The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 972-979
Copyright © 2001 by The Endocrine Society
The Insulin Receptor and Its Cellular Targets1
Yoshiaki Kido,
Jun Nakae and
Domenico Accili
Department of Medicine, Columbia University College of Physicians
and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Domenico Accili, M.D., Russ Berrie Science Pavilion, 1150 St. Nicholas Avenue, New York, New York 10032. E-mail: da230{at}columbia.edu
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Abstract
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The pleiotropic actions of insulin are mediated by a single receptor
tyrosine kinase. Structure/function relationships of the insulin
receptor have been conclusively established, and the early steps of
insulin signaling are known in some detail. A generally accepted
paradigm is that insulin receptors, acting through insulin receptor
substrates, stimulate the lipid kinase activity of phosphatidylinositol
3-kinase. The rapid rise in Tris-phosphorylated inositol
(PIP3) that ensues triggers a cascade of
PIP3-dependent serine/threonine kinases. Among the latter,
Akt (a product of the akt protooncogene) and atypical
protein kinase C isoforms are thought to be involved in insulin
regulation of glucose transport and oxidation; glycogen, lipid, and
protein synthesis; and modulation of gene expression. The presence of
multiple insulin-regulated, PIP3-dependent kinases is
consistent with the possibility that different pathways are required to
regulate different biological actions of insulin. Additional work
remains to be performed to understand the distal components of insulin
signaling. Moreover, there exists substantial evidence for insulin
receptor substrate- and/or phosphatidylinositol 3-kinase-independent
pathways of insulin action. The ultimate goal of these investigations
is to provide clues to the pathogenesis and treatment of the insulin
resistant state that is characteristic of type 2 diabetes.
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Introduction
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THIS YEAR MARKS the 50th anniversary of the
seminal paper in which Levine and co-workers reported that insulin’s
effect on glucose utilization was mediated by increased membrane
permeability to glucose (1). Twenty years later, Roth and
colleagues discovered the insulin receptor (2), thus
ushering in a new era of investigations that led to determination of
the molecular basis of insulin action. Activation of the insulin
receptor triggers complex biochemical reactions required for insulin’s
biological effects. However, a detailed road map of insulin receptor
signaling is, with some noticeable exceptions, not available. Indeed,
even in those instances where a defined chain of events from the
receptor to its effector(s) has been established, such molecular
mechanisms do not provide a complete explanation of the biological
actions of insulin. Thus, despite enormous strides in understanding the
elusive mechanism by which insulin regulates fuel homeostasis and
growth, numerous questions remain unanswered.
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Insulin receptor 1971–2000
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The insulin receptor is necessary and sufficient to mediate
insulin action. Humans and mice lacking insulin receptors are born at
term, but do not survive long, suggesting that insulin receptors are
essential for postnatal growth and fuel metabolism, but are not
required for fetal metabolism (3, 4). Since the landmark
paper describing specific insulin binding to rat liver membranes
(2), structure/function relationships of the insulin
receptor have been conclusively established using numerous approaches.
These include site-directed mutagenesis (5) and a host of
naturally occurring mutations identified in patients with genetic
syndromes of extreme insulin resistance (6). In recent
years, designer mice bearing constitutive or conditional null alleles
of the insulin receptor have provided substantial insight into its
in vivo function (4, 7, 8, 9, 10, 11). Moreover,
determination of the crystal structure of the receptor’s kinase domain
has provided a mechanistic link between insulin binding and receptor
activation (12, 13). The molecular basis of ligand binding
to the receptor and its unique kinetic properties [negative
cooperativity (14)] has proven more difficult to tackle
due to the difficulty of crystallizing the carbohydrate-rich
ectodomain.
The complete insulin receptor is a heterotetrameric membrane
glycoprotein composed of two 
- and two ß-subunits, linked together
by disulfide bonds (Fig. 1
). Insulin
binds to the receptor’s extracellular -subunit. Insulin binding
presumably brings the two -subunits closer together. This
conformational change enables ATP binding to the ß-subunit’s
intracellular domain. ATP binding activates receptor
autophosphorylation (12, 13), which, in turn, enables the
receptor’s kinase activity toward intracellular protein substrates.
There are numerous autophosphorylation sites in the ßsubunit’s
intracellular domain. Three main clusters have been recognized to play
a functionally important role. They include Y1158,
Y1160, and Y1162 in the
active loop of the catalytic domain, Y972 in the
juxtamembrane domain, and Y1328 and Y
1334 in the carboxyl-terminal domain.
