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J Biol Chem, Vol. 274, Issue 4, 1865-1868, January 22, 1999
From the Program in Molecular Medicine and Departments of
Insulin, the major hormonal regulator of glucose
transport in humans, has served as a prototypic molecule for
understanding cell signaling pathways since its discovery in 1922. It
was among the first proteins for which primary amino acid sequence and
three-dimensional structure were determined. The insulin receptor was
likewise among the first peptide receptors to be identified by ligand
binding, and its subunit structure was deduced in the earliest days of modern receptor biology (1). The structure of its tyrosine kinase
domain was the first of the tyrosine kinases to be solved by x-ray
crystallography (2). Further, much is now known about downstream
insulin receptor signaling components (3). Despite these advances, our
understanding of how insulin and the related proteins, insulin-like
growth factors I and II, stimulate glucose transport (via the
translocation of glucose transporter proteins from intracellular to
plasma membranes) is fragmentary. One reason for this is that the major
target for insulin signaling to glucose transport is a complex membrane
trafficking pathway that is likely to contain many unknown components.
As summarized in the preceding introductory comments (4) and detailed
in the companion minireviews to be published subsequently (5, 6),
glucose uptake via the GLUT4 isoform of mammalian hexose transporters
accounts for most of the stimulatory effect of insulin on this process
in muscle and fat cells. GLUT4 rapidly recycles through the plasma
membrane/endosomal membrane system in the presence of insulin. However,
in the basal state this transporter protein is directed to and retained
within specific intracellular membranes through the action of distinct
elements within the GLUT4 structure (7). Insulin causes movement of
GLUT4 out of this sequestered localization, leading to an increase in
its steady state concentration on the cell surface membrane where it
can catalyze glucose uptake. However, to accomplish this, insulin signaling is likely to regulate GLUT4 trafficking at multiple steps,
consistent with data showing insulin also enhances cell surface display
of proteins such as transferrin receptor and GLUT1 that recycle to a
large extent independently of GLUT4. To further complicate our
understanding of this system, different signaling elements may be
required to modulate each of these different putative regulated steps
in the GLUT4 trafficking pathway.
Substrate phosphorylation by the insulin receptor tyrosine kinase
appears to involve the binding of phosphorylated receptor tyrosine 960 to phosphotyrosine-binding
(PTB)1 domains of substrate
proteins (8). Adjacent Pleckstrin homology (PH) domains on some
substrate proteins also appear critical for receptor binding and
phosphorylation. Tyrosine kinase signaling is often initiated by the
recruitment of signaling proteins through their Src homology 2 (SH2) or
PTB domains to phosphotyrosine sites. In the case of insulin receptor,
tyrosine phosphorylation of four related substrate (IRS) proteins (8)
and Gab-1 (9) causes many candidate signaling proteins to be recruited,
including: 1) the p110-type phosphatidylinositol 3-kinase (PI
3-kinase) through the SH2 domains of p85 regulatory subunits; 2) Grb2
and the protein tyrosine phosphatase SH-PTP2, which appear to be
necessary for p21ras activation (10); 3) the tyrosine kinase
Fyn, which in turn may also activate the PI 3-kinase and p21ras
pathways; and 4) Rho-associated protein serine/threonine kinase ROK As illustrated in Fig. 1, p21ras
and the p85/p110-type PI 3-kinases represent two major initial switch
elements for insulin receptor signaling. There is also evidence that
the p21ras-related GTP-binding proteins Rap (14), Rho (15), and
Rac (16) are engaged by insulin receptor signal transduction. A central
paradigm of insulin signaling is the involvement of multiple protein
serine/threonine kinases downstream of both the p21ras and PI
3-kinase elements (Fig. 1). More recently, a group of non-receptor
tyrosine kinases denoted Btk/Itk/Tec has been found in hemopoietic
cells to respond to the generation of 3'-polyphosphoinositide, apparently by recruitment through their PH domains to membranes where
they can be tyrosine-phosphorylated and activated (17). It is not yet
known whether insulin or insulin-like growth factor-1 receptor
signaling can act through 3'-phosphoinositides on these or other
tyrosine kinases, and they are therefore not included in Fig. 1.
Another recently discovered class of likely downstream effectors of
3'-phosphoinositides includes proteins that regulate membrane-related
functions (Fig. 1) such as actin assembly (Rac GTPase), early endosome
fusion (EEA1), and guanine nucleotide exchange (GRP1, cytohesin-1, and
ARNO) or possibly GTPase activation ( Much effort has been directed toward identifying which of the above
insulin receptor signaling elements are actually linked to GLUT4
translocation. Although some evidence suggested p21ras
activation might influence glucose transport in fat (18) and muscle
(19), the weight of most of the data available indicates no direct
requirement of p21ras function for insulin action on GLUT4
trafficking (20). Rather, strong indications that p85/p110-type PI
3-kinase activity is necessary for this insulin response have
accumulated. Such evidence includes complete inhibition of insulin
action on glucose transport by specific inhibitors of PI 3-kinase such
as wortmannin (21) and LY29004 (22) and by microinjection or expression
of dominant inhibitory constructs of the p85 regulatory subunit of PI
3-kinase (23). Further, in some experiments expression of an activated form of the p110 PI 3-kinase in cultured adipocytes mimics the stimulatory effect of insulin on glucose transport (24), suggesting PI
3-kinase activity is also sufficient for glucose transporter translocation.
