INSULIN SIGNALING AND ACTION: GLUCOSE, LIPIDS,
Contents
PROTEIN
Contributors
Search
Chapter 2 - Bei B. Zhang, Ph.D.
April 1 , 2002
INTRODUCTION
Diabetes is a chronic metabolic disorder affecting ~ 5% of the population in the industrialized
nations. Lack of or severe reduction in insulin secretion due to autoimmune destruction of -cell is
responsible for type I diabetes mellitus. The more prevalent form, type 2 diabetes, accounts for
more than 90% of cases. The pathogenesis of type 2 diabetes is complex, involving progressive
development of insulin resistance and a relative deficiency in insulin secretion, leading to overt
hyperglycemia (1).
Insulin is essential for maintaining glucose homeostasis and regulating carbohydrate, lipid, and
protein metabolism (2). Insulin elicits a diverse array of biological responses by binding to its
specific receptor (3, 4). Mice lacking insulin receptor (IR) gene via targeted disruption are lethal
within the first week of birth due to severe diabetic ketoacidosis (5-7) (Table 1). Decreased
cellular responses to insulin or perturbation of the insulin signaling pathways are associated with a
number of pathological states. Mutations in insulin receptor gene which lead to alterations of
receptor synthesis, degradation, and function have been described in patients with several
uncommon syndromes associated with severe insulin resistance (8). Several studies have shown
modest decreases in insulin receptor number attributed to downregulation in response to
hyperinsulinemia in tissues or cells from type 2 diabetes patients (9, 10). Substantial decreases in
insulin-stimulated receptor tyrosine kinase activity and an even more substantial defect in insulin
signal transduction pathway, including receptor-mediated insulin receptor substrate (IRS)
phosphorylation or phosphoinositide (PI)-3 kinase activation, have been described using samples
of tissue (e.g. muscle or fat) from rodents or human subjects with Type 2 diabetes (11-14).
However, the detailed molecular basis for insulin resistance that proceeds, or is associated with,
common forms of type 2 diabetes remains poorly understood.
Table 1. Phenotypes of Mouse Models with Genetic Alteration of Insulin
Receptor.
TOTAL IR MUSCLE
K/O
IR K/O
LIVER IR
K/O
Fasting /
fed
glucose
Lethal
normal
Fasting /
fed
insulin
-
normal
Insulin
tolerance
-
normal
impaired
Glucose
tolerance
-
normal
impaired
FAT IR
K/O
BAT
IR K/O
 CELL
IR K/O
BRAIN IR
K/O
normal
-
-
normal
normal
-
impaired
impaired
impaired
-
 cell /
insulin
secretion
-
-
Hyperplasia
Body Wt
-
-
-
Lipids
-
-
insulin
secretion
insulin
secretion
-
-
MEDIATORS OF INSULIN SIGNAL TRANSDUCTION PATHWAY
Insulin receptor
The insulin receptor is a heterotetrameric protein consisting of two extracellular  subunits and
two transmembrane ß subunits. The binding of the ligand to the  subunit of IR stimulates the
tyrosine kinase activity intrinsic to the  subunit of the receptor. Extensive studies have indicated
that the ability of the receptor to autophosphorylate and phosphorylate intracellular substrates is
essential for its mediation of the complex cellular responses to insulin (15-18). Structure biology
studies reveal that the two  subunits jointly participate in insulin binding and that the kinase
domains in the two  subunits are in a juxtaposition that permits autophosphorylation of tyrosine
residues in the first step of insulin receptor activation (19, 20). The kinase domain undergoes
conformational change upon autophosphorylation, providing a basis for activation of the kinase
and binding of downstream signaling molecules (21, 22). The 3-D structure of the insulin receptor
complexed with insulin provides insight into the interaction of insulin with the receptor as well as
the mechanism of transmembrane signaling of this covalent multimeric receptor (Fig. 1).
Figure 1. Insulin/insulin receptor
complex. 1 (a) End view of the full-mass
representation of the IR dimer: left half,
surface rendering; right half, wire mesh
representation. Fitted structure of two IRadapted LCL regions (green and orangebrown) showing correspondence of
surface features and extent in uppermost
regions (L1). Arrow: cam-like region on
the CR domain. (b) Higher density solid
surface representation of the view rotated
slightly from panel a to show CR loop
regions (cams) of atomic structure
reaching the top portion of Fn2 domains
of the 3D reconstruction. (c and d)
Simplified schematic of structural changes
during activation of the insulin receptor.
(c) Inhibitory state: ectodomain of
dimeric subunits each with two differing
insulin binding sites and a blocking cam.
Unbound bivalent insulin: subunits resting
against cams, crossing membrane, with
tyrosine kinase (TK) domains separated.
Abbreviations: A-loop, activation loop; C,
catalytic region. Small on-axis circles (1
and 2) represent the two - disulfide
bonds. Arrows indicate thermally induced
motion. (d) Insulin bound state: blocking
cams rotated and subunits resting closer
to the center of the ectodomain. TK
domains are in position for
transphosphorylation via A-loops. Sets 1
and 2 indicate schematically different sets
of amino acids from monomers I and II
interacting with corresponding different
sites on insulin.
Reprinted with permission from “Mechanism of
Transmembrane Signaling: Insulin Binding and
the Insulin Receptor”. By Ottensmeyer, et al.,
Biochemistry, Vol 39, No. 40, p.12103-12112.
(2000). Copyright (2000) American Chemical
Society.
The IR exists in two isoforms as a result of alternative mRNA splicing of exon 11 of the
proreceptor transcript (23, 24). The type A (exon 11 minus) (25) and type B (exon 11 plus) (26)
receptors differ in the 12 amino acids encoded by exon 11 in the C terminus of the a chain of the
IR. The two alternatively spliced isoforms of the insulin receptor have subtle differences in insulin
binding affinity and the kinetics of ligand-stimulated internalization (27, 28). Insulin -like growth
factor (IGF)-II binds to type A insulin receptor with high affinity and to promote growth during
embryonic development in rodents (29). The high affinity binding of IGF-II to type A insulin
receptor has also been reported in human cancer cells, including those of breast and colon,
suggesting the role of such interaction in fetal growth and cancer biology (30, 31). In a recent
study, selective insulin signaling through type A and type B insulin receptor has been shown to
differentially regulate insulin and glucokinase genes in pancreatic  cells (32).
The insulin receptor is homologous to the insulin-like growth factor 1 receptor (IGF-1R) (Fig. 2)
and the highest degree of homology is observed in the tyrosine kinase domain (33, 34). Hybrid
receptors contain / halves of both the insulin and the IGF receptor have been identified as a
high-affinity IGF-1-binding species reacting with both IGF-1-receptor-specific and insulin-receptorspecific monoclonal antibodies. These hybrid receptors account for a substantial fraction of IGF-1
receptor in many mammalian tissues (35, 36). Another homologous receptor in the insulin
receptor family is the insulin receptor-related receptor (IRR) (37). The cognate hormone ligand for
and biological function of IRR are yet to be identified.
The insulin and IGF-1 receptors are evolutionarily conserved. Homologs of the receptors and
components of the signaling pathway have been identified in lower organisms such as Drosophila
and C. elegans (38, 39). Mutations in these genes are associated alterations in survival, life span
and neuroendocrine functions (40, 41). These findings may shed light on the understanding of the
role of mammalian insulin receptor signaling in aging and disease states such as obesity and
diabetes.
