Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression
of p85α
The Two Sides of a Coin
- Boris Draznin12
- 1Research Service, Denver VA Medical Center, Denver, Colorado
- 2Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
- Address correspondence and reprint requests to Dr. Boris Draznin, Research Service (151), Denver VA Medical Center, 1055 Clermont
St., Denver, CO 80220. E-mail: boris.draznin{at}med.va.gov
Abstract
Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible
for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies
in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the
insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and
utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate,
but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine
phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number
of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified.
Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine
phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85α has also been found to play
an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85α
and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance.
Even though insulin resistance has emerged as an enormous health care problem, trespassing the fields of obesity, diabetes,
hypertension, and cardiovascular diseases (1,2), its molecular mechanism remains incompletely understood. Clinically, the term insulin resistance implies that higher-than-normal
concentrations of insulin are required to maintain normoglycemia. On a cellular level, this term defines an inadequate strength
of insulin signaling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic
and mitogenic aspects of cellular function (3).
Insulin action is initiated by an interaction of insulin with its cell surface receptor (4). The insulin receptor is a heterotetrameric protein that consists of two extracellular α subunits and two transmembrane
β subunits connected by disulfide bridges (5–7). Insulin binding to the extracellular α subunit induces conformational changes of the insulin receptor that activate the
tyrosine kinase domain of the intracellular portion of the β subunit (8–11). Once the tyrosine kinase of insulin receptors is activated, it promotes autophosphorylation of the β subunit itself, where
phosphorylation of three tyrosine residues (Tyr-1158, Tyr-1162, and Tyr-1163) is required for amplification of the kinase
activity (12,13). Activation of the tyrosine kinase of the insulin receptor also leads to a rapid phosphorylation of the so-called “docking
proteins,” such as insulin receptor substrate (IRS)-1, -2, -3, and -4, and several Shc proteins (52-, 46-, and 64-kDa isoforms)
(14,15) that, in turn, attract multiple intracellular signaling intermediates.
Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible
for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling (16–18). Thus, numerous studies have demonstrated that the number and function (tyrosine kinase activity) of insulin receptors are
either normal or only slightly reduced in patients and experimental animals with insulin resistance, insufficiently to account
for a substantial reduction in insulin action.
The IRS and Shc proteins play an important regulatory role in the insulin signaling cascade, as in their phosphorylated form
they become points of anchoring for intracellular proteins containing Src-homology-2 (SH-2) domains (rev. in 19). Whereas interaction of IRS and Shc proteins with the intracellular domain of the insulin receptor constitutes the first
step in dispersing the directions of insulin signaling intracellularly, their ability to attract multiple signaling intermediates
to their own phosphorylated domains further partitions insulin signaling downstream, thus accounting for the multitude of
insulin's biological effects (20).
Most, if not all, of the metabolic and antiapoptotic effects of insulin are mediated by the signaling pathway involving IRS
proteins, phosphorylation, and activation of phosphatidylinositol (PI) 3-kinase, Akt (also known as protein kinase B), molecular
target of rapamycin (mTOR), and p70 S6 kinase (21–24). Activation of PI 3-kinase, Akt, and atypical protein kinase C (PKC) via the phosphoinositide-dependent protein kinase (25) appears to be critical in the mechanism of insulin action on GLUT-4 translocation and glucose transport. In contrast, nonmetabolic,
proliferative, and mitogenic effects of insulin are mediated largely via the activation of Ras (mostly through Shc and, to
a lesser degree, through IRS proteins), Raf, and mitogen-activated protein kinases Erk 1 and Erk 2 (26–30).
Subsequent studies (31–33) in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via
the IRS-1/PI 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However,
the nature of the culprit that initiates and sustains impaired insulin signal transduction along the IRS-1/PI 3-kinase pathway
is still largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation
for the reduced strength of the IRS-1/PI 3-kinase signaling pathway.
