may be a mediator of leptin production in humans. Life Sci 2000;66:2143-2149[Medline]
20.
Cheatham B., Kahn C. R. Insulin action and the insulin signaling network. Endocr. Rev. 1995;16:117-142
21. Tamemoto H., Kadowaki T., Tobe K., Yagi T., Sakura H., Hayakawa T., Terauchi Y., Ueki K., Kaburagi Y., Satoh S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature (Lond.) 1994;372:182-186[Medline]
22. Withers D. J., Gutierrez J. S., Towery H., Burks D. J., Ren J. M., Previs S., Zhang Y., Bernal D., Pons S., Shulman G. I., Bonner-Weir S., White M. F. Disruption of IRS-2 causes type 2 diabetes in mice. Nature (Lond.) 1998;391:900-904[Medline]
23.
Chaika O. V., Chaika N., Volle D. J., Hayashi H., Ebina Y., Wang L. M., Pierce J. H., Lewis R. E. Mutation of tyrosine 960 within the insulin receptor juxtamembrane domain impairs glucose transport but does not inhibit ligand-mediated phosphorylation of insulin receptor substrate-2 in 3T3–L1 adipocytes. J. Biol. Chem. 1999;274:12075-12080
24.
Liu S. C., Wang Q., Lienhard G. E., Keller S. R. Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J. Biol. Chem. 1999;274:18093-18099
25. Wang Q., Bilan P. J., Tsakiridis T., Hinek A., Klip A. Actin filaments participate in the relocalization of phosphatidylinositol 3-kinase to glucose transporter-containing compartments and in the stimulation of glucose uptake in 3T3–L1 adipocytes. Biochem. J. 1998;331:917-928
26. Tsakiridis T., Tong P., Matthews B., Tsiani E., Bilan P. J., Klip A., Downey G. P. Role of the actin cytoskeleton in insulin action. Microsc. Res. Technol. 1999;47:79-92[Medline]
27. Frevert E. U., Kahn B. B. Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3–L1 adipocyes. Mol. Cell. Biol. 1997;17:190-198[Abstract]
28.
Okada T., Sakuma L., Fukui Y., Hazeki O., Ui M. Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase. J. Biol. Chem. 1994;269:3563-3567
29.
Tanti J. F., Gremeaux T., Grillo S., Calleja V., Klippel A., Williams L. T., Van Obberghen E., Le Marchand-Brustel Y. Overexpression of a constitutively active form of phosphatidylinositol 3-kinase is sufficient to promote GLUT4 translocation in adipocytes. J. Biol. Chem. 1996;271:25227-25232
30. Shepherd P. R., Withers D. J., Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 1998;333:471-490
31.
Nakanishi S., Catt K. J., Balla T. A wortmannin-sensitive phosphadylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. Proc. Natl. Acad. Sci. U.S.A. 1995;92:5317-5321
32.
Cross M. J., Stewart A., Hodgkin M. N., Kerr D. J., Wakelam M.J.O. Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. J. Biol. Chem. 1995;270:25352-25355
33.
Kim S., Jung Y., Kim D., Koh H., Chung J. Extracellular zinc activates p70 S6 kinase through the phosphatidylinositol 3-kinase signaling pathway. J. Biol. Chem. 2000;275:25979-25984
34. Nave B. T., Haigh R. J., Hayward A. C., Siddle K., Shepherd P. R. Compartment-specific regulation of phosphoinositide 3-kinase by platelet-derived growth factor and insulin in 3T3–L1 adipocytes. Biochem. J. 1996;318:55-60
35.
Czech M. P., Corvera S. Signaling mechanisms that regulate glucose transport. J. Biol. Chem. 1999;274:1865-1868
36.
Imamura T., Vollenweider P., Egawa K., Clodi M., Ishibashi K., Nakashima N., Ugi S., Adams J. W., Brown J. H., Olefsky J. M. G alpha-q/11 protein plays a key role in insulin-induced glucose transport in 3T3–L1 adipocytes. Mol. Cell. Biol. 1999;19:6765-6774
37.
Vepa S., Scribner W. M., Parinandi N. L., English D., Garcia J. G., Natarajan V. Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in vascular endothelial cells. Am. J. Physiol. 1999;277:L150-L158
38.
Sonoda Y., Watanabe S., Matsumoto Y., Aizu-Yokota E., Kasahara T. FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. J. Biol. Chem. 1999;274:10566-10570
39.
Frank S., Upender S., Hansen S. H., Casanova J. E. ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. J. Biol. Chem. 1998;273:23-27
40.
Standaert M. L., Bandyopadhyay G., Perez L., Price D., Galloway L., Poklepovic A., Sajan M. P., Cenni V., Sirri A., Moscat J., Toker A., Farese R. V. Insulin activates protein kinases C-zeta and C-lambda by an autophosphorylation-dependent mechanism and stimulates their translocation to GLUT4 vesicles and other membrane fractions in rat adipocytes. J. Biol. Chem. 1999;274:25308-25316
41.
Foran P.G.P., Fletcher L. M., Oatey P. B., Mohammed N., Dolly J. O., Tavare J. M. Protein kinase B stimulates the translocation of GLUT4 but not GLUT1 or transferrin receptors in 3T3–L1 adipocytes by a pathway involving SNAP-23, synaptobrevin-2, and/or cellubrevin. J. Biol. Chem. 1999;274:28087-28095
42.
Kupriyanova T. A., Kandror K. V. Akt-2 binds to GLUT4-containing vesicles and phosphorylates their component proteins in response to insulin. J. Biol. Chem. 1999;274:1458-1464
This article has been cited by other articles:
|
|
 |
|
  J. Wang, Y. Song, L. Elsherif, Z. Song, G. Zhou, S. D. Prabhu, J. T. Saari, and L. Cai Cardiac Metallothionein Induction Plays the Major Role in the Prevention of Diabetic Cardiomyopathy by Zinc Supplementation Circulation, January 31, 2006; 113(4): 544 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cote, M. Chiasson, M. R Peralta III, K. Lafortune, L. Pellegrini, and K. Toth Cell type-specific action of seizure-induced intracellular zinc accumulation in the rat hippocampus J. Physiol., August 1, 2005; 566(3): 821 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Song, I. K. Hwang, M. J. Rosenthal, D. M. Harris, D. T. Yamaguchi, I. Yip, and V. L. W. Go Anti-Hyperglycemic Activity of Zinc Plus Cyclo (His-Pro) in Genetically Diabetic Goto-Kakizaki and Aged Rats Experimental Biology and Medicine, December 1, 2003; 228(11): 1338 - 1345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Barnes, P. R. Hanlon, and E. A. Kircher Effects of Inorganic HgCl2 on Adipogenesis Toxicol. Sci., October 1, 2003; 75(2): 368 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Catalano, J. P. Kirwan, S. Haugel-de Mouzon, and J. King Gestational Diabetes and Insulin Resistance: Role in Short- and Long-Term Implications for Mother and Fetus J. Nutr., May 1, 2003; 133(5): 1674S - 1683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Maret From the Cover: Crosstalk of the group IIa and IIb metals calcium and zinc in cellular signaling PNAS, October 23, 2001; 98(22): 12325 - 12327. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