Figure 2. Domain structure
and homology of insulin
receptor and IGF1 receptor.
IRS proteins
The binding of the ligand to the  subunit of IR not only concentrates insulin at its site of action,
but also induces conformational changes in the receptor, which in turn stimulates the tyrosine
kinase activity intrinsic to the  subunit of the IR and trigger the signaling cascades (Fig. 3).
Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including
insulin receptor substrate (IRS) proteins 1 - 4, Shc, and Gab 1, Cbl, APS, and P60dok. Each of
these provides specific docking sites for other signaling proteins containing Src homology 2 (SH2)
domains (42). These events lead to the activation of downstream signaling molecules including
phosphotidylinsositol-3-OH (PI3) kinase.
Figure 3. Diagram of insulin signal
transduction pathways.
The four IRS proteins identified to date are highly homologous with overlapping and differential
tissue distribution. Studies with genetic deletion in mouse models and cell lines indicate that the
IRS proteins serve complimentary functions in different tissues as immediate substrates for insulin
and IGF-I receptors (Table 2). IRS-1-knockout mice exhibit growth retardation due to resistance
to insulin and IGF-1,  cell hyperplasia, and impaired glucose tolerance (43-45). IRS-2-knockout
mice exhibit more severe insulin resistance in the liver and peripheral tissues and develop overt
type 2 diabetes as a result of profound insulin resistance combined with impaired  cell function
(46). Combined heterozygous deletions of insulin receptor, IRS-1, and IRS-2 in different tissues
develop severe insulin resistance in skeletal muscle and liver and marked -cell hyperplasia. These
data indicate tissue-specific differences in the roles of IRS proteins to mediate insulin action, with
IRS-1 playing a prominent role in skeletal muscle and IRS-2 in liver (47). Although normal
phenotypes have been observed in mice lacking IRS-3 or IRS-4 genes (48), recent studies implied
that IRS-3 and IRS-4 impair IGF-1 mediated IRS-1 and IRS-2 signaling in cells (49).
Table 2. Phenotypes of Mouse Models with Deletion of Components of the
Insulin Signaling Pathway.
Gene
Phenotype
Insulin receptor
Severe diabetes; postnatal death at 3-7
days
IGF 1 receptor
Growth retardation, normal glucose
homeostatsis
IRS-1
Insulin and IGF 1 resistance; b cell
hyperplasia; metabolic syndrome
IRS-2
Insulin resistance; reduced b cell mass;
type 2 diabetes
IRS-3
No apparent phenotype
IRS-4
No apparent phenotype
P85 (hetero)
Improved insulin sensitivity
Akt2
Insulin resistance and glucose intolerance
PTP1B
Improved insulin sensitivity; resistance to
high-fat diet induced obesity
SHIP2 (hetero)
Improved insulin sensitivity
IKK (hetero)
Improved insulin sensitivity
GLUT4
GLUT4 (muscle)
GLUT4 (fat)
Cardiac hypertrophy; normal glucose
homeostasis
Severe insulin resistance; glucose
intolerance
Glucose intolerance; hyperinsulinemia;
insulin resistance
PI3 kinase/Akt pathways
PI3 kinase plays a pivotal role in the metabolic and mitogenic actions of insulin. The PI3K is a
heterodimeric enzyme consisting of the p85 regulatory subunit as well as the p110 catalytic
subunit. Activated PI3K specifically phosphorylates PI substrates to produce PI(3)P, PI(3,4)P2, and
PI(3,4,5)P3. Acting as second messengers, these phospholipids recruit the PI3K-dependent
serine/threonine kinases (PDK1) and Akt from cytoplasm to the plasma membrane by binding to
the "pleckstrin homology domain" (PH domain) of kinases. Lipid binding and membrane
translocation lead to conformational changes in Akt that is subsequently phosphorylated on Thr
308 and Ser 473 by PDK1. Phosphorylation by PDK1 leads to full activation of Akt (50-52).
Activated Akt phosphorylates and regulates the activity of many downstream proteins involved in
multiple aspects of cellular physiology. Among others, Akt phosphorylates and regulates
components of the glucose transporter 4 (GLUT4) complex, protein kinase C (PKC) isoforms, and
GSK3, all of which are critical in insulin-mediated metabolic effects (51-54). Pharmacological
inhibition of PI3K by wortmannin and LY294002 is associated with blockade of insulin-stimulated
translocation of GLUT4 to cell surface and glucose uptake into cells (55-58). Overexpression of
constitutively active forms of PI3K p110 catalytic subunit or Akt stimulates (54, 59, 60), whereas
that of dominant-negative p85 regulatory subunit constructs blocks, insulin-mediated metabolic
effects (59, 61-64). Although it is still controversial regarding the role of Akt in insulin-mediated
GLUT4 translocation (65), recent report that Akt2- but not Akt1-deficiency in mice is associated
with insulin resistance and diabetes strongly supports the notion that Akt is important in insulin
action (66, 67).
PTP1B, SHIP2/PTEN
Protein tyrosine phosphatases (PTPase) catalyze the dephosphorylation of insulin receptor and its
substrates, leading to attenuation of insulin action. A number of PTPases have been implicated as
the negative regulator of insulin signaling. Among them, the intracellular PTPase, PTP1B, has been
shown to function as the insulin receptor phosphatase. Mice lacking PTP1B have increased insulin
sensitivity and improve glucose tolerance (68, 69). These mice also have increased energy
expenditure and are resistant to the development of obesity. These findings demonstrate that
activation of central and peripheral insulin receptor signaling plays an important role in regulating
whole body energy homeostasis and imply that specific inhibition of PTP1B represents a valid
therapeutic target for treating obesity and diabetes. Vanadate inhibits protein tyrosine
phosphatase (PTP) and augments tyrosyl phosphorylation of a wide variety of cellular proteins,
including the IR (70). Vanadate has been shown to have antidiabetic effects in animal models and
in human diabetic subjects (71-73).
As discussed above, the PI3 kinase is a critical player in insulin signal transduction. The activity of
the PI3 kinase pathway is also determined by phosphatidylinositol-3-phosphatases such as PTEN
and the SH2 domain-containing inositol-5-phosphatase SHIP2. Overexpression of these lipid
phosphatases leads to decreased levels of PI(3,4,5)P3 in the cell, which could dampen or
terminate insulin signaling.
PTEN was identified and cloned as a tumor suppresser gene found to be mutated in many animal
and human cancers (74). PTEN gene encodes a protein of 403 residues that shows homology to
dual-specificity protein phosphatases. It has been demonstrated that PTEN negatively regulates
insulin signaling. In cultured cells, overexpression of PTEN protein has been found to inhibit
insulin-induced PI(3,4)P2 and PI(3,4,5)P3 production, Akt activation, GLUT4 translocation to the
cell membrane, and finally glucose uptake into cells (75, 76). Additionally, microinjection of an
anti-PTEN antibody increases basal and insulin-stimulated GLUT4 translocation (75). In contrast to
the overexpression of the wild type PTEN, overexpression of catalytically inactive PTEN mutant
does not negatively affect insulin signaling (76), indicating that lipid phosphatase activity is
required for the action of PTEN on insulin signaling. Finally, it was reported that treatment with an
antisense oligonucleotide which specifically inhibits the expression of PTEN (80% reduction in
mRNA level in liver and adipose tissue) normalizes plasma glucose in the db/db mice (77). Taken
together, these studies indicate that PTEN plays a negative role in insulin signaling and its
inhibition improves insulin sensitivity.