Phosphorylation of residues in the active loop is essential to promote
the receptor’s kinase activity. The carboxyl-terminal phosphorylation
sites may play a role in the receptor’s mitogenic activity. The
juxtamembrane autophosphorylation site plays an important role in the
interaction between the receptor and its intracellular substrates,
providing a docking site to increase the stability of the
receptor/substrate complex (5).
In addition to binding insulin, the insulin receptor can bind
insulin-like growth factors (IGF-I and IGF-II). The affinity of IGF-I
binding to the insulin receptor is in the high nanomolar range,
approximately 100- to 1000-fold lower than insulin’s affinity
(15). However, as circulating IGF-I levels are
approximately 100-fold higher than those of insulin, the potential
exists for IGF-I binding and acting through the insulin receptor.
Strongly supportive evidence to this effect comes from the observation
that the growth of mice lacking both IGF-I receptor and IGF-II receptor
is rescued by insulin receptors, presumably in response to IGF-I
binding (16).
IGF-II binds with equal affinity to both IGF-I receptor and insulin
receptor. In rodents, during embryonic growth, IGF-II binds to the
insulin receptor to promote growth (17, 18, 19). The molecular
basis for high affinity IGF-II binding to the insulin receptor has been
proposed to reside within the alternatively spliced exon 11 of the
insulin receptor gene. The insulin receptor is expressed as two
isoforms, resulting from alternative splicing of exon 11. Isoform B
contains a 12-amino acid peptide located at the carboxyl-terminal end
of the receptor’s -subunit. Isoform A lacks this insertion. Frasca
and colleagues have suggested that splicing of exon 11 to yield isoform
A bestows on the insulin receptor the ability to bind IGF-II with high
affinity (20).
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Insulin receptor substrates (IRSs)
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IRSs represent key elements in insulin and IGF actions
(21). Insulin, IGF-I, and certain cytokine receptors
phosphorylate IRSs at specific Y-x-x-M motifs. These motifs serve as
molecular adhesives. Phosphorylation of their tyrosine residues
increases the affinity with which IRS proteins bind other signaling
molecules. Each tyrosine-phosphorylated motif binds to a specific
signaling molecule. In this way, protein-protein complexes are formed,
and various signaling pathways are engaged, providing a potential
explanation for the diversity of insulin signaling (22)
(Fig. 2).
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Figure 2. Insulin signaling pathways. The
diversity of insulin action can potentially be explained by the
activation of multiple signaling pathways. The pathways emanating from
activation of IRS proteins are described. The IRS/PI 3-K pathway leads
to the generation of PIP3 and the consequent activation of
PIP3-dependent kinases. The Ras/mitogen-activated protein
kinase kinase pathway can be activated by insulin through the formation
of complexes between the exchange factors SOS and growth factor
receptor binding protein 2 (GRB2) and may play a role in certain
tissues to stimulate the actions of insulin on growth and
proliferation. SOS, son-of-sevenless; GAP, GTPase-associated
protein; PDK, PI-dependent protein kinase; MAPKK, mitogen-activated
protein kinase kinase; MAPK, mitogen-activated protein kinase; GSK3,
glycogen synthase kinase 3.
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Different roles of IRS proteins
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The IRS family is composed of four closely related members (IRS-1
to -4) (23, 24, 25, 26) and a more distantly related homolog,
Gab-1 (27). Genetic ablation studies in mice have
conclusively shown substantial differences in the abilities of various
IRSs to mediate insulin action. Ablation of IRS-1 causes severe growth
retardation with mild insulin resistance (28, 29),
suggesting an important role of IRS-1 in both insulin and IGF actions.
In contrast, ablation of IRS-2 causes combined insulin resistance in
peripheral tissues and impaired growth of pancreatic ß-cells
(30). The findings in the IRS-2-deficient mouse
recapitulate the natural history of type 2 diabetes and have led to the
suggestion that IRS-2 is a diabetes-predisposing gene, a conclusion
that is not borne out by genetic analyses carried out to date
(31, 32, 33). Ablation of IRS-3 is devoid of a clear phenotype
(34), whereas ablation of IRS-4 is associated with modest
growth retardation and insulin resistance (35). Finally,
inactivation of Gab-1 has an embryonic lethal phenotype that suggests a
role in hepatic growth factor, rather than insulin, signaling
(36).