Although the above results strongly support the hypothesis that
p85/p110-type PI 3-kinase activation through its recruitment to
phosphotyrosine sites on insulin receptor substrate proteins mediates
GLUT4 translocation, it is instructive to review the limitations
related to the current supporting data. First, the inhibitors
wortmannin and LY29004 are not fully specific for PI 3-kinase activity
and in any case are known to block PI 3-kinase isoforms lacking known
regulatory subunits that contain SH2 or other domains that can be
recruited to phosphotyrosine sites. Such other PI 3-kinase isoforms
(25) rather than, or in addition to, the type p110 PI 3-kinase may be
necessary for exocytosis of GLUT4. The use of the truncated p85 subunit
containing SH2 domains as a dominant inhibitory reagent to inhibit
native p85/p110 PI 3-kinase function also has the potential limitation
of inadequate specificity. When expressed at high concentrations, SH2
domains can be promiscuous in binding phosphotyrosines within various amino acid sequences and thus may not be restricted to binding sites
specific for endogenous p85/p110-type PI 3-kinase. Thus, although a key
role for this PI 3-kinase in GLUT4 regulation by insulin seems almost
certain, there are potential gaps in our understanding of even this point.
Recent results call into question the hypothesis that PI 3-kinase
activation by insulin is sufficient for GLUT4 translocation. For
example, it is well established that recruitment of PI 3-kinase to
phosphotyrosines on the platelet-derived growth factor (PDGF) receptor
in response to PDGF, which occurs in 3T3-L1 adipocytes to the same
extent as recruitment of PI 3-kinase to protein phosphotyrosines in
response to insulin, has virtually no effect on GLUT4 translocation (26). Recruitment of PI 3-kinase to IRS proteins in response to
interleukin-4 (27) or cell surface integrin cross-linking (28) also
fails to enhance glucose transport in the absence or presence of
submaximal concentrations of insulin. Conversely, severe inhibition of
insulin-mediated IRS protein tyrosine phosphorylation and recruitment
of PI 3-kinase in response to incubation of 3T3-L1 adipocytes with PDGF
failed to diminish glucose transport stimulation by insulin at all
concentrations along the dose-response relationship (29).
The lack of correlation between PI 3-kinase activation and GLUT4
translocation in the studies cited above may reflect an additional insulin-specific signaling pathway or pathways required to operate in
conjunction with PI 3-kinase activation to effect this biological response. According to this model, agents such as interleukin-4 and
anti-integrin antibody fail to enhance glucose transport because they
are unable to mimic the effect of insulin on this other signaling pathway. Recent surprising results support this hypothesis. In these
experiments, a cell-permeable analog of the PI 3-kinase product
PI(3,4,5)P3, thought to be a downstream effector for
insulin action through PI 3-kinase, was unable to cause GLUT4
translocation when added alone to cells (30). However, in the presence
of insulin and wortmannin, a condition where no stimulation of glucose transport is observed, the PI(3,4,5)P3 analog was able to
enhance cellular uptake of glucose (30). These results suggest that insulin may uniquely act to initiate PI 3-kinase-independent signaling events in the presence of wortmannin that collaborate with the PI
3-kinase signaling pathway to effect GLUT4 translocation.
Substantial recent information suggests that PI 3-kinase-independent
mechanisms also regulate GLUT4 translocation in skeletal muscle during
contraction. For example, the stimulations of glucose transport in
skeletal muscle caused by insulin and contraction are additive, but
only the effect of the former is blocked by wortmannin (31). In concert
with this result, insulin but not contraction stimulates PI 3-kinase
activity and the downstream protein kinase Akt/protein kinase B (32).
Conversely, the 5'-AMP-activated protein kinase (AMPK), thought to be
responsive to cell stress, is stimulated by rat hind limb contraction
but not insulin (33). Another activator of AMPK,
5-aminoimidazole-4-carboximide ribonucleoside, mimicked the action of
contraction to enhance glucose uptake in a wortmannin-insensitive mode
(33). Taken together, these recent findings suggest the hypothesis that
AMPK may mediate, at least in part, exercise-stimulated glucose uptake
in skeletal muscle.
Another cell signaling pathway that appears to markedly stimulate
glucose uptake in muscle involves nitric oxide, which stimulates guanylate cyclase to produce cyclic GMP. The NO donor sodium
nitroprusside and dibutyryl-cGMP both accelerated epitrochlearis (34),
soleus (35, 36), and extensor digitorum longus (36) muscle glucose transport. Upon raising NO levels by nitroprusside, cellular cGMP concentrations were found to rise in epitrochlearis muscle, as expected, but contraction did not elevate cGMP (34). Although there is
general agreement that the effect of insulin on glucose uptake in
muscle is not mediated through the actions of NO (34-38), studies
differ on whether NO is involved in glucose transport regulation by
contraction. NO synthase inhibitors failed to block increased glucose
uptake in response to contraction in rat epitrochlearis muscle (34),
but such inhibitors did ablate exercise-mediated glucose uptake in
other studies (36, 38).
Phorbol ester-sensitive protein kinase C isoforms may also be
significant regulators of muscle glucose uptake. Thus, the protein kinase activator 12-deoxyphorbol 13-phenylacetate 20-acetate causes a
3-4-fold stimulation of glucose transport in isolated rat
epitrochlearis muscle (39). The effect of phorbol ester on muscle
glucose uptake is additive to the effects of insulin or hypoxia (39),
indicating protein kinase C acts through a separate pathway and is an
unlikely candidate to mediate the responses to these stimulants.
Trimeric G protein-linked receptor agonists have been reported to exert
significant stimulatory effects on glucose transport, as exemplified by
It should be noted that effects of most of the signaling systems
discussed in this section that act to enhance glucose transport have
not yet been tested in GLUT4-deficient mice (6). Thus it is not clear
whether some of these insulin-independent modulations of glucose
transport involve other glucose transporter isoforms. It appears, for
example, that cell surface GLUT1 transporter activity can be regulated,
in some cases potentially independent of its recruitment to the cell
surface (47). This may be particularly relevant in tissues that express
significant levels of this glucose transporter isoform, such as brown
fat. Table I summarizes many of the
cellular regulators reported to stimulate glucose transport, and the
isoform likely to be involved.