SHIP2 is another negative regulator of insulin signaling and such negative regulation depends on
its 5'-phopshatase activity. Overexpression of SHIP2 protein decreases insulin-dependent
PI(3,4,5)P3 production as well as insulin-stimulated Akt activation, GSK3 inactivation, and
glycogen synthetase activation (78). The inhibitory effects of SHIP2 on insulin signaling are lipid
phosphatase activity-dependent. The potential of SHIP2 as a target for diabetes treatments was
implicated by a recent study demonstrating that genetic deletion of SHIP2 increases insulin
sensitivity in vivo (79). SHIP2-/- newborn mice have severe hypoglycemia and mortality that can
be rescued by infusion of either glucose or an insulin-neutralizing antibody. Tissues of the
newborn knockout mice also have decreased expression of glyconeogenesis genes. Most
interestingly, while SHIP2+/- mice do not have hypoglycemia or increased mortality, they have
improved insulin sensitivity and glucose tolerance. SHIP2+/- mice also demonstrate increased
translocation of GLUT4 and glycogen synthesis in skeletal muscles. These results suggest that
inhibitors of SHIP2 may represent a novel class of therapeutics for the treatments of type 2
diabetes by improving insulin sensitivity.
GLUT4 translocation
Insulin promotes glucose uptake by muscle and adipose tissue via stimulation of glucose
transporter (GLUT) 4 from intracellular sites to the plasma membrane. Attenuated GLUT4
translocation and glucose uptake by muscle and fat cells following insulin stimulation represent a
prime defect in insulin resistance (80). The PI3 kinase/Akt pathway has been demonstrated to be
upstream of GLUT4 translocation. In addition, recent studies have shown that Glu4 translocation is
also downstream of a PI3 kinase independent pathway (81). Insulin stimulates tyrosine
phosphorylation of c-Cbl in the metabolically responsive cells. C-Cbl is recruited to complex with
insulin receptor via the adaptor protein CAP (c-Cbl-associated protein) (82). Upon Cbl
phosphorylation, the Cbl/CAP complex is translocated to the plasma membrane domain enriched
in lipid rafts or caveolae. In the lipid rafts, CAP associates with caveolar protein flotillin and forms
a complex with a number of proteins including TC10, CRKII and other accessory proteins involved
in vesicular trafficking and membrane fusion (83). Expression of a dominant negative CAP mutant
completely block insulin stimulated glucose uptake and GLUT4 translocation. These data suggest
that the PI3 kinase/Akt pathway and the CPA/Cbl complex represent two compartmentalized
parallel pathways leading to GLUT4 translocation.
The importance of GLUT4 in glucose homeostasis has been studied extensively in recent years.
Mice with heterozygous deletion of GLUT4 are only moderately glucose intolerant (84). Whole
body GLUT4 homozygous knockout mice manifest a phenotype of mild hyperglycemia, cardiac and
adipose abnormalities, and short lifespan (85). Targeted disruption of GLUT4 selectively in muscle
result in insulin resistance and glucose intolerance, demonstrating that GLUT4-mediated glucose
transport in muscle is essential to the maintenance of glucose homeostasis (86). Moreover,
adipose-selective disruption of GLUT4 in mice leads to secondary insulin resistance in liver and
muscle and impaired glucose tolerance (87). Taken together, these studies imply that alteration of
GLU4 expression and/or function could contribute to the development of insulin resistance and
diabetes.
Insights into insulin resistance from knockout mouse models
In recent years, genetic manipulation has been widely used to delete specific genes in the insulin
signal transduction pathway. The outcome of such studies has provided significant insights into
molecular mechanism and biochemical pathways of human type 2 diabetes. The key role of IR in
insulin action is demonstrated by the observation that targeted ablation of the IR gene results in
neonatal death from severe diabetic ketoacidosis (5-7). Alterations of IR in specific tissues via
genetic manipulation have been shown to produce varying degrees of insulin resistance and
diabetes in mice (88-93) (Table 1, see above). Whole body or tissue specific deletion of other
components of the insulin signaling pathway (Table 2, see above) has revealed monogenic defects
in insulin action. In addition, combination of different gene deletions has enabled reconstruction of
diabetes as a polygenic disease. These studies also provide experimental evidence that challenges
the traditional views of the role of various tissues in insulin action and glucose homeostasis (94).
REGULATION OF GLUCOSE AND LIPID METABOLISM
Glycogen synthesis and gluconeogenesis
Insulin suppresses hepatic glucose output by stimulating glycogen synthesis and inhibiting
glycogenolysis and gluconeogenesis. Increased rates of hepatic glucose production result in the
development of overt hyperglycemia, especially fasting hyperglycemia, in patients with type 2
diabetes (95). Insulin exerts direct effect on the liver (96) as well as influences the substrate
availability and fluxes of free fatty acids (97). There are several important enzymatic checkpoints
that act to control hepatic glycolysis and glycogen synthesis (glucokinase, glycogen synthase
kinase-3), glycogenolysis (phosphorylase), gluconeogenesis (phosphoenolpyruvate carboxykinase,
fructose 1,6 bisphosphatase), or steps that are common to the pathways (glucose-6phosphatase). Some of them are directly controlled by insulin via phosphorylation and
dephosphorylation.
Glycogen synthase kinase 3 (GSK-3) is a cytoplasmic serine/theronine kinase that plays key roles
in insulin signal transduction and metabolic regulation (98-100). This enzyme also has a key role
in Wnt signaling that is critical for determination of cell fates during embryonic development (98).
In the insulin signaling pathway, GSK-3 is active in the absence of insulin and it phosphorylates
(and thereby inhibits) glycogen synthase and several other substrates. Insulin binding to the
receptor activates a phosphorylation cascade, leading to inhibitory phosphorylation of GSK-3 by
Akt. Thus, insulin activates glycogen synthase by promoting its dephosphorylation through the
inhibition of GSK-3. Lithium and other small molecule inhibitors of GSK-3 have been shown to
activate glycogen synthase in cells and have antidiabetic effects in animal models of diabetes,
suggesting that specific inhibitors of GSK-3 hold the potential as novel therapeutics for diabetes
(101). In addition to regulating GSK-3 via Akt, insulin also stimulates compartmentalized
activation of protein phosphatase 1 (PP1) in the complex containing glycogen particles, glycogentargeting subunits and enzymes for glycogen synthesis and breakdown (102).
The expression of a number of genes important for glycolysis, glycogenolysis, and
gluconeogenesis is under the concerted control of insulin, glucagon, and glucocorticoids (103).
Recent studies indicate that forkhead family of transcription factors (FKHR) are phosphorylated in
an insulin-dependent manner by Akt kinase (104-113). FKHR is a transcriptional enhancer that
regulates genes involved in glucose production, cell cycle regulation, and apoptosis. Under basal
conditions, FKHR resides in the nucleus. Upon insulin stimulation and phosphorylation by Akt,
FKHR is excluded from the nucleus to the cytoplasm, thereby providing a powerful mechanism by
which insulin could down-regulate a number of genes including IGF-binding protein-1,
phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase. PGC-1 represents
another transcriptional coactivator that plays an important role in the regulation of genes involved
in hepatic gluconeogenesis (114, 115). PGC-1 is strongly induced in liver in fasting mice and in
mouse models of diabetes as well as in liver-specific insulin receptor knockout mice. PGC-1 is
induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviralmediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates key
gluconeogenic enzymes, including PEPCK and glucose-6-phosphatase, leading to increased
gluconeogenesis by the liver. Interaction of PGC-1 with the glucocorticoid receptor and the liverenriched transcription factor HNF-4a is required for full transcriptional activation of the PEPCK
promoter. These results shed new light on the modulation of hepatic gluconeogenesis.