As IRS-1 and IRS-2 have widely overlapping tissue distribution, these
finding are consistent with the possibility that each molecule
subserves a specific set of functions. We and others have proposed that
IRS-1 is the main IRS in skeletal muscle, whereas IRS-2 is the main
signaling molecule in liver (9, 30, 37).
An emerging area of investigation is the role of IRS proteins in
ß-cells. Ablation of IRS-2 is associated with impaired ß-cell
growth (30, 38). In contrast, lack of IRS-1 is associated
with impaired coupling of glucose sensing to insulin secretion,
suggesting that IRS-1 signaling is important for ß-cell function
(39). Interestingly, ablation of insulin receptors in
ß-cells results in abnormalities similar to those seen in IRS-1
knockout mice, whereas lack of IGF-I receptors increases the severity
of the IRS-2 knockout phenotype. These findings have lead to the
suggestion that insulin and IGF-I receptor signaling play physiological
roles in ß-cell function (10, 38, 40).
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Are all the actions of insulin mediated through IRS
proteins?
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To address this question, it is interesting to compare the
phenotypes of insulin receptor- and IRS-deficient mice. In every case,
ablation of IRS proteins is associated with a much milder phenotype
than lack of insulin receptors. Even the lack of IRS-2 does not have
such a rapidly lethal effect as the lack of insulin receptors.
Moreover, lack of IRS-2 is associated with a specific ß-cell defect
and does not lead to extreme insulin resistance. Even after three of
four IRS-1 and IRS-2 alleles have been ablated (for example, in
Irs-1-/-Irs-2+/-
mice), insulin resistance in newborn mice is not nearly as severe as
that in insulin receptor knockout mice (38). On the other
hand, mice lacking both IRS-1 and IRS-2 die before implantation,
resulting in one of the most dramatic embryonic lethal phenotypes
observed in mice with targeted gene mutations (38). This
phenotype is substantially more severe than the phenotype due to
combined lack of insulin and IGF-I receptors (18),
suggesting that IRS proteins play additional roles to mediate the
actions of other receptors, as predicted by studies of cytokine
receptor signaling (22). The phenotype of insulin
receptor-deficient mice indicates that multiple substrates are required
to mediate insulin action. The conclusion of these studies is that the
search for IRSs is not over.
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Role of phosphatidylinositol 3-kinase (PI 3-kinase) in insulin
action
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The enzyme PI 3-kinase catalyzes the addition of phosphate on the
D3 position of the inositol ring of phospoinositol, leading to the
generation of PI 3-phosphate. The enzyme is composed of a regulatory
subunit, which exists in several isoforms (p85-, p85-ß, p55/AS53,
p55PIK, and p50), and a catalytic 110-kDa
subunit. 3-Phosphorylated inositides act as intracellular messengers,
leading to activation of PI-dependent kinases, changes in intracellular
trafficking, and growth stimulation (41). In addition, the
enzyme has protein kinase activity, although there is no evidence yet
for the latter’s involvement in insulin action (42).
Activation of PI 3-kinase is important for many of insulin’s actions.
Thus, blocking PI 3-kinase with the fungal inhibitor wortmannin is
associated with inhibition of insulin-stimulated glucose uptake
(43, 44); glycogen (45, 46), lipid
(44), and protein (47, 48) synthesis; and
modulation of gene expression (49, 50). PI 3-kinase
appears to play a permissive, rather than a necessary and sufficient,
role in insulin action (51). The evidence generally
offered to buttress this conclusion is that although several growth
factors result in activation of PI 3-kinase, only insulin has the
ability to stimulate processes such as glucose transporter 4 (GLUT4)
translocation. This controversy has raged in the literature for the
past decade and is not entirely settled. Convincing evidence for a
direct role of PI 3-kinase in insulin action comes from mice carrying a
deletion of the gene encoding the p85 subunit. These mice develop
hypoglycemia due to increased basal levels of glucose uptake in several
insulin-sensitive tissues (52). One possible
interpretation of these data is that the p85 subunit exerts an
inhibitory role on the kinase activity, and that its ablation increases
the enzyme’s catalytic activity, possibly through association with
other regulatory subunits, such as p50 and p55. Although the latter
point requires further investigation, these data indicate that PI
3-kinase is crucial for insulin action.