Of the regulatory mechanisms for glucose transport described
above, research on the PI 3-kinase pathways has been the most extensive. Whether IRS proteins are required for PI 3-kinase signaling to act on the GLUT4 system is unclear at present. Microinjection or
expression of the dominant inhibitory PTB or SAIN domains of IRS-1 in
insulin-sensitive cultured adipocytes is able to block the mitogenic
and membrane-ruffling effects of insulin but not the stimulation of
glucose transport (48). These dominant inhibitory constructs are
expected to block binding of all IRS protein isoforms to the insulin
receptor through binding to the insulin receptor juxtamembrane sequence
surrounding Tyr-960, the docking site for IRS and Shc protein PTB
domains. Indeed, nearly complete inhibition of IRS-1 tyrosine
phosphorylation by insulin was caused by expression of its PTB domain
in these studies (48).
In contrast to what would be predicted from these results, expression
of IRS proteins in primary rat adipocytes apparently enhances GLUT4
translocation (49). Mutation of insulin receptor tyrosine 960, the site
of IRS protein binding required for its phosphorylation, abolishes
insulin action of glucose transport (50). Furthermore, studies in
animals in which the IRS-1 or the
IRS-2 gene has been ablated provide support for a
role of these proteins in glucose transport regulation. Mice lacking
IRS-1 exhibit some insulin resistance although no diabetes (51, 52), and heterozygotes for loss of both IRS-1 and insulin receptor genes are
both insulin-resistant and develop diabetes (53). IRS-2 gene ablation in mice alone causes both
impaired insulin signaling to glucose uptake and diabetes (54). Insulin
action on glucose uptake in adipocytes from animals lacking IRS-1
protein has been suggested to involve the IRS-3 isoform (55), which is
tyrosine-phosphorylated in response to insulin. Such redundancy may
account in part for some of these apparently conflicting results. The
information gained from IRS knockout mice provide compelling support
for a role of these proteins in glucose transport regulation by
insulin, with the caveat that unrelated changes in response to IRS loss
during development may contribute to the phenotypes observed. Taken
together, the data reported to date related to the role of IRS proteins
in GLUT4 translocation are difficult to reconcile unless we again
invoke the hypothesis that PI 3-kinase·IRS protein complexes are
necessary but not sufficient for GLUT4 translocation by insulin.
An important question about the role of PI 3-kinase docking proteins in
regulating GLUT4 trafficking is whether they function to localize the
enzyme to specific cellular sites required for regulation of GLUT4
trafficking. IRS-1 (56), IRS-3 (57), and to a lesser extent IRS-2 (58)
are present in cells as both cytosolic and membrane-bound proteins,
both in basal and insulin-stimulated conditions. Membrane binding of PI
3-kinase, through its binding to docking proteins, is expected to be
necessary for the enzyme to come into contact with its phospholipid
substrate. The exact cellular location of membrane-bound PI
3-kinase·IRS complexes is not known, but endosomes and
GLUT4-containing vesicles, potentially through binding AP3 adaptin
complexes (59) and cytoskeletal elements (60), have been suggested.
Only a very small fraction of the insulin-stimulated, IRS-1-bound PI
3-kinase activity co-purifies with GLUT4-containing vesicles, but the
downstream protein kinase Akt appears to be recruited as well (61).
Directed expression of PI 3-kinase activity on these vesicles in
adipocytes using a GLUT4/p85 SH2 domain chimera failed to stimulate
GLUT4 translocation (62). This latter result is not inconsistent with
the hypothesis that a second signaling pathway is necessary for GLUT4
translocation, however.
The insulin-sensitive p85/p110 PI 3-kinases can catalyze
phosphorylation of PI, PI(4)P, or PI(4,5)P2 at the D-3
position of the inositol ring to produce the PI(3)P,
PI(3,4)P2, or PI(3,4,5)P3. Recent results
indicate PI(3,4,5)P3 is necessary for insulin action on
glucose transport, based on the inhibitory effect of microinjection of
a phosphatase specific for this species into 3T3-L1 adipocytes (63). It
is not yet clear whether the other two PI 3-kinase products are also
necessary, but the recent identification of a protein target, EEA1,
that binds PI(3)P through its RING finger and functions in the context
of Rab5 in early endosome fusion (64) deserves further investigation
(Fig. 1). Also, a class of proteins (65) denoted GRP1, ARNO, and
cytohesin-1 containing PH domains that bind PI(3,4,5)P3
with high affinity and a Sec7 domain that catalyzes guanine nucleotide
exchange of ARF1, -5, and -6 proteins has been shown to be recruited to
plasma membranes in response to insulin (66). The data available
suggest these proteins may be involved in ARF6 function in membrane
ruffling and actin rearrangements in response to insulin (67), but
future studies on these and similar proteins in relation to GLUT4
translocation are warranted. The potential connection between PI
3-kinase signaling in insulin action and ARF function is highlighted by
the discovery of polyphosphoinositide-binding protein
Intense research has focused on protein serine/threonine kinases
downstream of PI(3,4)P2 and PI(3,4,5)P3 that
may regulate GLUT4. For example, recent reports (69) have shown that
protein kinase C Over the past few years many new components of the insulin
receptor signaling network have been discovered and their cDNA clones isolated. Particularly exciting has been the identification of
downstream targets of the insulin-regulated PI 3-kinase lipid products,
including protein kinase C isoforms We thank the members of the Czech and Corvera
laboratories for their contributions and creative discussions, and Drs.
Jerry Olefsky, Jeffrey Pessin, and Maureen Charron for helpful comments on this review. We thank Jane Erickson for excellent assistance in
preparation of this manuscript. We regret the number of references had
to be restricted due to space limitations.