SERINE PHOSPHORYLATION OF IRS-1
First, it became apparent that serine phosphorylation of IRS proteins can reduce the ability of IRS proteins to attract PI
3-kinase, thereby minimizing its activation (34–40), and can also lead to an accelerated degradation of IRS-1 protein (41). Thus, in contrast to a signal promoting tyrosine phosphorylation, excessive serine phosphorylation of IRS proteins could
become detrimental for normal conductance of the metabolic insulin signaling downstream, causing insulin resistance. Serine
phosphorylation of IRS proteins can occur in response to a number of intracellular serine kinases (Table 1).
A cellular nutrient sensor, mTOR, has been identified as a critical element integrating cellular metabolism with growth factor
signaling (42–45). In response to insulin and amino acids, mTOR, which is a serine/threonine kinase, phosphorylates and modulates activities
of p70 S6 kinase (S6K1 kinase) and an inhibitor of translational initiation, eIF-4E binding protein (46–48). While insulin activates mTOR and S6K1 kinase via the IRS-1/PI 3-kinase/Akt pathway (49,50), amino acids seem to exert their effect through a direct influence of mTOR (44,51,52). In any event, activation of mTOR and S6K1 kinase causes serine phosphorylation of IRS-1, with a subsequent decline in the
IRS-1–associated PI 3-kinase activity (Fig. 1A). In contrast to wild-type littermates, transgenic mice lacking S6K1 kinase (S6K1-deficient mice) displayed a strong resistance
to age- and diet-induced obesity and insulin resistance (37). Moreover, because wild-type mice on a high-fat diet demonstrated significantly elevated S6K1 kinase activity and serine
phosphorylation of IRS-1, it has been suggested that under conditions of nutrient saturation, S6K1 kinase may negatively regulate
insulin signaling and sensitivity (37,53,54).
Because insulin resistance can be induced by mechanisms other than nutritional excess, serine phosphorylation of IRS-1 has
been examined under various circumstances. It appears that in addition to the mTOR-S6K1–dependent mechanism, various serine
kinases, such as c-Jun NH2-terminal kinase (JNK), stress-activated protein kinases, tumor necrosis factor (TNF)α, and PKC, among others, can promote
serine phosphorylation of IRS-1 (Table 1 and Fig. 1A).
Activation of JNK by free fatty acids, stress, and inflammation (55–58) has been shown to increase serine phosphorylation of IRS-1 with a resulting decline in the strength of insulin signaling
along the metabolic pathway. Blocking JNK activation rescued the cellular and molecular defects induced by free fatty acids
(56). Furthermore, JNK-1 knockout mice were found to be resistant to diet-induced obesity and insulin resistance (55). Similarly, activation of the proinflammatory kinase that phosphorylates the inhibitor of nuclear factor-κB (IKKβ) has been
shown to induce insulin resistance (59–61). In an unstimulated state, nuclear factor-κB dimers are restrained in the cytoplasm in association with inhibitory protein
inhibitor of κBs (IκB). In response to proinflammatory stimuli, such as TNFα, IKKβ is activated and phosphorylates two serine
residues of the IκB. Phosphorylated IκB is rapidly degraded by proteasomes, releasing nuclear factor-κB for translocation
to the nucleus where it activates transcription of target genes. Inhibition of IKKβ with salicylates has been shown to prevent
and reverse diet- and obesity-induced insulin resistance (62,63).
TNFα, an agent responsible for cachexia, has been shown to be increased in adipose tissue of obese, insulin-resistant humans
and animals. Because removal of TNFα appeared to reverse insulin resistance in animal models, it has been suggested that TNFα
plays an important role in the pathogenesis of insulin resistance in obesity (64–,66). Furthermore, mice lacking TNFα function were protected from obesity-induced insulin resistance (67). More recently, TNFα has been shown to block insulin signaling by promoting serine phosphorylation of IRS-1 (68), with a resultant decline in IRS-1–associated PI 3-kinase activity.
Recently, a hypothesis that mitochondrial dysfunction or reduced mitochondrial content accompanied by a decreased mitochondrial
fatty acid oxidation and accumulation of fatty acid acyl CoA and diacylglycerol can cause insulin resistance has gained substantial
experimental support (69–71). The mechanism of insulin resistance in these cases has been suggested to involve activation of a novel PKC that either
by itself or via IKKβ or JNK-1 could lead to increased serine phosphorylation of IRS-1.