Lipid synthesis and degradation
Insulin is an anabolic hormone and promotes lipid synthesis and suppresses lipid degradation.
Recent studies indicate that the transcription factor steroid regulatory element-binding protein
(SREBP)-1c is a major mediator of insulin action on the expression of glucokinase and lipogenesisrelated genes in the liver (116-118). Transgenic mice expressing SREBP-1c in adipose tissue
exhibit a phenotype of abnormal adipose differentiation, marked insulin resistance and diabetes
mellitus (119). Increased levels of SREBP-1c are associated with fatty livers in two mouse models
of diabetes (120). In streptozotocin-induced diabetes rat model, insulin stimulate lipid synthesis
by selectively increases hepatic SREBP-1c mRNA levels (121). Moreover, studies in lipodystrophic
mice and the obese ob/ob mice demonstrate that there exits a vicious cycle of differential insulin
resistance in IRS-2 signaling and selective increased insulin sensitivity in SREBP-1c in the liver,
leading to abnormally high levels of glucose production and lipid synthesis (122).
In addition to promoting lipogenesis in the liver, insulin also stimulates lipid synthesis enzymes
(fatty acid synthase, acetyl-CoA carboxylase) and inhibits lipolysis in adipose tissue. The antilipolysis effect of insulin is primarily mediated by inhibition of hormone sensitive lipase through a
mechanism that involves activation of a cAMP-specific phosphodiesterase (123-125).
MODULATION OF INSULIN SIGNALING
Obesity and insulin resistance
Obesity and its associated insulin resistance and hyperlipidemia are hallmarks of the metabolic
syndrome (126, 127) and are the major risk factors for type 2 diabetes mellitus (128, 129).
Adipose tissue plays an important role in the development of insulin resistance. Elevated
circulating levels of free fatty acids (FFA) derived from adipocytes have been demonstrated in
numerous insulin resistance states. FFAs contribute to insulin resistance by inhibiting glucose
uptake, glycogen synthesis, glycolysis, and by increasing hepatic glucose production (97, 130132). In the proximal insulin signaling pathway, elevated FFAs are associated with impaired IRS-1
phosphorylation and PI3-kinase activation following insulin stimulation (133). FFAs also stimulate
expression of gluconeogenic enzymes, including glucose-6-phosphatase (134). Peripheral insulin
resistance has also been linked to intramyocellular triglyceride and long-chain fatty-acyl-CoA
accumulation (135-139). Selective depletion of intramyocellular lipids is accompanied by reversal
of insulin resistance associated with morbid obesity (140). The link between tissue lipid levels and
insulin resistance has been further substantiated in transgenic mice that selectively overexpress
lipoprotein lipase in liver or muscle (141).
In addition to tyrosine phosphorylation, the insulin receptor and IRS proteins undergo serine
phosphorylation, which attenuates insulin signaling by inhibiting insulin- stimulated tyrosine
phosphorylation and promoting association with other regulatory molecules (80). Elevation of
lipid-derived metabolites (such as diacylglycerol) can lead to activation of a number of protein
kinases, including protein kinase C, and result in serine/theronine phosphorylation of insulin
receptor and IRS proteins (142-148). These serine phosphorylation events function as negative
feedback loops for insulin signal transduction and provide a basis for cross talk with other
pathways that may mediate insulin resistance. Several serine/theronine kinases have been
implicated in this process, including the inhibitor of nuclear factor-B (IB) kinase (IKK).
Inhibition of signaling through the IKK/IB/NF-B ?pathway, either through the use of high dose
salicylate treatment (a known but non-selective inhibitor of IKK) or heterozygous deletion of
IKK, is associated with diminished insulin resistance. Specifically, mice with heterozygous
deletion of IKK gene exhibit increased insulin sensitivity when rendered insulin resistant via high
fat diet, acute lipid infusion, or crossed with ob/ob mice (149, 150).
PC-1 is a membrane glycoprotein that interacts with the  subunits of insulin receptor and inhibits
insulin action (151-153). Increased PC-1 content in tissues could correlate with impaired insulin
action (154).
Adipose-secreted proteins
Adipose is now recognized as an active endocrine organ that secrets a variety of hormones that
regulate cellular processes. Elevated TNF-a expression has been observed in adipose tissue
derived from obese animal models and human subjects. TNF-a has also been implicated as a
causative factor in the development of insulin resistance associated with obesity and diabetes
(155-158). Treatment of cells with TNF-a produces impaired insulin signaling through IRS-1
serine phosphorylation (159, 160) or through reduced expression of IRS-1 and GLUT4 (161). TNFa suppresses adipocyte differentiation and expression of adipocyte-specific genes in vitro (162).
Peroxisome proliferator-activated receptor (PPAR) is an adipocyte-specific nuclear hormone
receptor that functions as a key transcriptional regulator of adipogenesis. Agonists of PPAR such
as TZDs (e.g., troglitazone, pioglitazone, and rosiglitazone) promote adipocyte differentiation and
improve insulin sensitivity in animal models of obesity and diabetes as well as in type 2 diabetic
patients (163). TNF-a and PPAR signaling pathways are mutually antagonistic and activation of
PPAR can attenuate the negative metabolic effects of TNF-a in cells and in vivo (164-166).
Leptin belongs to the cytokine family of hormones and is secreted by adipose tissue. Leptin exerts
it effect by interacting with its receptors in the central nervous system and periphery (127).
Severe leptin deficiency or leptin signaling deficiency is associated with insulin resistance as
manifested in db/db, ob/ob mice, Zucker fatty rats, or animal models of genetic lipodystrophic
diabetes (167). In addition to its effect on satiety and body weight, leptin can also modulate
insulin action in liver and muscle (168-170). Leptin replacement in human subjects with
lipodystrophy and leptin deficiency leads to improved glycemia control and decreased lipid levels
(171).
Acrp30 (adipocyte complement-related protein of 30 kDa, also known as adiponectin) was cloned
as a novel serum protein secreted by adipocytes and is similar to complement protein C1q (172).
The circulating level of Acrp30 or adiponectin is reduced in obesity and type 2 diabetes and is
correlated with insulin resistance and hyperinsulinemia (173, 174). PPAR ligands increase
expression and plasma concentrations of this protein (175, 176). This protein has also been shown
to enhances hepatic insulin action (177), reverses insulin resistance associated with both
lipoatrophy and obesity (178), and increase fatty acid oxidation in muscle and cause weight loss in
mice (179).
Resistin is another adipocyte secreted hormone that potentially links obesity to type 2 diabetes.
Initial studies indicated that resistin levels are elevated in animal models of diabetes and obesity
and treatment with insulin sensitizing agents (such as TZDs) results in reduction of circulating
resistin levels (180, 181), although the role and regulation of resistin still remain controversial
(182). Correlation of increased resistin expression with obesity and insulin resistance has been
observed in some human subjects (183), but not others (184-186). Further studies will be
required to elucidate the role of resistin in human obesity and diabetes.