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Targets of PI 3-kinase
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Arguably, the most important question in insulin action is to
identify targets of PI 3-kinase that may account for the specificity of
insulin signaling. The rapid increase in Tris-phosphorylated inositol
(PIP3) concentration in response to insulin
stimulation activates several PIP3-dependent
serine/threonine kinases, such as PI-dependent protein kinase-1 and -2
(53), Akt (a product of the akt protooncogene)
(54), salt- and glucocorticoid-induced kinases
(55), protein kinase C (PKC) (56),
wortmannin-sensitive and insulin-stimulated serine kinase
(57), and others (58). Among the
PIP3-dependent kinases, Akt has received much
attention. The Akt kinase exists as three different isoforms, all
of which are activated by phosphorylation on T308
and S473 (59, 60). Upon growth
factor stimulation, Akt localizes near the plasma membrane, where it
becomes phosphorylated. The activated enzyme has the ability to
translocate to the nucleus (61) (Fig. 3). Expression of constitutively active
Akt stimulates glucose uptake in 3T3-L1 adipocytes
(62, 63, 64), whereas Akt inhibition through the use of
dominant negative mutants does not completely inhibit the insulin
effect on glucose transport (65). These results suggest
that regulation of glucose transport may involve multiple kinases. Akt
has the ability to phosphorylate proteins that regulate lipid synthesis
(66), glycogen synthesis (67, 68), cell
survival (69), and protein synthesis (70, 71). This mechanism provides a direct link between insulin
receptor signaling and biological effects. Nevertheless, it is not
clear whether Akt plays a unique or redundant role in insulin
action.
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Figure 3. Akt in insulin action. The rapid increase in
intracellular PIP3 leads to activation of the PI-dependent
kinase-1 and -2 (PDK1 and PDK2). PDK1 and PDK2 phosphorylate Akt on
amino acid residues T308 and S473, leading to
its activation. The identity of PDK2 has not been established, and
there is evidence that PDK1 is the S473 kinase. After
insulin stimulation, Akt undergoes phosphorylation and nuclear
translocation. Some of the known cellular targets of Akt are indicated.
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Members of the PKC family of serine/threonine kinases have been
implicated in several of insulin’s actions. There are four subgroups
of PKCs; the classical ones are activated by calcium binding, whereas
the other three groups can be activated by diacylglycerol or other
phospholipids, such as PIP3 (atypical PKCs).
Different isoforms of PKC have been shown to undergo translocation from
the cytosol to the membrane in response to insulin stimulation in
different tissues (72). Atypical PKCs (
and 
) have
been proposed to play a role in insulin-dependent glucose transport
(73, 74) and protein synthesis (75). It is
also known that PKCs can activate the mitogen-activated protein kinase
pathway and the transcription factor nuclear factor-
B, leading to
increased gene expression and protein synthesis.
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An insulin receptor/PI 3-kinase pathway regulates metabolism and
survival in Caenorhabditis elegans
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The nematode C. elegans has provided novel insight into
the mechanism of insulin action (76). The life span of
C. elegans consists of four developmental stages leading to
the maturation of larvae into adult hermaphrodites. When larvae are
grown at high density or in the presence of high levels of pheromone,
they enter the dauer stage, a reversible arrest of
development characterized by reduced metabolic activity, increased fat
content, and a near doubling of life span (77). A
constitutive dauer stage can be brought about by mutations
in specific genes. The alleles causing a constitutive dauer
phenotype have been dubbed Daf alleles. Mutations of the Daf-2 gene
cause a constitutive dauer phenotype, as do mutations of the
Age-1, Akt-1, and Akt-2 genes (78). The Daf-2 gene encodes
the C. elegans homolog of the insulin/IGF-I receptor gene,
whereas the Age-1 gene is the homolog of PI 3-kinase, and the two Akt
genes represent the homologs of mammalian Akt (79, 80, 81)
(Fig. 4). A parallel pathway implicates
transforming growth factor-ß signaling through SMAD proteins (Daf-1,
Daf-4, Daf-8, and Daf-14 mutations) in the same process
(82). Considerable interest has been generated by the
study of mutations that suppress the effects of the Daf-2, Age-1,
Akt-1, and Akt-2 mutations. Two of them are especially relevant to
insulin signaling through PI 3-kinase: Daf-16 and Daf-18. Daf-16
mutations completely suppress the dauer phenotype due to
Daf-2 mutations, whereas Daf-18 mutations have a less complete ability
to rescue Daf-2 mutations. Daf-16 encodes a transcription factor with
homology to the mammalian forkhead transcription factors
(83), whereas Daf-18 encodes a phosphoinositide
phosphatase with homology to the mammalian phosphatase- and
tensin-homolog deleted on chromosome 10 tumor suppressor gene
(84). Daf-16 is a substrate of Akt (85). The
observations that Daf-16 and Daf-18 are important for insulin receptor
signaling in C. elegans and are regulated in a
PIP3-dependent manner suggest that similar
mechanisms play a role in the regulation of mammalian metabolism.