The proinflammatory novel PKCθ has been found to cause serine phosphorylation of IRS-1 (72,73), while PKCθ knockout mice have been shown to be protected from fat-induced insulin resistance (74). Increased activity of PKCθ, along with increased activity of JNK, has also been found in skeletal muscle of obese and type
2 diabetic subjects (58,75), supporting a potential role of these serine kinases in the pathogenesis of insulin resistance.
INCREASED EXPRESSION OF p85α
A second molecular mechanism that can potentially lead to insulin resistance is a disruption in the balance between the amounts
of the PI 3-kinase subunits (81). PI 3-kinase belongs to the class 1a 3-kinases (82), which exist as heterodimers, consisting of a regulatory subunit (p85), which is tightly associated with a catalytic subunit,
p110. The regulatory subunit, p85, is encoded by at least three genes that generate highly homologous products. Two isoforms
are termed p85α (PIK3R1) and p85β (products of the two genes). Three splice variants of p85α have been reported, including
p85α itself, p55α, and p50α. The third gene product is p55γ. p85α, however, appears to be the most abundant isoform (82).
Normally, the regulatory subunit exists in stoichiometric excess to the catalytic one, resulting in a pool of free p85 monomers
not associated with the p110 catalytic subunit. Thus, there exists a balance between the free p85 monomer and the p85-p110
heterodimer, with the latter being responsible for the PI 3-kinase activity. Increases or decreases in expression of p85 shift
this balance in favor of either free p85 or p85-p110 complexes (83–86). Because the p85 monomer and the p85-p110 heterodimer compete for the same binding sites on the tyrosine-phosphorylated
IRS proteins, an imbalance could cause either increased or decreased PI 3-kinase activity (Fig. 1B). This possibility has been recently supported by studies in insulin-resistant states induced by human placental growth hormone
(87), obesity, and type 2 diabetes (58) and by short-term overfeeding of lean nondiabetic women (88).
One of the first indications that an imbalance between the abundance of p85 and p110 can alter PI 3-kinase activity came from
experiments with l-6 cultured skeletal muscle cells treated with dexamethazone (89). This treatment significantly reduced PI 3-kinase activity, despite an almost fourfold increase in expression of p85α (no
change in p85β) and only a minimal increase in p110. The authors concluded that p85α competes with the p85-p110 heterodimer,
thus, reducing PI 3-kinase activity (Table 2).
Subsequently, animals with a targeted disruption of p85α (p85+/− heterozygous mice) have been found to have a higher ratio of p85-p110 dimer to free p85 and to be more sensitive to insulin
(80,81,89–91). To determine this ratio, the authors immunodepleted p110 and blotted both the immunoprecipitates and the supernatant with
p85 antibody. The amounts of p85 in the p110 immunoprecipitates denote p85 bound to p110, while the amount of p85 in the supernatant
represents free (excess) p85. The greater the ratio of bound to free, the greater the insulin sensitivity the mice display.
The same group of authors then overexpressed p85α in cultured cells. This overexpression significantly inhibited the PI 3-kinase
activity (85,86,92). Overexpression of p50α or p55α did not inhibit PI 3-kinase activity to the same extent. These experimental results were
consistent with the competition hypothesis.
Recently, Barbour and colleagues (87,93) demonstrated that insulin resistance of pregnancy is likely due to increased expression of skeletal muscle p85 in response
to increasing concentrations of human placental growth hormone. Furthermore, women remaining insulin resistant postpartum
have been found to display higher levels of p85 in the muscle (94). Thus, results reported in the literature support the hypothesis that the p85 monomer completes with a p85-p110 dimer and
that the removal of the excess of p85 improves insulin sensitivity by allowing the remaining isoforms to bring p110 to its
site of action.
Finally, in a small study of eight healthy lean women without a family history of diabetes, Cornier et al. (88) were able to show that 3 days of overfeeding (50% above usual caloric intake) led to a significant increase in expression
of p85α, ratio of p85α to p110, and a decline in insulin sensitivity. Within this experimental time frame, overfeeding did
not cause any change in serine phosphorylation of either IRS-1 or S6K1 (88), suggesting that increased expression of p85α may be an early molecular step in the pathogenesis of the nutritionally induced
insulin resistance.