Insulin receptor activators
Since insulin receptor play an important role in the regulation of whole body metabolism and
pathogenesis of diabetes, small molecule agents that can activate insulin receptor or potentiate
insulin action at the receptor level will prove useful as novel therapeutics for diabetes. In recent
years, activators of insulin receptor have been shown to activate insulin signaling in cells and
decrease blood glucose levels in murine models of diabetes when dosed orally (187-190).
Although these agents are still in early preclinical research stage, the identification of these agents
demonstrates, in principle, the feasibility of an "insulin pill" for treatment of diabetes mellitus, a
longstanding but elusive goal of drug discovery research.
Perspectives
Since the cloning of insulin receptor in 1985, significant progress has been made in the
understanding of insulin signal transduction pathways and their alterations in the development of
insulin resistance and pathogenesis of diabetes. Much work is still needed to further unravel the
detailed molecular mechanisms by which insulin regulates the intricate cellular processes in a
variety of tissues. Given the recognition of increasing importance of adipose tissue in insulin
sensitivity, it is anticipated that novel hormones synthesized and secreted by adipocytes will be
identified. These hormones could act on other insulin target tissues, including liver and muscle,
and modulate whole body glucose, lipid, and protein metabolism. Elucidation of the insulin
signaling mechanisms will yield new therapeutic targets for insulin resistance and diabetes and
hopefully lead to discovery of novel treatments for the metabolic derangement.
Go to Chapter 5 - PATHOGENESIS OF TYPE 1A DIABETES
1. Taylor SI 1999 Deconstructing type 2 diabetes. Cell 97:9-12
2. Saltiel AR, Kahn CR 2001 Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806
3. Goldfine ID 1987 The insulin receptor: molecular biology and transmembrane signaling. Endocr Rev 8:235-255
4. White MF, Kahn CR 1994 The insulin signaling system. J Biol Chem 269:1-4
5. Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H 1996 Early neonatal death in mice homozygous for a null
allele of the insulin receptor gene. Nat Genet 12:106-9
6. Joshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J, Bucchini D 1996 Targeted disruption of the insulin receptor gene in the mouse results in
neonatal lethality. Embo J 15:1542-7
7. Accili D, Nakae J, Kim JJ, Park BC, Rother KI 1999 Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development. J
Pediatr Endocrinol Metab 12:475-85
8. Taylor SI 1992 Lilly lecture: molecular mechanisms of insulin resistance, lessons from patients with mutations in the insulin-receptor gene. Diabetes 41:14731490
9. Olefsky JM 1976 Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest 57:1165-1172
10. Caro JF, Itoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, Jenquin M, Silverman JF, Khazanie PG, Sinha MK 1986 Studies on the mechanism of insulin
resistance in the liver from humans with noninsulin-dependent diabetes. J Clin Invest 78:249-258
11. Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG, Meelheim D, Dohm GL 1987 Insulin receptor kinase in human skeletal muscle from obese
subjects with and without non-insulin dependent diabetes. J Clin Invest 79:1330-1337
12. Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL 1995 Insulin receptor autophosphorylation, insulin receptor substrate-1 phosphorylation,
and phophatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195-2204
13. Kerouz NJ, Horsch D, Pons S, Kahn CR 1997 Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase
isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest 100:3164-72
14. Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H 1998 Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects.
Diabetes 47:1281-6.
15. Kasuga M, Karlsson FA, Kahn CR 1982 Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185-187
16. Rosen OM, Herrera R, Olowe Y, Petruzzelli M, Cobb MH 1983 Phosphorylation activates the insulin receptor tyrosine protein kinase. Proc Natl Acad Sci USA
80:3237-3240
17. Yu KT, Czech MP 1984 Tyrosine phosphorylation of the insulin receptor beta subunit activates the receptor-associated tyrosine kinase activity. J Biol Chem
259:5277-86
18. Ellis L, Morgan DO, Clauser E, Roth RA, Rutter WJ 1987 A Membrane-Anchored Cytoplasmic Domain of the Human Insulin Receptor Mediates a Constitutively
Elevated Insulin-Independent Uptake of 2-Deoxyglucose. Mol Endocrinol 1:15-24
19. Luo RZ, Beniac DR, Fernandes A, Yip CC, Ottensmeyer FP 1999 Quaternary structure of the insulin-insulin receptor complex. Science 285:1077-80
20. Ottensmeyer FP, Beniac DR, Luo RZ, Yip CC 2000 Mechanism of transmembrane signaling: insulin binding and the insulin receptor. Biochemistry 39:12103-12
21. Hubbard SR 1997 Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. Embo J 16:5572-81
22. Hubbard SR, Wei L, Ellis L, Hendrickson WA 1994 Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372:746-754
23. Seino S, Bell GI 1989 Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun 159:312-316
24. Moller DE, Yokota A, Caro JF, Flier JS 1989 Tissue-specific expression of two alternatively spliced insulin receptor mRNA's in man. Mol Endocrinol 3:1263-1269
25. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM,
Ramachandran J 1985 Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756-761
26. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ 1985 The human insulin receptor cDNA:
the structural basis for hormone-activated transmembrane signalling. Cell 40:747-758
27. McClain DA 1991 Different ligand affinities of the two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action.
Mol Endocrinol 5:734-739
28. Yamaguchi Y, Flier JS, Yokota A, Benecke H, Backer JM, Moller DE 1991 Functional properties of two naturally occurring isoforms of the human insulin receptor
in Chinese hamster ovary cells. Endocrinology 129:2058-2066
29. Louvi A, Accili D, Efstratiadis A 1997 Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol 189:3348
30. Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F, Scalia P, Sbraccia P, Goldfine ID, Vigneri R, Belfiore A 1999 Insulin receptor activation by IGF-II in
breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 18:2471-9
31. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R 1999 Insulin receptor isoform A, a newly recognized, highaffinity insulin- like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 19:3278-88
32. Leibiger B, Leibiger IB, Moede T, Kemper S, Kulkarni RN, Kahn CR, de Vargas LM, Berggren PO Selective insulin signaling through A and B insulin receptors
regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell 7:559-70
33. Adams TE, Epa VC, Garrett TP, Ward CW 2000 Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 57:1050-93
34. Nakae J, Kido Y, Accili D 2001 Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 22:818-35.
35. Siddle K, Soos MA, Field CE, Nave BT 1994 Hybrid and atypical insulin/insulin-like growth factor I receptors. Horm Res 41 Suppl 2:56-64; discussion 65
36. Pessin JE 1993 Molecular properteries of insulin/IGF-1 hybrid recetpors. 4th International Symposium on Insulin, IGFs and their Receptors. Adv. Exp. Med.
Biol. 343:133-44
37. Shier P, Watt VM 1989 Primary structure of a putative receptor for a ligand of the insulin family. J Biol Chem 264:14605-14608
38. Kenyon C 2001 A conserved regulatory system for aging. Cell 105:165-8.
39. Finch CE, Ruvkun G 2001 The genetics of aging. Annu Rev Genomics Hum Genet 2:435-62
40. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS 2001 A mutant Drosophila insulin receptor homolog that extends life-span and impairs
neuroendocrine function. Science 292:107-10.
41. Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L 2001 Extension of life-span by loss of CHICO, a Drosophila insulin
receptor substrate protein. Science 292:104-6.