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Figure 4. Conserved insulin signaling pathways in
C. elegans and mammals. The pathways regulating cellular
metabolism and survival in mammalian cells are conserved in the
nematode C. elegans. Activation of the insulin receptor
ortholog Daf-2 leads to stimulation of Age-1, the PI 3-kinase ortholog.
Targets of Age-1 include Akt-1 and -2, which, in turn, phosphorylate
Daf-16. Age-1 is regulated by Daf-18, the PI phosphatase phosphate- and
tensin-homolog deleted on chromosome 10 ortholog.
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FKHR, the mammalian homologue of the C. elegans Daf-16 gene,
regulates insulin-dependent gene expression
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The Daf-16 gene product belongs to the forkhead family of
transcription factors. These proteins were first identified as the
homeotic gene product of the forkhead mutation in Drosophila
(86). They contain a highly conserved DNA-binding domain,
the forkhead or winged helix domain (87). A subgroup of
forkhead proteins known as FKHR is the closest mammalian homolog of the
Daf-16 gene product. These proteins were first identified as the
products of chromosomal translocations associated with alveolar
rhabdomyosarcoma, hence the acronym ForKhead in
Human Rhabdomyosarcoma (88). The
family includes three expressed genes, FKHR,
FKHRL1, and AFX, and two pseudogenes
(89).
Indeed, based on the presence of binding sites for the forkhead
transcription factor HNF-3, Unterman was the first to propose that such
transcription factors might represent transcriptional regulators of
insulin-responsive genes such as IGF-binding protein-1,
phospho-enolpyruvate carboxykinase, and glucose-6-phosphatase
(49, 90). Several groups have shown that FKHR is
phosphorylated in an insulin-responsive manner by
PIP3-dependent kinases, such as Akt and others
(91, 92, 93, 94, 95, 96, 97, 98, 99, 100). FKHR is a transcriptional enhancer, the targets
of which include genes regulating apoptosis, glucose production, and
entry into the cell cycle (69, 101). Under basal
conditions, FKHR and its homologs, FKHRL-1 and AFX, reside within the
nucleus. When cells are exposed to insulin or other known stimulators
of PI 3-kinase, these transcription factors become phosphorylated at
Akt consensus sites. Phosphorylation is followed by nuclear exclusion
and cytoplasmic retention (69, 101). It follows that FKHR
phosphorylation is a powerful mechanism by which insulin inhibits gene
transcription. The full array of FKHR target genes as well as the
spectrum of FKHR kinases in addition to Akt remain to be
determined.
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What makes GLUT4 tick
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Insulin stimulation of glucose uptake is mediated by translocation
of an intracellular pool of GLUT4 to the plasma membrane (102, 103). Two approaches are being employed to identify elements in
the signal transduction chain leading to GLUT4 translocation: a forward
approach, starting from the insulin receptor, and a backward approach
starting from GLUT4. Like two teams digging up a tunnel starting at
both sides of a mountain, the two approaches will hopefully merge at
some point, although none can predict when. In the worst-case scenario,
we may end up with two tunnels.
The status of the forward approach is summarized in the IRS/PI 3-kinase
and CAP-cbl sections of this review. What do we know about the distal
components of this pathway? Two models have been proposed to account
for insulin’s effect on GLUT4 translocation: a retention model and a
synaptic vesicle model (104). The former would predict
that GLUT4 molecules are prevented from joining the constitutive
cellular recycling compartment from an inhibitory mechanism, or
molecule, that would be inactivated by insulin. The latter envisions a
mechanism analogous to neurotransmitter release, in which a specialized
GLUT4 vesicle would dock onto and fuse with the plasma membrane via a
v-SNARE protein (Vesicle SNAP
Receptor) pairing with appropriate target membrane or
t-SNAREs. It is easily realized that the two models need not be
mutually exclusive.