SUMMARY
There have been substantial strides made in our understanding of the genesis of insulin resistance. A number of serine kinases
that could phosphorylate serine residues of IRS-1 and thereby diminish insulin signal transduction have been identified. Potential
triggering mechanisms such as mitochondrial dysfunction have also been proposed and supported by experimental and observational
data. On the other hand, an additional and possibly complementary mechanism involving increased expression of p85α has also
been found to play an important role in the pathogenesis of insulin resistance under certain circumstances. Conceivably, a
combination of both increased expression of p85α and increased serine phosphorylation of IRS-1 is needed to induce clinically
apparent insulin resistance. Further studies are needed in order to evaluate this hypothesis.
FIG. 1.
Inhibition of the metabolic insulin signaling. IRS-1 is phosphorylated by the tyrosine kinase of the insulin receptor in response
to insulin binding. Protein/lipid kinase, PI 3-kinase, binds to the specific MYMX motifs of IRS-1, containing phosphorylated
tyrosine residues. PI 3-kinase is then activated and initiates a downstream cascade of events leading to the phosphorylation
and activation of Akt, mTOR, and p70S6 kinase. Activation of Akt appears to be important for glucose transport, while activation
of mTOR and p70S6 kinase participates in the process of protein synthesis. A: Hyperactivation of mTOR by amino acids, Akt, or hyperinsulinemia results in serine phosphorylation of IRS-1 by p70S6 kinase,
with a subsequent decrease in the strength of the IRS-1/PI 3-kinase signaling. In addition, serine phosphorylation of IRS-1
can be promoted by JNK, PKC, IKKβ, and TNFα. B: Increased expression of p85α monomer competes with and displaces the p85-p110 heterodimer from the IRS-1 binding sites.
The resultant decrease in association of p110 with IRS-1 diminishes PI 3-kinase activity and the downstream effects of this
kinase. Steroids, growth hormone (GH), human placental growth hormone (hPGH), short-term overfeeding, obesity, and type 2
diabetes (T2DM) have been shown to increase p85α expression (see text for details and references).
TABLE 1
Causes of IRS-1 serine phosphorylation
TABLE 2
Causes of an imbalance between PI 3-kinase subunits
Footnotes
-
- Accepted April 24, 2006.
- Received March 23, 2006.
- DIABETES
REFERENCES
- ↵
Olefsky JM: The insulin receptor: a multifunctional protein.
Diabetes39
:1009
–1016,1990
- ↵
Reaven GM: Role of insulin resistance in human disease.
Diabetes37
:1595
–1607,1998
- ↵
Ginsberg H: Insulin resistance and cardiovascular disease.
J Clin Invest106
:453
–458,2000
- ↵
Shulman GI: Cellular mechanisms of insulin resistance in humans.
Am J Cardiol84
:3J
–10J,1999
- ↵
Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli IM, Dull TJ, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg
PH, Grunfeld C, Rosen OM, Ramachandran J: Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.
Nature313
:756
–761,1985
-
Ebina Y, Ellis L, Jarnagin K, Edery M, Grat L, Clauser E, Ou J-H, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ: The
human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signaling.
Cell40
:747
–758,1985
- ↵
Seino S, Seino M, Nishi S, Bell GI: Structure of human insulin receptor gene and characterization of its promoter.
Proc Natl Acad Sci U S A86
:114
–118,1989
- ↵
Kasuga M, Karisson FA, Kahn CR: Insulin stimulates the phosphorylation of the 95,000 Dalton subunit of its own receptor.
Science215
:185
–187,1982
-
Wilden PA, Siddle K, Haring E, Backer JM, White MF, Kahn CR: The role of insulin receptor-kinase domain autophosphorylation
in receptor-mediated activities.
J Biol Chem267
:13719
–13727,1992
-
De Meyts P, Christoffersen CT, Tornqvist H, Seedorf K: Insulin receptors and insulin action.