42. White MF, Yenush L 1998 The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. Curr Top Microbiol Immunol
228:179-208
43. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, et al. 1994 Insulin resistance and growth
retardation in mice lacking insulin receptor substrate-1. Nature 372:182-6.
44. Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, 3rd, Johnson RS, Kahn CR 1994 Alternative pathway of insulin signalling in mice with targeted disruption of
the IRS-1 gene. Nature 372:186-90.
45. Tamemoto H, Tobe K, Yamauchi T, Terauchi Y, Kaburagi Y, Kadowaki T 1997 Insulin resistance syndrome in mice deficient in insulin receptor substrate-1. Ann
N Y Acad Sci 827:85-93.
46. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF 1998 Disruption of IRS-2
causes type 2 diabetes in mice. Nature 391:900-4.
47. Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D 2000 Tissue-specific insulin resistance in mice with mutations in the insulin receptor,
IRS-1, and IRS-2. J Clin Invest 105:199-205
48. Fantin VR, Wang Q, Lienhard GE, Keller SR 2000 Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose
homeostasis. Am J Physiol Endocrinol Metab 278:E127-33.
49. Tsuruzoe K, Emkey R, Kriauciunas KM, Ueki K, Kahn CR 2001 Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol
Cell Biol 21:26-38.
50. Avruch J 1998 Insulin signal transduction through protein kinase cascades. Mol Cell Biochem 182:31-48.
51. Czech MP, Corvera S 1999 Signaling mechanisms that regulate glucose transport. J Biol Chem 274:1865-8.
52. Farese RV 2001 Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. Exp Biol Med (Maywood) 226:283-95.
53. Shepherd PR, Withers DJ, Siddle K 1998 Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333:471-90.
54. Ueki K, Yamamoto-Honda R, Kaburagi Y, Yamauchi T, Tobe K, Burgering BM, Coffer PJ, Komuro I, Akanuma Y, Yazaki Y, Kadowaki T 1998 Potential role of
protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. J Biol Chem 273:5315-22.
55. Okada T, Sakuma L, Fukui Y, Hazeki O, Ui M 1994 Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective
inhibition of phosphatidylinositol 3-kinase. J Biol Chem 269:3563-7.
56. Clarke JF, Young PW, Yonezawa K, Kasuga M, Holman GD 1994 Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol
3-kinase inhibitor, wortmannin. Biochem J 300:631-5.
57. Kanai F, Ito K, Todaka M, Hayashi H, Kamohara S, Ishii K, Okada T, Hazeki O, Ui M, Ebina Y 1993 Insulin-stimulated GLUT4 translocation is relevant to the
phosphorylation of IRS-1 and the activity of PI3-kinase. Biochem Biophys Res Commun 195:762-8.
58. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR 1994 Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6
kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14:4902-11.
59. Katagiri H, Asano T, Ishihara H, Inukai K, Shibasaki Y, Kikuchi M, Yazaki Y, Oka Y 1996 Overexpression of catalytic subunit p110alpha of phosphatidylinositol
3-kinase increases glucose transport activity with translocation of glucose transporters in 3T3-L1 adipocytes. J Biol Chem 271:16987-90.
60. Martin SS, Haruta T, Morris AJ, Klippel A, Williams LT, Olefsky JM 1996 Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement
and GLUT4 translocation in 3T3-L1 adipocytes. J Biol Chem 271:17605-8.
61. Kohn AD, Summers SA, Birnbaum MJ, Roth RA 1996 Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake
and glucose transporter 4 translocation. J Biol Chem 271:31372-8
62. Calera MR, Martinez C, Liu H, Jack AK, Birnbaum MJ, Pilch PF 1998 Insulin increases the association of Akt-2 with Glut4-containing vesicles. J Biol Chem
273:7201-4
63. Sakaue H, Ogawa W, Takata M, Kuroda S, Kotani K, Matsumoto M, Sakaue M, Nishio S, Ueno H, Kasuga M 1997 Phosphoinositide 3-kinase is required for
insulin-induced but not for growth hormone- or hyperosmolarity-induced glucose uptake in 3T3-L1 adipocytes. Mol Endocrinol 11:1552-62.
64. Sharma PM, Egawa K, Huang Y, Martin JL, Huvar I, Boss GR, Olefsky JM 1998 Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene
transfer and its effect on insulin action. J Biol Chem 273:18528-37.
65. Hajduch E, Litherland GJ, Hundal HS 2001 Protein kinase B (PKB/Akt)--a key regulator of glucose transport? FEBS Lett 492:199-203.
66. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ 2001 Insulin resistance and a
diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728-31.
67. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ 2001 Akt1/pkbalpha is required for normal growth but dispensable for maintenance of glucose
homeostasis in mice. J Biol Chem 276:38349-52.
68. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ,
Tremblay ML, Kennedy BP 1999 Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene [see comments].
Science 283:1544-8
69. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn
BB 2000 Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol
20:5479-89
70. Huyer G, Liu S, Kelly J, Moffat J, Payette P, Kennedy B, Tsaprailis G, Gresser MJ, Ramachandran C 1997 Mechanism of inhibition of protein-tyrosine
phosphatases by vanadate and pervanadate. J Biol Chem 272:843-51
71. Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR 1995 In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus. Mol Cell Biochem
153:217-31
72. Boden G, Chen X, Ruiz J, van Rossum GD, Turco S 1996 Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulindependent diabetes mellitus. Metabolism 45:1130-5.
73. Halberstam M, Cohen N, Shlimovich P, Rossetti L, Shamoon H 1996 Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic
subjects. Diabetes 45:659-66.
74. Ali IU, Schriml LM, Dean M 1999 Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91:1922-32.
75. Nakashima N, Sharma PM, Imamura T, Bookstein R, Olefsky JM 2000 The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J
Biol Chem 275:12889-95.
76. Ono H, Katagiri H, Funaki M, Anai M, Inukai K, Fukushima Y, Sakoda H, Ogihara T, Onishi Y, Fujishiro M, Kikuchi M, Oka Y, Asano T 2001 Regulation of
phosphoinositide metabolism, Akt phosphorylation, and glucose transport by PTEN (phosphatase and tensin homolog deleted on chromosome 10) in 3T3-L1
adipocytes. Mol Endocrinol 15:1411-22.
77. McKay RA, Bulter M, Popoff IA, Gaarde W, Witchell D, Dean NM, Monia BP 2000 Specific inhibition of PTEN expression with an antisense oligonucleotide
normalizes plasma glucose in db/db mice. Diabetes 49:A51
78. Blero D, De Smedt F, Pesesse X, Paternotte N, Moreau C, Payrastre B, Erneux C 2001 The SH2 domain containing inositol 5-phosphatase SHIP2 controls
phosphatidylinositol 3,4,5-trisphosphate levels in CHO-IR cells stimulated by insulin. Biochem Biophys Res Commun 282:839-43.
79. Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux
C, Hue L, Schurmans S 2001 The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409:92-7.
80. Shulman GI 2000 Cellular mechanisms of insulin resistance. J Clin Invest 106:171-6.
81. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR 2000 CAP defines a second signalling pathway
required for insulin-stimulated glucose transport. Nature 407:202-7.
82. Ribon V, Printen JA, Hoffman NG, Kay BK, Saltiel AR 1998 A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. Mol
Cell Biol 18:872-9.
83. Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, Macara IG, Pessin JE, Saltiel AR 2001 Insulin-stimulated GLUT4 translocation
requires the CAP-dependent activation of TC10. Nature 410:944-8.
84. Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ 1997 GLUT4 heterozygous knockout mice develop muscle
insulin resistance and diabetes. Nat Med 3:1096-101.
85. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ 1995 Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature
377:151-5.
86. Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB 2000
Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6:924-8.
87. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB 2001 Adipose-selective targeting of the GLUT4 gene impairs insulin
action in muscle and liver. Nature 409:729-33.
88. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR 1998 A muscle-specific insulin receptor knockout exhibits features of
the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2:559-69
89. Guerra C, Navarro P, Valverde AM, Arribas M, Bruning J, Kozak LP, Kahn CR, Benito M 2001 Brown adipose tissue-specific insulin receptor knockout shows
diabetic phenotype without insulin resistance. J Clin Invest 108:1205-13
90. Kulkarni RN, Winnay JN, Daniels M, Bruning JC, Flier SN, Hanahan D, Kahn CR 1999 Altered function of insulin receptor substrate-1-deficient mouse islets and
cultured beta-cell lines. J Clin Invest 104:R69-75
91. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR 1999 Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an
insulin secretory defect similar to that in type 2 diabetes. Cell 96:329-39
92. Lauro D, Kido Y, Castle AL, Zarnowski MJ, Hayashi H, Ebina Y, Accili D 1998 Impaired glucose tolerance in mice with a targeted impairment of insulin action in
muscle and adipose tissue [see comments]. Nat Genet 20:294-8
93. Mauvais-Jarvis F, Virkamaki A, Michael MD, Winnay JN, Zisman A, Kulkarni RN, Kahn CR 2000 A model to explore the interaction between muscle insulin
resistance and beta-cell dysfunction in the development of type 2 diabetes. Diabetes 49:2126-34
94. Mauvais-Jarvis F, Kahn CR 2000 Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from
transgenic and knockout mice? Diabetes Metab 26:433-48
95. DeFronzo RA, Bonadonna RC, Ferannini E 1992 Patholgenesis of NIDDM: A balanced overview. Diab Care 15:318-368
96. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR 2000 Loss of insulin signaling in hepatocytes leads to severe insulin
resistance and progressive hepatic dysfunction. Mol Cell 6:87-97.
97. Bergman RN, Ader M 2000 Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 11:351-6.
98. Harwood AJ 2001 Regulation of GSK-3: a cellular multiprocessor. Cell 105:821-4.
99. Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH 2001 Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphateprimed substrate specificity and autoinhibition. Cell 105:721-32.
100. Frame S, Cohen P, Biondi RM 2001 A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by
phosphorylation. Mol Cell 7:1321-7.
101. Ryves WJ, Harwood AJ 2001 Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 280:720-5.
102. Newgard CB, Brady MJ, O'Doherty RM, Saltiel AR 2000 Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein
phosphatase-1. Diabetes 49:1967-77.
103. Pilkis S, Granner D 1992 Molecular physiology of the regulation of hepatic glyconeogenesis and glycolysis. Annu. Rev. Physiol. 54:885-909
104. Nakae J, Park BC, Accili D 1999 Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive
pathway. J Biol Chem 274:15982-5.
105. Scheimann AO, Durham SK, Suwanichkul A, Snuggs MB, Powell DR 2001 Role of three FKHR phosphorylation sites in insulin inhibition of FKHR action in
hepatocytes. Horm Metab Res 33:631-8.
106. Barthel A, Schmoll D, Kruger KD, Bahrenberg G, Walther R, Roth RA, Joost HG 2001 Differential regulation of endogenous glucose-6-phosphatase and
phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. Biochem Biophys Res Commun 285:897902.
107. Yeagley D, Guo S, Unterman T, Quinn PG 2001 Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like
growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences. J Biol Chem 276:3370510.
108. Lochhead PA, Coghlan M, Rice SQ, Sutherland C 2001 Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and
phosphoenolypyruvate carboxykinase gene expression. Diabetes 50:937-46.
109. Rena G, Prescott AR, Guo S, Cohen P, Unterman TG 2001 Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3
binding, transactivation and nuclear targetting. Biochem J 354:605-12.
110. Cahill CM, Tzivion G, Nasrin N, Ogg S, Dore J, Ruvkun G, Alexander-Bridges M 2001 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and
function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem 276:13402-10.
111. Tomizawa M, Kumar A, Perrot V, Nakae J, Accili D, Rechler MM, Kumaro A 2000 Insulin inhibits the activation of transcription by a C-terminal fragment of the
forkhead transcription factor FKHR. A mechanism for insulin inhibition of insulin-like growth factor-binding protein-1 transcription. J Biol Chem 275:7289-95.
112. Tang ED, Nunez G, Barr FG, Guan KL 1999 Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274:16741-6.
113. Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T 1999 Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates
effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 274:17184-92.
114. Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, Puigserver P, Spiegelman B, Montminy M 2001 CREB regulates
hepatic gluconeogenesis through the coactivator PGC-1. Nature 413:179-83.
115. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM 2001 Control of
hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131-8.
116. Brown MS, Goldstein JL 1998 Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake. Nutr Rev 56:S1-3;
discussion S54-75.
117. Foretz M, Guichard C, Ferre P, Foufelle F 1999 Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of
glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A 96:12737-42.
118. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, Le Liepvre X, Berthelier-Lubrano C, Spiegelman B, Kim JB, Ferre P, Foufelle F 1999 ADD1/SREBP-1c
is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 19:3760-8.
119. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS 1998 Insulin resistance and diabetes mellitus in transgenic mice
expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182-94.
120. Shimomura I, Bashmakov Y, Horton JD 1999 Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J
Biol Chem 274:30028-32.
121. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL 1999 Insulin selectively increases SREBP-1c mRNA in the livers of rats with
streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 96:13656-61.
122. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL 2000 Decreased IRS-2 and increased SREBP-1c lead to mixed insulin
resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6:77-86.
123. Botion LM, Green A 1999 Long-term regulation of lipolysis and hormone-sensitive lipase by insulin and glucose. Diabetes 48:1691-7.
124. Rosenstock M, Greenberg AS, Rudich A 2001 Distinct long-term regulation of glycerol and non-esterified fatty acid release by insulin and TNF-alpha in 3T3-L1
adipocytes. Diabetologia 44:55-62.
125. Sztalryd C, Komaromy MC, Kraemer FB 1995 Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest
95:2652-61.
126. Kahn BB, Flier JS 2000 Obesity and insulin resistance. J Clin Invest 106:473-81
127. Spiegelman BM, Flier JS 2001 Obesity and the regulation of energy balance. Cell 104:531-43.
128. Reaven GM 1993 Role of insulin resistance in the pathophysiology of non-insulin dependent diabetes mellitus. Diabetes Metab Rev 9 Suppl 1:5S-12S
129. Zimmet P, Alberti KG, Shaw J 2001 Global and societal implications of the diabetes epidemic. Nature 414:782-7.
130. Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD 1988 Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with
NIDDM. Diabetes 37:1020-4.
131. McGarry JD 1992 What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258:766-770
132. Boden G, Chen X, Ruiz J, White JV, Rossetti L 1994 Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93:2438-46.
133. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI 1999 Effects
of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253-9.
134. Massillon D, Barzilai N, Hawkins M, Prus-Wertheimer D, Rossetti L 1997 Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion.