*
This minireview will be reprinted
in the 1999 Minireview Compendium, which
will be available in December, 1999. This is the first article of three in the
"Insulin-stimulated Glucose Transport Minireview Series."
§
To whom correspondence should be addressed: Program in Molecular
Medicine, University of Massachusetts Medical Center, 373 Plantation
St., Worcester, MA 01605. Tel.: 508-856-2254; Fax: 508-856-1617;
E-mail: Michael.Czech{at}ummed.edu.
The abbreviations used are:
PTB, phosphotyrosine-binding; PH, Pleckstrin homology; SH2, Src homology 2; PI, phosphatidylinositol; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; AMPK, 5'-AMP-activated protein kinase.
MINIREVIEW
Signaling Mechanisms That Regulate Glucose Transport*
§ and Biochemistry and Molecular Biology
and ¶ Cell Biology, University of
Massachusetts Medical Center, Worcester, Massachusetts 01655
INTRODUCTION
Top
Introduction
References
Insulin Receptor Signaling Circuits
(11), which may modulate processes such as actin assembly and
mitogenesis under control of the small GTPase Rho. Insulin receptor
signaling can also engage p21ras through tyrosine
phosphorylation of Shc and its subsequent binding to complexes of Grb2
and Sos (12). Recently, it has been discovered that proteins can bind
directly to the autophosphorylated insulin receptor through their SH2
domains, opening new avenues for investigation (13).
-centaurin) of ARF proteins. It
is certain that the list of potential downstream effectors of insulin
receptor signaling will rapidly expand, as additional protein targets
of 3'-phosphoinositides are discovered.
View larger version (28K):
[in a new window]
Fig. 1.
Signaling elements downstream of
p21ras and phosphatidylinositol 3-kinase products regulated
by insulin and insulin-like growth factor receptors. PKC,
protein kinase C; MAP, mitogen-activated protein;
MEK, MAP kinase kinase.
Multiple Signaling Pathways Regulate Glucose Transport
-adrenergic agonists in skeletal muscle (40) and brown fat (41),
-adrenergic agonists in heart muscle (42), bradykinin in skeletal
muscle (43), thrombin in platelets, reflecting GLUT3 translocation
(44), and adenosine in white (45) and brown fat (46). These effects of
catecholamines and bradykinin are not blocked by wortmannin, suggesting
independence of the actions of most known isoforms of PI 3-kinase.
Particularly interesting is the reported effect of adenosine to
potentiate the stimulation by insulin of glucose uptake in brown fat
cells from 15- to 30-fold (46). The data suggest that the adenosine
receptor-coupled Gq protein species is linked to glucose
transport regulation.
Regulators and signaling pathways reported to stimulate glucose
transport
Role of Docking Proteins and PI 3-Kinase Localization
Downstream Targets of 3'-Phosphoinositides
-centaurin, which contains some sequence similarity to ARF
GTPase-activating protein (68). Taken together, these discoveries of
proteins that bind directly to PI 3-kinase products and regulate known
membrane modulators such as ARF proteins highlight a potentially rich
interface between signaling and membrane trafficking.
(Fig. 1) is activated by polyphosphoinositides, is
stimulated in intact cells by insulin in a wortmannin-sensitive manner,
and may contribute to glucose transport regulation. Another prime candidate has been Akt/protein kinase B, which is activated in conjunction with its binding to these lipids by the
3'-polyphosphoinositide-dependent protein kinase PDK1 and
another protein kinase (70). Expression of membrane-directed constructs
of Akt/protein kinase B in 3T3-L1 adipocytes (71), primary adipocytes
(72), and L6 myotubes (73) stimulates GLUT4 translocation, and it is
claimed that a dominant inhibitory construct blocks this process (72).
However, in well controlled experiments using a mutant Akt/protein
kinase B with alanines substituted at phosphorylation sites threonine 308 and serine 473 as a dominant inhibitory construct in both Chinese
hamster ovary cells and 3T3-L1 adipocytes, protein synthesis but not
insulin-stimulated glucose transport was inhibited (74). These studies
have recently been extended (75) to suggest that protein kinase C
is
directly involved in GLUT4 translocation. Taken together, there is not
yet a clear consensus of data derived from multiple laboratories that
any of the known protein kinases downstream of PI 3-kinase directly
mediates insulin action on glucose transport.
Conclusions and Future Directions
and , regulatory protein
kinases of the Akt/protein kinase B system, tyrosine kinases Itk/Btk/Tec, the early endosome regulator EEA1, and ARF exchange factors GRP1, ARNO, and cytohesin-1. Because PI 3-kinase appears to be
required for glucose transport regulation by insulin, future work is
likely to connect one or more of these proteins (or additional ones to
be discovered) to specific membrane trafficking components involved in
GLUT4 translocation. We have also learned that additional cellular
signaling elements such as trimeric G proteins, NO, and cGMP can
regulate glucose transport and that unknown signaling events may be
required in conjunction with PI 3-kinase for insulin to act. In the
meantime, progress is being made on understanding the components of
membrane systems through which GLUT4 traverses in insulin-sensitive
cells, as will be discussed in the accompanying minireviews on this
topic (5, 6). Merging these two fertile research fields, signaling and
membrane trafficking, will be the natural result of future exciting
work on the mechanisms that underlie GLUT4 regulation.