Curr Opin Endocrinol Diabetes3
:369
–377,1996
- ↵
Rhodes CJ, White MF: Molecular insights into insulin action and secretion.
Eur J Clin Invest32 (Suppl. 3)
:3
–13,2002
- ↵
White MF, Shoelson SE, Keutmann H, Kahn CR: A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase
of the insulin receptor.
J Biol Chem263
:2969
–2980,1988
- ↵
Tornqvist HE, Avruch J: Relationship of site-specific beta subunit tyrosine autophosphorylation to insulin activation of the
insulin receptor (tyrosine) protein kinase activity.
J Biol Chem263
:4593
–4601,1988
- ↵
Myers MG Jr, White MF: Insulin signal transduction and the IRS proteins.
Annu Rev Pharmacol Toxicol36
:615
–658,1996
- ↵
Paz K, Voliovitch H, Hadari YR, Roberts CT, LeRoith D, Zick Y: Interaction between the insulin receptor and its downstream
effectors.
J Biol Chem271
:6998
–7003,1996
- ↵
Kolterman OG, Insel J, Saekow M, Olefsky JM: Mechanisms of insulin resistance in human obesity: evidence for receptor and
post-receptor defects.
J Clin Invest65
:1272
–1284,1980
-
Marshal S, Olefsky JM: Effects if insulin incubation on insulin binding, glucose transport, and insulin degradation by isolated
rat adipocytes: evidence for hormone-induced desensitization at the receptor and post-receptor level.
J Clin Invest66
:763
–772,1980
- ↵
Haring HU: The insulin receptor: signaling mechanism and contribution to the pathogenesis of insulin resistance.
Diabetologia34
:848
–861,1991
- ↵
Cheatham B, Kahn CR: Insulin action and the insulin signaling network.
Endocrine Rev16
:117
–141,1995
- ↵
Kahn CR: Insulin action, diabetogenes, and the cause of type 2 diabetes.
Diabetes43
:1066
–1084,1994
- ↵
Cheatham B: Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70S6 kinase, DNA synthesis,
and glucose transporter translocation.
Mol Cell Biol14
:4902
–4911,1994
-
Shepherd PR, Nave BT, Siddle K: Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin
and rapamycin in 3T3–L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6
kinase.
Biochem J305
:25
–28,1995
-
Lazar D: Mitogen-activated kinase kinase inhibition does not block the stimulation of glucose utilization by insulin.
J Biol Chem270
:20801
–20807,1995
- ↵
Sutherland C, Waltner-Law M, Gnudi L, Kahn BB, Granner DK: Activation of the Ras mitogen-activated protein kinase-ribosomal
protein kinase pathway is not required for the repression of phosphoenolpyruvate carboxykinase gene transcription by insulin.
J Biol Chem273
:3198
–3204,1998
- ↵
Bandyopadhyay GK, Standaert ML, Zhao L, Yu B, Avignon A, Galloway L, Karnam P, Moscat J, Farese RV: Activation of protein
kinase (α, β, and ξ) by insulin in 3T3–L1 cells: transfection studies suggest a role for PKC-zeta in glucose transport.
J Biol Chem272
:2551
–2558,1997
- ↵
Jiang ZY, Lin Y-W, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL: Characterization of selective
resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats.
J Clin Invest104
:447
–457,1999
-
Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ: Insulin resistance
differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.
J Clin Invest105
:311
–320,2000
-
Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, Johansen M, Kucik DF, Quon MJ, Draznin B: Inhibition
of phosphatidylinositol 3-kinase enhances mitogenic action of insulin in endothelial cells.
J Biol Chem277
:1794
–1799,2002
-
Wang C, Gurevich I, Draznin B: Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling
pathways.
Diabetes52
:2562
–2569,2003
- ↵
Sartipy P, Loskutoff DJ: Monocyte chemoattractant protein 1 in obesity and insulin resistance.
Proc Natl Acad Sci U S A100
:7265
–7270,2003
- ↵
Kahn BB, Flier JS: Obesity and insulin resistance.
J Clin Invest106
:473
–481,2000
-
Pessin JE, Saltiel AR: Signaling pathways in insulin action: molecular targets of insulin resistance.