Diabetes 46:153-7.
135. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI 1999 Intramyocellular lipid concentrations are correlated
with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113-6.
136. Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L 1999 Intramyocellular
triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2
diabetic parents. Diabetes 48:1600-6.
137. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Haring HU 1999 Association of increased
intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 48:1113-9.
138. Ruderman NB, Saha AK, Vavvas D, Witters LA 1999 Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 276:E1-E18.
139. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen AM, Yki-Jarvinen H 2001 Intramyocellular lipid is
associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes
50:2337-43.
140. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E 2002 Insulin resistance in morbid
obesity: reversal with intramyocellular fat depletion. Diabetes 51:144-51.
141. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI 2001 Tissue-specific
overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 98:7522-7.
142. De Fea K, Roth RA 1997 Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J Biol Chem
272:31400-6.
143. De Fea K, Roth RA 1997 Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939-47.
144. Delahaye L, Mothe-Satney I, Myers MG, White MF, Van Obberghen E 1998 Interaction of insulin receptor substrate-1 (IRS-1) with phosphatidylinositol 3kinase: effect of substitution of serine for alanine in potential IRS-1 serine phosphorylation sites. Endocrinology 139:4911-9.
145. Qiao LY, Goldberg JL, Russell JC, Sun XJ 1999 Identification of enhanced serine kinase activity in insulin resistance. J Biol Chem 274:10625-32
146. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF 2001 Phosphorylation of SER307 in IRS-1 blocks interactions with the insulin receptor and
inhibits insulin action. J Biol Chem 17:17
147. Ravichandran LV, Esposito DL, Chen J, Quon MJ 2001 Protein Kinase C-zeta Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate
Phosphatidylinositol 3-Kinase in Response to Insulin. J Biol Chem 276:3543-3549
148. Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF 2001 Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at
inhibitory Ser307 via distinct pathways. J Clin Invest 107:181-9
149. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE 2001 Reversal of obesity- and diet-induced insulin resistance with salicylates or
targeted disruption of Ikkbeta. Science 293:1673-7.
150. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI 2001 Prevention of fat-induced insulin
resistance by salicylate. J Clin Invest 108:437-46.
151. Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA, Reaven GM, Goldfine ID 1995 Membrane
glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373:448-451
152. Frittitta L, Youngren JF, Sbraccia P, D'Adamo M, Buongiorno A, Vigneri R, Goldfine ID, Trischitta V 1997 Increased adipose tissue PC-1 protein content, but
not tumour necrosis factor-alpha gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase
activity. Diabetologia 40:282-9.
153. Maddux BA, Goldfine ID 2000 Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit.
Diabetes 49:13-9.
154. Goldfine ID, Maddux BA, Youngren JF, Trischitta V, Frittitta L 1999 Role of PC-1 in the etiology of insulin resistance. Ann N Y Acad Sci 892:204-22.
155. Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose tissue expression of tumor necrosis factor alpha: Direct role in obesity-linked insulin resistance.
Science 259:87-90
156. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor-a in human obesity and
insulin resistance. J Clin Invest 95:2409-2415
157. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB 1995 The expression of tumor necrosis factor in human adipose tissue. Regulation by
obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:2111-9.
158. Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA 1996 The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest
97:1111-6.
159. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-aand obesity-induced insulin resistance. Science 271:665-668
160. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A 1993 Tumor necrosis factor-a suppresses insulin-induced tyrosine phosphorylation of insulin receptor
and its substrates. J Biol Chem 268:26055-26058
161. Stephens JM, Lee J, Pilch PF 1997 Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor
substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem 272:971-6.
162. Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE 1996 Negative regulation of peroxisome proliferator-activated
receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 10:1457-66
163. Olefsky JM 2000 Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 106:467-72.
164. Szalkowski D, White-Carrington S, Berger J, Zhang B 1995 Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-a on
differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinol 136:1474-1481
165. Souza SC, Yamamoto MT, Franciosa MD, Lien P, Greenberg AS 1998 BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new
insulin-sensitizing mechanism for thiazolidinediones. Diabetes 47:691-5.
166. Miles PD, Romeo OM, Higo K, Cohen A, Rafaat K, Olefsky JM 1997 TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes
46:1678-83.
167. Friedman JM, Halaas JL 1998 Leptin and the regulation of body weight in mammals. Nature 395:763-70.
168. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM 1995 Weight-reducing effects of the plasma protein
encoded by the obese gene. Science 269:543-6.
169. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL 1999 Leptin reverses insulin resistance and diabetes mellitus in mice with congenital
lipodystrophy. Nature 401:73-6.
170. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB 2002 Leptin stimulates fatty-acid oxidation by activating AMP-activated protein
kinase. Nature 415:339-43.
171. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-replacement
therapy for lipodystrophy. N Engl J Med 346:570-8.
172. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem
270:26746-9
173. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo
K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem
Biophys Res Commun 257:79-83
174. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close
association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930-5
175. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T,
Shimomura I, Matsuzawa Y 2001 PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes
50:2094-9
176. Combs TP, Wagner JA, Berger J, Debber T, Wang W-J, Zhang BB, Tanen M, Berg AH, O'Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener
KMr, Gertz BJ, Charron MJn, Scherer PE, Moller DE 2002 Induction of Acrp30 Levels by PPARg Agonists: a Potential Mechanism of Insulin Sensitization.
Endocrinology 143:998-1007
177. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE 2001 The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947-53
178. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C,
Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin
reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941-6
179. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte
complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005-10
180. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes.
Nature 409:307-12.
181. Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu GD, Lazar MA 2001 A family of tissue-specific resistinlike molecules. Proc Natl Acad Sci U S A 98:502-6.
182. Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR, Jr., Willson TM, Kliewer SA, Hotamisligil GS 2001 Adipose tissue resistin
expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 276:25651-3.
183. McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S 2002 Resistin, central obesity, and type 2 diabetes. Lancet 359:46-7.
184. Nagaev I, Smith U 2001 Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys
Res Commun 285:561-4.
185. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S 2001 Resistin / Fizz3 expression in relation to obesity and peroxisome
proliferator-activated receptor-gamma action in humans. Diabetes 50:2199-202.
186. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM 2002 Resistin gene expression in human adipocytes is not related to insulin resistance. Obes Res 10:1-5.
187. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez MT, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV,
Smith RG, Moller DE 1999 Discovery of a small molecule insulin mimetic with antidiabetic activity in mice Science 284:974-7
188. Qureshi SA, Ding V, Li Z, Szalkowski D, Biazzo-Ashnault D, Xie D, Saperstein R, Brady E, Huskey S, Shen X, Liu K, Xu L, Salituro GM, Heck JV, Moller DE,
Jones AB, Zhang BB 2000 Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators. J Biol Chem
275:36590-36595
189. Manchem VP, Goldfine ID, Kohanski RA, Cristobal CP, Lum RT, Schow SR, Shi S, Spevak WR, Laborde E, Toavs DK, Villar HO, Wick MM, Kozlowski MR 2001 A
novel small molecule that directly sensitizes the insulin receptor in vitro and in vivo. Diabetes 50:824-30
190. Li M, Youngren JF, Manchem VP, Kozlowski M, Zhang BB, Maddux BA, Goldfine ID 2001 Small molecule insulin receptor activators potentiate insulin action in
insulin-resistant cells. Diabetes 50:2323-8