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
Top
Introduction
References
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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C. A. Eyster, Q. S. Duggins, and A. L. Olson Expression of Constitutively Active Akt/Protein Kinase B Signals GLUT4 Translocation in the Absence of an Intact Actin Cytoskeleton J. Biol. Chem., May 6, 2005; 280(18): 17978 - 17985. [Abstract] [Full Text] [PDF]
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M. Sadagurski, G. Weingarten, C. J. Rhodes, M. F. White, and E. Wertheimer Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport J. Biol. Chem., April 15, 2005; 280(15): 14536 - 14544. [Abstract] [Full Text] [PDF]
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J. Yang and G. D. Holman Insulin and Contraction Stimulate Exocytosis, but Increased AMP-activated Protein Kinase Activity Resulting from Oxidative Metabolism Stress Slows Endocytosis of GLUT4 in Cardiomyocytes J. Biol. Chem., February 11, 2005; 280(6): 4070 - 4078. [Abstract] [Full Text] [PDF]
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M. D. Bruss, E. B. Arias, G. E. Lienhard, and G. D. Cartee Increased Phosphorylation of Akt Substrate of 160 kDa (AS160) in Rat Skeletal Muscle in Response to Insulin or Contractile Activity Diabetes, January 1, 2005; 54(1): 41 - 50. [Abstract] [Full Text] [PDF]
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A. Navarrete Santos, S. Tonack, M. Kirstein, S. Kietz, and B. Fischer Two insulin-responsive glucose transporter isoforms and the insulin receptor are developmentally expressed in rabbit preimplantation embryos Reproduction, November 1, 2004; 128(5): 503 - 516. [Abstract] [Full Text] [PDF]
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D. Sbrissa, O. C. Ikonomov, J. Strakova, and A. Shisheva Role for a Novel Signaling Intermediate, Phosphatidylinositol 5-Phosphate, in Insulin-Regulated F-Actin Stress Fiber Breakdown and GLUT4 Translocation Endocrinology, November 1, 2004; 145(11): 4853 - 4865. [Abstract] [Full Text] [PDF]
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A. Guilherme, N. A. Soriano, P. S. Furcinitti, and M. P. Czech Role of EHD1 and EHBP1 in Perinuclear Sorting and Insulin-regulated GLUT4 Recycling in 3T3-L1 Adipocytes J. Biol. Chem., September 17, 2004; 279(38): 40062 - 40075. [Abstract] [Full Text] [PDF]
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P. Mitra, X. Zheng, and M. P. Czech RNAi-based Analysis of CAP, Cbl, and CrkII Function in the Regulation of GLUT4 by Insulin J. Biol. Chem., September 3, 2004; 279(36): 37431 - 37435. [Abstract] [Full Text] [PDF]
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J. P. Kirwan, A. Varastehpour, M. Jing, L. Presley, J. Shao, J. E. Friedman, and P. M. Catalano Reversal of Insulin Resistance Postpartum Is Linked to Enhanced Skeletal Muscle Insulin Signaling J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4678 - 4684. [Abstract] [Full Text] [PDF]
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M. Kanzaki, M. Furukawa, W. Raab, and J. E. Pessin Phosphatidylinositol 4,5-Bisphosphate Regulates Adipocyte Actin Dynamics and GLUT4 Vesicle Recycling J. Biol. Chem., July 16, 2004; 279(29): 30622 - 30633. [Abstract] [Full Text] [PDF]
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L. Raimondi, P. De Paoli, E. Mannucci, G. Lonardo, L. Sartiani, G. Banchelli, R. Pirisino, A. Mugelli, and E. Cerbai Restoration of Cardiomyocyte Functional Properties by Angiotensin II Receptor Blockade in Diabetic Rats Diabetes, July 1, 2004; 53(7): 1927 - 1933. [Abstract] [Full Text] [PDF]
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S. Murakami, T. Sasaoka, T. Wada, K. Fukui, K. Nagira, H. Ishihara, I. Usui, and M. Kobayashi Impact of Src Homology 2-Containing Inositol 5'-Phosphatase 2 on the Regulation of Insulin Signaling Leading to Protein Synthesis in 3T3-L1 Adipocytes Cultured with Excess Amino Acids Endocrinology, July 1, 2004; 145(7): 3215 - 3223. [Abstract] [Full Text] [PDF]
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M. Blaustein, F. Pelisch, O. A. Coso, M. J. Bissell, A. R. Kornblihtt, and A. Srebrow Mammary Epithelial-Mesenchymal Interaction Regulates Fibronectin Alternative Splicing via Phosphatidylinositol 3-Kinase J. Biol. Chem., May 14, 2004; 279(20): 21029 - 21037. [Abstract] [Full Text] [PDF]
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T. Sasaoka, T. Wada, K. Fukui, S. Murakami, H. Ishihara, R. Suzuki, K. Tobe, T. Kadowaki, and M. Kobayashi SH2-containing Inositol Phosphatase 2 Predominantly Regulates Akt2, and Not Akt1, Phosphorylation at the Plasma Membrane in Response to Insulin in 3T3-L1 Adipocytes J. Biol. Chem., April 9, 2004; 279(15): 14835 - 14843. [Abstract] [Full Text] [PDF]
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T. J. Povsic, T. A. Kohout, and R. J. Lefkowitz {beta}-Arrestin1 Mediates Insulin-like Growth Factor 1 (IGF-1) Activation of Phosphatidylinositol 3-Kinase (PI3K) and Anti-apoptosis J. Biol. Chem., December 19, 2003; 278(51): 51334 - 51339. [Abstract] [Full Text] [PDF]
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A. L. Olson, C. A. Eyster, Q. S. Duggins, and J. B. Knight Insulin Promotes Formation of Polymerized Microtubules by a Phosphatidylinositol 3-Kinase-Independent, Actin-Dependent Pathway in 3T3-L1 Adipocytes Endocrinology, November 1, 2003; 144(11): 5030 - 5039. [Abstract] [Full Text] [PDF]