J Clin Invest106
:165
–169,2000
- ↵
LeRoith D, Zick Y: Recent advances in our understanding of insulin action and insulin resistance.
Diabetes Care24
:588
–597,2001
- ↵
Qiao L, Goldberg JL, Russell JC, Sun XJ: Identification of enhanced serine kinase activity in insulin resistance.
J Biol Chem274
:10625
–10632,1999
-
White MF: Insulin signaling in health and disease.
Science302
:1710
–1711,2003
-
Birnbaum MJ: Turning down insulin signaling.
J Clin Invest108
:655
–659,2001
- ↵
Um SH, Frogerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G: Absence
of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.
Nature431
:200
–205,2004
-
Patti M-E, Kahn BB: Nutrient sensor links obesity with diabetes risk.
Nat Med10
:1049
–1050,2004
-
Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF: Phosphorylation of Ser307 in insulin receptor substrate-1 blocks
interactions with the insulin receptor and inhibits insulin action.
J Biol Chem277
:1531
–1537,2002
- ↵
Qiao L, Zhande R, Jetton TL, Zhou G, Sun XJ: In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel
serine kinase in insulin-resistant rodents.
J Biol Chem277
:26530
–26539,2002
- ↵
Shah OJ, Wang Z, Hunter T: Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance,
and cell survival deficiencies.
Curr Biol14
:1650
–1656,2004
- ↵
Raught B, Gingras AC, Sonenberg N: The target of rapamycin (TOR) proteins.
Proc Natl Acad Sci U S A98
:7037
–7044,2001
-
Rohde J, Heitman J, Cardenas ME: The TOR kinases link nutrient sensing to cell growth.
J Biol Chem276
:9583
–9586,2001
- ↵
Khamzina L, Veilleux A, Bergeron S, Marette A: Increased activation of the mammalian target of rapamycin pathway in liver
and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance.
Endocrinol146
:1473
–1481,2005
- ↵
Trembley F, Gagnon A, Veilleux A, Sorisky A, Marette A: Activation of the mammalian target of rapamycin pathway acutely inhibits
insulin signaling to Akt and glucose transport in 3T3–L1 and human adipocytes.
Endocrinol146
:1328
–1337,2005
- ↵
Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM: RAFT1 phosphorylation of the translational regulators p70S6 kinase
and 4E-BP1.
Proc Natl Acad Sci U S A95
:1432
–1437,1998
-
Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng OP, Kasuga M, Nishimoto I, Avruch J: Regulation of eIF-4E BP1
phosphorylation by mTOR.
J Biol Chem272
:26457
–26463,1997
- ↵
Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K: Immunopurified mammalian target of rapamycin phosphorylates
and activates p70S6 kinase α in vitro.
J Biol Chem274
:34493
–34498,1999
- ↵
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR: Mammalian target of rapamycin is a direct target for protein kinase
B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation.
Biochem J344
:427
–431,1999
- ↵
Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr: Evidence of insulin-stimulated phosphorylation and activation of the
mammalian target of rapamycin mediated by a protein kinase B signaling pathway.
Proc Natl Acad Sci U S A95
:7772
–7777,1998
- ↵
Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, Van Obberghen E: Amino acids and leucine allow insulin activation of
the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice.
FASEB J18
:1894
–1896,2004
- ↵
Pham P-TT, Heydrick SJ, Fox HL, Kimball SR, Jefferson LS Jr, Lynch CJ: Assessment of cell-signaling pathways in the regulation
of mammalian target of rapamycin (mTOR) by amino acids in rat adipocytes.
J Cell Biochem79
:427
–441,2000
- ↵
Pende M, Kozma SC, Jaquet M, Oorshcot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G: Hypoinsulinaemia,
glucose intolerance and diminished β-cell size in S6K1-deficient mice.
Nature408
:994
–997,2000
- ↵
Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldhausl W, Marette A, Roden M: Overactivation
of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability.
Diabetes54
:2674
–2684,2005
- ↵
Hirosumi J, Tuncman G, Chang L, Gorzun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity
and insulin resistance.