Considerable progress has been made in identifying the v-SNAREs and
t-SNAREs that facilitate GLUT4 vesicle translocation. VAMP-2 is the
main v-SNARE found in GLUT4 vesicles. The main t-SNAREs found in the
plasma membrane of insulin-sensitive tissues are syntaxin 4 and SNAP-23
(104). Many of the accessory components of GLUT4 vesicles
have been identified, and intensive efforts are underway to isolate
every single constituent of this important subcellular organelle.
Adapter molecules that regulate the interaction between VAMP-2 and
syntaxin-4 in an insulin-dependent manner have been cloned from
protein-protein yeast interaction libraries from 3T3-L1 adipocytes.
Synip is a syntaxin 4-binding protein (105). Insulin
catalyzes Synip dissociation from syntaxin 4. Moreover, inhibition of
Synip dissociation by a dominant negative mutant results in inhibition
of GLUT4 translocation. The mechanism by which insulin causes Synip
dissociation remains unknown. Another syntaxin 4-binding protein is
Munc18. Insulin inhibits binding of Munc18c to syntaxin 4, thereby
increasing binding of VAMP2 to syntaxin 4 (106).
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PI 3-kinase independent pathways of insulin signaling
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As stated above, the possibility exists that not all of the
actions of insulin are mediated through the IRS/PI 3-kinase pathway.
One such example is the pathway mediated through the protein Cbl. Cbl
is a substrate of the insulin receptor kinase in differentiated 3T3-L1
adipocytes, but not in preadipocytes (107). This
differential phosphorylation is due to expression of a Cbl-associated
protein (CAP) (108). Although CAP is not phosphorylated in
response to insulin, it is able to target Cbl to the insulin receptor.
After phosphorylation, Cbl translocates to caveolae, a specialized
subdomain of the plasma membrane. Inhibition of the CAP-Cbl interaction
by dominant negative CAP correlates with inhibition of
insulin-stimulated glucose transport and GLUT4 translocation in a
wortmannin-independent fashion, suggesting that Cbl participates in a
PI 3-kinase-independent mechanism whereby insulin stimulates GLUT4
translocation in adipocytes (109).
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Role of tyrosine phosphatases in insulin action
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Tyrosine phosphatases play a key role in terminating the signal
generated through tyrosine kinases. This family of enzymes comprises
more than 100 different genes. Therefore, it has proven difficult to
identify physiological phosphatases that regulate insulin signaling by
dephosphorylating the insulin receptor and its targets. Experiments in
various cell types have suggested that the receptor type leukocyte
common antigen-related phosphatase is an insulin receptor phosphatase
(110). Accordingly, mice lacking leukocyte common
antigen-related phosphatase exhibit a complex syndrome of insulin
sensitivity and insulin resistance (111). Likewise, mice
lacking protein tyrosine phosphatase 1b present with an insulin
sensitivity syndrome that has suggested that this phosphatase
represents an important modulator of insulin action. Ablation of PTP-1b
in mice is associated with failure to develop insulin resistance when
exposed to a high fat diet (112, 113). These studies
implicate PTP-1b as a physiological mediator of insulin action and as a
potential therapeutic target to develop therapies against diet-induced
obesity.
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Conclusions
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Substantial progress has been made in understanding how insulin
mediates its effects on fuel metabolism. Through a combination of
approaches, from cellular and molecular techniques to transgenic and
knockout mice, many pathways of insulin signaling have been
reconstructed in detail. As outlined in this review, significant
questions remain unanswered. First and foremost is the identification
of the complete chain of events leading from IRS phosphorylation and PI
3-kinase activation to the biological effects of insulin. Second and
not less important is to dissect the role of PI 3-kinase-dependent and
-independent pathways of insulin action. Finally, it remains to be
determined how these complex pathways interact in vivo and
how different tissues contribute to the pathogenesis of the insulin
resistant state of type 2 diabetes.
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Acknowledgments
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We apologize to colleagues whose work we are prevented from
citing either in the text or in the reference section by space
limitations. The expert assistance of Ms. Sharon Jones in manuscript
preparation is gratefully acknowledged.
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Footnotes
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1 This work was supported by NIH Grants DK-58282 and DK-57539 and
Juvenile Diabetes Foundation International Grant 2000-893. 
Received August 29, 2000.
Revised October 10, 2000.
Accepted October 20, 2000.
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Abstract
Introduction