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L.-B. Liu, W. Omata, I. Kojima, and H. Shibata Insulin Recruits GLUT4 from Distinct Compartments via Distinct Traffic Pathways with Differential Microtubule Dependence in Rat Adipocytes J. Biol. Chem., August 8, 2003; 278(32): 30157 - 30169. [Abstract] [Full Text] [PDF]
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H. Sakoda, Y. Gotoh, H. Katagiri, M. Kurokawa, H. Ono, Y. Onishi, M. Anai, T. Ogihara, M. Fujishiro, Y. Fukushima, et al. Differing Roles of Akt and Serum- and Glucocorticoid-regulated Kinase in Glucose Metabolism, DNA Synthesis, and Oncogenic Activity J. Biol. Chem., July 3, 2003; 278(28): 25802 - 25807. [Abstract] [Full Text] [PDF]
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Z. Y. Jiang, Q. L. Zhou, K. A. Coleman, M. Chouinard, Q. Boese, and M. P. Czech Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing PNAS, June 24, 2003; 100(13): 7569 - 7574. [Abstract] [Full Text] [PDF]
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W. Lee-Kwon, K. Kawano, J. W. Choi, J. H. Kim, and M. Donowitz Lysophosphatidic Acid Stimulates Brush Border Na+/H+ Exchanger 3 (NHE3) Activity by Increasing Its Exocytosis by an NHE3 Kinase A Regulatory Protein-dependent Mechanism J. Biol. Chem., May 2, 2003; 278(19): 16494 - 16501. [Abstract] [Full Text] [PDF]
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H. Sano, S. Kane, E. Sano, C. P. Miinea, J. M. Asara, W. S. Lane, C. W. Garner, and G. E. Lienhard Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation J. Biol. Chem., April 18, 2003; 278(17): 14599 - 14602. [Abstract] [Full Text] [PDF]
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I. Usui, T. Imamura, J. Huang, H. Satoh, and J. M. Olefsky Cdc42 Is a Rho GTPase Family Member That Can Mediate Insulin Signaling to Glucose Transport in 3T3-L1 Adipocytes J. Biol. Chem., April 11, 2003; 278(16): 13765 - 13774. [Abstract] [Full Text] [PDF]
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J. T. Brozinick Jr, B. R. Roberts, and G. L. Dohm Defective Signaling Through Akt-2 and -3 But Not Akt-1 in Insulin-Resistant Human Skeletal Muscle: Potential Role in Insulin Resistance Diabetes, April 1, 2003; 52(4): 935 - 941. [Abstract] [Full Text] [PDF]
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B. Kalderon, N. Mayorek, L. Ben-Yaacov, and J. Bar-Tana Adipose tissue sensitization to insulin induced by troglitazone and MEDICA 16 in obese Zucker rats in vivo Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E795 - E803. [Abstract] [Full Text] [PDF]
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F. Tremblay, C. Lavigne, H. Jacques, and A. Marette Dietary Cod Protein Restores Insulin-Induced Activation of Phosphatidylinositol 3-Kinase/Akt and GLUT4 Translocation to the T-Tubules in Skeletal Muscle of High-Fat-Fed Obese Rats Diabetes, January 1, 2003; 52(1): 29 - 37. [Abstract] [Full Text] [PDF]
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Y. Nakamichi, M. Ohara-Imaizumi, H. Ishida, and S. Nagamatsu An insulin-related peptide expressed in 3T3L1 adipocytes is localized in GLUT4 vesicles and secreted in response to exogenous insulin, which augments the insulin-stimulated glucose uptake J. Cell Sci., January 1, 2003; 116(1): 73 - 79. [Abstract] [Full Text] [PDF]
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O. C. Ikonomov, D. Sbrissa, K. Mlak, and A. Shisheva Requirement for PIKfyve Enzymatic Activity in Acute and Long-Term Insulin Cellular Effects Endocrinology, December 1, 2002; 143(12): 4742 - 4754. [Abstract] [Full Text] [PDF]
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A. Kalandadze, Y. Wu, and M. B. Robinson Protein Kinase C Activation Decreases Cell Surface Expression of the GLT-1 Subtype of Glutamate Transporter. REQUIREMENT OF A CARBOXYL-TERMINAL DOMAIN AND PARTIAL DEPENDENCE ON SERINE 486 J. Biol. Chem., November 22, 2002; 277(48): 45741 - 45750. [Abstract] [Full Text] [PDF]
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M. Armoni, M. J. Quon, G. Maor, S. Avigad, D. N. Shapiro, C. Harel, D. Esposito, Y. Goshen, I. Yaniv, and E. Karnieli PAX3/Forkhead Homolog in Rhabdomyosarcoma Oncoprotein Activates Glucose Transporter 4 Gene Expression in Vivo and in Vitro J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5312 - 5324. [Abstract] [Full Text] [PDF]
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J. Farhang-Fallah, V. K. Randhawa, A. Nimnual, A. Klip, D. Bar-Sagi, and M. Rozakis-Adcock The Pleckstrin Homology (PH) Domain-Interacting Protein Couples the Insulin Receptor Substrate 1 PH Domain to Insulin Signaling Pathways Leading to Mitogenesis and GLUT4 Translocation Mol. Cell. Biol., October 15, 2002; 22(20): 7325 - 7336. [Abstract] [Full Text] [PDF]
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H. Ishihara, T. Sasaoka, M. Ishiki, T. Wada, H. Hori, S. Kagawa, and M. Kobayashi Membrane Localization of Src Homology 2-Containing Inositol 5'-Phosphatase 2 via Shc Association Is Required for the Negative Regulation of Insulin Signaling in Rat1 Fibroblasts Overexpressing Insulin Receptors Mol. Endocrinol., October 1, 2002; 16(10): 2371 - 2381. [Abstract] [Full Text] [PDF]