Nature420
:333
–336,2002
- ↵
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J: Inhibition of insulin sensitivity by free fatty acids requires
activation of multiple serine kinases in 3T3–L1 adipocytes.
Mol Endocrinol18
:2024
–2034,2004
-
Nguyen MTA, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat B, Chi N-W, Olefsky JM: JNK and
tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3–L1 adipocytes.
J Biol Chem280
:35361
–35371,2005
- ↵
Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM: Increased p85/55/50 expression and decreased phosphatidylinositol 3-kinase
activity in insulin-resistant human skeletal muscle.
Diabetes54
:2351
–2359,2005
- ↵
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE: Reversal of obesity- and diet-induced insulin resistance
with salicylates or targeted disruption of IKK-beta.
Science293
:1673
–1677,2001
-
Perseghin G, Petersen K, Shulman GI: Cellular mechanism of insulin resistance: potential links with inflammation.
Int J Obes Relat Metab Disord27 (Suppl. 3)
:S6
–S11,2003
- ↵
Gao Z, Hwang D, Bataille F, Lefevre, York D, Quon MJ, Ye J: Serine phosphorylation of insulin receptor substrate 1 by inhibitor
kB kinase complex.
J Biol Chem277
:48115
–48121,2002
- ↵
Kim JK, Kim Y-J, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI: Prevention
of fat-induced insulin resistance by salicylate.
J Clin Invest108
:437
–446,2001
- ↵
Hundal RS, Petersen KF, Mayerson AB, Rahdhawa PS, Inzucchi S, Shoelson SE, Shulman GI: Mechanism by which high-dose aspirin
improves glucose metabolism in type 2 diabetes.
J Clin Invest109
:1321
–1326,2002
- ↵
Hotamisligil GS, Spiegelman BM: Tumor necrosis factor α: a key component of the obesity-diabetes link.
Diabetes43
:1271
–1278,1994
-
Qi C, Pekala PH: Tumor necrosis factor-alpha-induced insulin resistance in adipocytes.
Proc Soc Exp Biol Med223
:128
–135,2000
- ↵
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked
insulin resistance.
Science259
:87
–91,1993
- ↵
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS: Protection from obesity-induced insulin resistance in mice lacking TNF-alpha
function.
Nature389
:610
–614,1997
- ↵
Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM: IRS-1-mediated inhibition of insulin receptor tyrosine
kinase activity in TNF-alpha and obesity-induced insulin resistance.
Science271
:665
–668,1996
- ↵
Lowell BB, Shulman GI: Mitochondrial dysfunction and type 2 diabetes.
Science307
:384
–387,2005
-
Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI: Mitochondrial dysfunction
in the elderly: possible role in insulin resistance.
Science300
:1140
–1142,2003
- ↵
Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI: Impaired mitochondrial activity in the insulin-resistant offspring
of patients with type 2 diabetes.
N Engl J Med350
:664
–671,2004
- ↵
Li Y, Soos TJ, Li X, Wu J, Degennaro M, Sun X, Littman DR, Birnbaum MJ, Polakiewicz RD: Protein kinase θ inhibits insulin
signaling by phosphorylating IRS1 at Ser1101.
J Biol Chem279
:45304
–45307,2004
- ↵
Bell KS, Shcmitz-Peiffer C, Lim-Fraser M, Biden TJ, Cooney GJ, Kraegen EW: Acute reversal of lipid-induced muscle insulin
resistance is associated with rapid alteration in PKC-θ localization.
Am J Physiol Endocrinol Metab279
:E1196
–E1201,2000
- ↵
Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O’Brien WR, Littman DR, Shulman
GI: PKC-θ knockout mice are protected from fat-induced insulin resistance.
J Clin Invest114
:823
–827,2004
- ↵
Itani SI, Pories WJ, Macdonald KG, Dohm GL: Increased protein kinase C θ in skeletal muscle of diabetic patients.
Metabolism50
:553
–557,2001
- ↵
Ueno M, Carvalheira JBC, Tambascia RC, Bezzera RMN, Amara ME, Carneiro EM, Folli F, Franchini KG, Saad MJA: Regulation of
insulin signaling by hyperinsulinemia: role of IRS-1/2 serine phosphorylation and mTOR/p70 S6K pathway.
Diabetologia48
:506
–518,2005
-
Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M: A rapamycin-sensitive pathway down-regulates
insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1.
Mol Endocrinol14
:783
–794,2000
-
Tremblay F, Marette A: Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway: a negative feedback mechanism
leading to insulin resistance in skeletal muscle.
J Biol Chem276
:38052
–38060,2001
- ↵
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I,
Downes CP, Lamb RE: The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.
J Cell Biol166
:213
–223,2004
- ↵
Lee YH, Giraud J, Davis RJ, White MF: C-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling
cascade.
J Biol Chem278
:2896
–2902,2003
- ↵
Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR: Molecular balance between the regulatory and catalytic subunits
of phosphoinositide 3-kinase regulates cell signaling and survival.
Mol Cell Biol22
:965
–977,2002
- ↵
Shepherd PR, Withers DJ, Siddle K: Phosphoinositide 3-kinase: the key switch mechanism in insulin signaling.
Biochem J333
:471
–490,1998
- ↵
Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K, Nakajima H, Hanafusa
T, Matsuzawa Y, Sekihara H, Yin Y, Barrett JC, Oda H, Ishikawa T, Akanuma Y, Komuro I, Suzuki M, Yamamura K, Kodama T, Suzuki
H, Kadowaki T: Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3-kinase.
Nat Genet21
:230
–235,1999
-
Ueki K, Algenstaedt P, Mauvais-Jarvis F, Kahn CR: Positive and negative regulation of phosphoinositide 3-kinase-dependent
signaling pathways by three different gene products of the p85α regulatory subunit.
Mol Cell Biol20
:8035
–8046,2000
- ↵
Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR: Reduced
expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes.
J Clin Invest109
:141
–149,2000
- ↵
Ueki K, Fruman DA, Yballe CM, Fasshauer M, Klein J, Asano T, Cantley LC, Kahn CR: Positive and negative roles of p85α and
p85β regulatory subunits of phosphoinositide 3-kinase in insulin signaling.
J Biol Chem278
:48453
–48466,2003
- ↵
Barbour LA, Shao J, Qiao L, Leitner W, Anderson M, Friedman JE, Draznin B: Human placental growth hormone increases expression
of p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle.
Endocrinology145
:1144
–1150,2004
- ↵
Cornier M-A, Bessesen DH, Gurevich I, Leitner JW, Draznin B: Nutritional up-regulation of p85α expression is an early molecular
manifestation of insulin resistance.
Diabetologia49
:748
–754,2006
- ↵
Giorgino F, Pedrini MT, Matera L, Smith RJ: Specific increase in p85α expression in response to dexamethazone is associated
with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells.
J Biol Chem272
:7455
–7463,1997
-
Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC: Increased insulin sensitivity in mice lacking p85β
subunit of phosphoinositide 3-kinase.
Proc Natl Acad Sci U S A99
:419
–424,2002
- ↵
Lamia KA, Peroni OD, Kim Y-B, Rameh LE, Kahn BB, Cantley LC: Increased insulin sensitivity and reduced adiposity in phosphatidylinositol
5-phosphate 4-kinase β-/- mice.
Mol Cell Biol24
:5080
–5087,2004
- ↵
Luo J, Field SJ, Lee JY, Engelman JA, Cantley LC: The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1
signaling via the formation of a sequestration complex.
J Cell Biol170
:455
–464,2005
- ↵
Barbour L, Rahman SM, Gurevich I, Leitner JW, Fisher S, Roper M, Knotts T, Vo Y, Yakar S, LeRoith D, Kahn CR, Cantley L, Friedman
J, Draznin B: Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin
resistance associated with growth hormone excess.
J Biol Chem280
:37489
–37494,2005
- ↵
Kirwan J, Varastehpour A, Jing M, Presley L, Shao J, Friedman JE, Catalano PM: Reversal of insulin resistance post-partum
is linked to enhanced skeletal muscle insulin signaling.
JClin Endocrinol Metab89
:4678
–4684,2004