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B. A. Zinker, C. M. Rondinone, J. M. Trevillyan, R. J. Gum, J. E. Clampit, J. F. Waring, N. Xie, D. Wilcox, P. Jacobson, L. Frost, et al. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice PNAS, August 20, 2002; 99(17): 11357 - 11362. [Abstract] [Full Text] [PDF]
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H. Hori, T. Sasaoka, H. Ishihara, T. Wada, S. Murakami, M. Ishiki, and M. Kobayashi Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice Diabetes, August 1, 2002; 51(8): 2387 - 2394. [Abstract] [Full Text] [PDF]
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M. Tsuru, H. Katagiri, T. Asano, T. Yamada, S. Ohno, T. Ogihara, and Y. Oka Role of PKC isoforms in glucose transport in 3T3-L1 adipocytes: insignificance of atypical PKC Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E338 - E345. [Abstract] [Full Text] [PDF]
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A. Zeigerer, M. A. Lampson, O. Karylowski, D. D. Sabatini, M. Adesnik, M. Ren, and T. E. McGraw GLUT4 Retention in Adipocytes Requires Two Intracellular Insulin-regulated Transport Steps Mol. Biol. Cell, July 1, 2002; 13(7): 2421 - 2435. [Abstract] [Full Text] [PDF]
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T. Ogihara, T. Asano, K. Ando, H. Sakoda, M. Anai, N. Shojima, H. Ono, Y. Onishi, M. Fujishiro, M. Abe, et al. High-Salt Diet Enhances Insulin Signaling and Induces Insulin Resistance in Dahl Salt-Sensitive Rats Hypertension, July 1, 2002; 40(1): 83 - 89. [Abstract] [Full Text] [PDF]
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N. Shojima, H. Sakoda, T. Ogihara, M. Fujishiro, H. Katagiri, M. Anai, Y. Onishi, H. Ono, K. Inukai, M. Abe, et al. Humoral Regulation of Resistin Expression in 3T3-L1 and Mouse Adipose Cells Diabetes, June 1, 2002; 51(6): 1737 - 1744. [Abstract] [Full Text] [PDF]
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H. Katagiri, T. Asano, T. Yamada, T. Aoyama, Y. Fukushima, M. Kikuchi, T. Kodama, and Y. Oka Acyl-Coenzyme A Dehydrogenases Are Localized on GLUT4-Containing Vesicles via Association with Insulin-Regulated Aminopeptidase in a Manner Dependent on Its Dileucine Motif Mol. Endocrinol., May 1, 2002; 16(5): 1049 - 1059. [Abstract] [Full Text] [PDF]
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S. Shigematsu, A. H. Khan, M. Kanzaki, and J. E. Pessin Intracellular Insulin-Responsive Glucose Transporter (GLUT4) Distribution But Not Insulin-Stimulated GLUT4 Exocytosis and Recycling Are Microtubule Dependent Mol. Endocrinol., May 1, 2002; 16(5): 1060 - 1068. [Abstract] [Full Text] [PDF]
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T. A. Kupriyanova, V. Kandror, and K. V. Kandror Isolation and Characterization of the Two Major Intracellular Glut4 Storage Compartments J. Biol. Chem., March 8, 2002; 277(11): 9133 - 9138. [Abstract] [Full Text] [PDF]
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F. S.L. Thong, W. Derave, B. Kiens, T. E. Graham, B. Urso, J. F.P. Wojtaszewski, B. F. Hansen, and E. A. Richter Caffeine-Induced Impairment of Insulin Action but Not Insulin Signaling in Human Skeletal Muscle Is Reduced by Exercise Diabetes, March 1, 2002; 51(3): 583 - 590. [Abstract] [Full Text] [PDF]
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T. Suhara, H.-S. Kim, L. A. Kirshenbaum, and K. Walsh Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation Mol. Cell. Biol., January 15, 2002; 22(2): 680 - 691. [Abstract] [Full Text] [PDF]
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Z. Y. Jiang, A. Chawla, A. Bose, M. Way, and M. P. Czech A Phosphatidylinositol 3-Kinase-independent Insulin Signaling Pathway to N-WASP/Arp2/3/F-actin Required for GLUT4 Glucose Transporter Recycling J. Biol. Chem., January 4, 2002; 277(1): 509 - 515. [Abstract] [Full Text]
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S. F. Kralik, P. Liu, B. J. Leffler, and J. S. Elmendorf Ceramide and Glucosamine Antagonism of Alternate Signaling Pathways Regulating Insulin- and Osmotic Shock-Induced Glucose Transporter 4 Translocation Endocrinology, January 1, 2002; 143(1): 37 - 46. [Abstract] [Full Text] [PDF]
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J. Shao, H. Yamashita, L. Qiao, B. Draznin, and J. E. Friedman Phosphatidylinositol 3-Kinase Redistribution Is Associated With Skeletal Muscle Insulin Resistance in Gestational Diabetes Mellitus Diabetes, January 1, 2002; 51(1): 19 - 29. [Abstract] [Full Text] [PDF]
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C. J. Tanner, T. R. Koves, R. L. Cortright, W. J. Pories, Y.-B. Kim, B. B. Kahn, G. L. Dohm, and J. A. Houmard Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E147 - E153. [Abstract] [Full Text] [PDF]
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J. G. Park, A. Bose, J. Leszyk, and M. P. Czech PYK2 as a Mediator of Endothelin-1/Galpha 11 Signaling to GLUT4 Glucose Transporters J. Biol. Chem., December 14, 2001; 276(51): 47751 - 47754. [Abstract] [Full Text] [PDF]
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J. C. Molero, J. P. Whitehead, T. Meerloo, and D. E. James Nocodazole Inhibits Insulin-stimulated Glucose Transport in 3T3-L1 Adipocytes via a Microtubule-independent Mechanism J. Biol. Chem., November 16, 2001; 276(47): 43829 - 43835. [Abstract] [Full Text] [PDF]
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S. Kristiansen, J. N. Nielsen, S. Bourgoin, A. Klip, M. Franco, and E. A. Richter GLUT-4 translocation in skeletal muscle studied with a cell-free assay: involvement of phospholipase D Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E608 - E618. [Abstract] [Full Text] [PDF]
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A. Takano, I. Usui, T. Haruta, J. Kawahara, T. Uno, M. Iwata, and M. Kobayashi Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin Mol. Cell. Biol., August 1, 2001; 21(15): 5050 - 5062. [Abstract] [Full Text] [PDF]
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J. T. R. Lawrence and M. J. Birnbaum ADP-Ribosylation Factor 6 Delineates Separate Pathways Used by Endothelin 1 and Insulin for Stimulating Glucose Uptake in 3T3-L1 Adipocytes Mol. Cell. Biol., August 1, 2001; 21(15): 5276 - 5285. [Abstract] [Full Text] [PDF]
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A. Takano, T. Haruta, M. Iwata, I. Usui, T. Uno, J. Kawahara, E. Ueno, T. Sasaoka, and M. Kobayashi Growth Hormone Induces Cellular Insulin Resistance by Uncoupling Phosphatidylinositol 3-Kinase and Its Downstream Signals in 3T3-L1 Adipocytes Diabetes, August 1, 2001; 50(8): 1891 - 1900. [Abstract] [Full Text] [PDF]
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F. Tremblay, C. Lavigne, H. Jacques, and A. Marette Defective Insulin-Induced GLUT4 Translocation in Skeletal Muscle of High Fat-Fed Rats Is Associated With Alterations in Both Akt/Protein Kinase B and Atypical Protein Kinase C ({zeta}/{lambda}) Activities Diabetes, August 1, 2001; 50(8): 1901 - 1910. [Abstract] [Full Text] [PDF]
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J. Ostrowski, Y. Kawata, D. S. Schullery, O. N. Denisenko, Y. Higaki, C. K. Abrass, and K. Bomsztyk Insulin alters heterogeneous nuclear ribonucleoprotein K protein binding to DNA and RNA PNAS, July 19, 2001; (2001) 161284098. [Abstract] [Full Text] [PDF]
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J. S. Bogan, A. E. McKee, and H. F. Lodish Insulin-Responsive Compartments Containing GLUT4 in 3T3-L1 and CHO Cells: Regulation by Amino Acid Concentrations Mol. Cell. Biol., July 15, 2001; 21(14): 4785 - 4806. [Abstract] [Full Text] [PDF]
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N. Spravchikov, G. Sizyakov, M. Gartsbein, D. Accili, T. Tennenbaum, and E. Wertheimer Glucose Effects on Skin Keratinocytes: Implications for Diabetes Skin Complications Diabetes, July 1, 2001; 50(7): 1627 - 1635. [Abstract] [Full Text] [PDF]
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C. Aguayo, C. Flores, J. Parodi, R. Rojas, G. E Mann, J. D Pearson, and L. Sobrevia Modulation of adenosine transport by insulin in human umbilical artery smooth muscle cells from normal or gestational diabetic pregnancies J. Physiol., July 1, 2001; 534(1): 243 - 254. [Abstract] [Full Text] [PDF]
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G. Condorelli, G. Vigliotta, A. Trencia, M. A. Maitan, M. Caruso, C. Miele, F. Oriente, S. Santopietro, P. Formisano, and F. Beguinot Protein Kinase C (PKC)-{alpha} Activation Inhibits PKC-{zeta} and Mediates the Action of PED/PEA-15 on Glucose Transport in the L6 Skeletal Muscle Cells Diabetes, June 1, 2001; 50(6): 1244 - 1252. [Abstract] [Full Text]
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 X.-h. Tang and N. F. Shay Zinc Has an Insulin-Like Effect on Glucose Transport Mediated by Phosphoinositol-3-Kinase and Akt in 3T3-L1 Fibroblasts and Adipocytes J. Nutr., May 1, 2001; 131(5): 1414 - 1420. [Abstract] [Full Text]
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 S. Salvi Protecting the Myocardium From Ischemic Injury : A Critical Role for {{alpha}}1-Adrenoreceptors? Chest, April 1, 2001; 119(4): 1242 - 1249. [Abstract] [Full Text] [PDF]
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V. P. Manchem, I. D. Goldfine, R. A. Kohanski, C. P. Cristobal, R. T. Lum, S. R. Schow, S. Shi, W. R. Spevak, E. Laborde, D. K. Toavs, et al. A Novel Small Molecule That Directly Sensitizes the Insulin Receptor In Vitro and In Vivo Diabetes, April 1, 2001; 50(4): 824 - 830. [Abstract] [Full Text]
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V. A. Skeberdis, J.-y. Lan, X. Zheng, R. S. Zukin, and M. V. L. Bennett Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis PNAS, March 13, 2001; 98(6): 3561 - 3566. [Abstract] [Full Text] [PDF]
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T. Wada, T. Sasaoka, M. Funaki, H. Hori, S. Murakami, M. Ishiki, T. Haruta, T. Asano, W. Ogawa, H. Ishihara, et al. Overexpression of SH2-Containing Inositol Phosphatase 2 Results in Negative Regulation of Insulin-Induced Metabolic Actions in 3T3-L1 Adipocytes via Its 5'-Phosphatase Catalytic Activity Mol. Cell. Biol., March 1, 2001; 21(5): 1633 - 1646. [Abstract] [Full Text]
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 D. Le Roith and Y. Zick Recent Advances in Our Understanding of Insulin Action and Insulin Resistance Diabetes Care, March 1, 2001; 24(3): 588 - 597. [Abstract] [Full Text]
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