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INTRODUÇÃO
Após a descoberta da insulina por Banting e Best, em 1922(1), o diabetes foi considerado
uma doença causada exclusivamente pela deficiência da secreção desse hormônio. Dez
anos depois, Himsworth notou variações nas respostas de pacientes diabéticos à insulina
e sugeriu que a redução da sensibilidade à insulina, e não sua deficiência, constituía o
mecanismo fisiopatológico central em muitos diabéticos(2). Essa idéia permaneceu
desacreditada até o desenvolvimento do radioimunoensaio(3-5), que comprovou
definitivamente que pacientes com diabetes iniciado na vida adulta tinham, na realidade,
altos níveis de insulina circulante. Estudos posteriores(6-9) sedimentaram as bases para a
idéia de que a resistência à insulina é essencial para o desenvolvimento do diabetes do
tipo 2.
Uma vez ativado, o receptor de insulina fosforila vários substratos protéicos em tirosina.
Atualmente, dez substratos do receptor de insulina já foram identificados. Quatro desses
pertencem à família dos substratos do receptor de insulina, as proteínas IRS(16). Outros
substratos incluem Shc, Gab-1, p60dok, Cbl, JAK2 e APS(11, 17-19). A fosforilação em
tirosina das proteínas IRS cria sítios de reconhecimento para moléculas contendo
domínios com homologia a Src 2 (SH2). Dentre elas destaca-se a fosfatidilinositol 3-
quinase (PI 3-quinase). As funções fisiológicas do IRS-1 e do IRS-2 foram
estabelecidas por meio da produção de camundongos sem os genes que codificam esses
substratos (camundongos "knockout" para IRS-1 e IRS-2). O camundongo que não
expressa IRS-1 apresenta resistência à insulina e retardo de crescimento, mas não é
hiperglicêmico(20). Foi sugerido que o IRS-2 poderia compensar parcialmente a ausência
de IRS-1, o que explicaria o fenótipo de resistência à insulina sem hiperglicemia do
camundongo "knockout" para IRS-1. O camundongo que não expressa o IRS-2 foi
gerado há alguns anos(21) e apresenta um fenótipo diferente do camundongo sem IRS-1:
hiperglicemia acentuada decorrente de diversas anormalidades na ação da insulina nos
tecidos periféricos e falência da atividade secretória das células beta acompanhada de
redução significativa da massa de células beta pancreáticas. Em contraste, camundongos
"knockout" para IRS-3 e IRS-4 têm crescimento e metabolismo de glicose quase
normais(22, 23).
O receptor de insulina, além de ser fosforilado em tirosina, também pode ser fosforilado
em serina, o que atenua a transmissão do sinal pela diminuição da capacidade do
receptor em se fosforilar em tirosina após estímulo com insulina(24). Essas fosforilações
inibitórias causam "feedback" negativo na sinalização insulínica e podem provocar
resistência à insulina(25). Estudos recentes indicam que a resistência à insulina induzida
pela obesidade pode ser decorrente da ativação seqüencial da proteína quinase C (PKC)
e da quinase inibidora do fator nuclear kB (IKkB); entretanto, os detalhes dessa via de
sinalização ainda não são claros(26, 27).
A via CAP/Cbl
Além da ativação da PI 3-quinase, outros sinais também podem ser necessários para que
a insulina estimule o transporte de glicose(11). Essa segunda via envolve a fosforilação
do protooncogene c-Cbl(45) e é aparentemente independente da ativação da PI 3-quinase.
Na maioria dos tecidos sensíveis à insulina, Cbl está associado com a proteína
adaptadora CAP ("Cbl-associated protein")(46). Após a fosforilação, o complexo Cbl-
CAP migra para a membrana celular e interage com a proteína adaptadora CrkII, que
também está constitutivamente associada com a proteína C3G(47, 48). A C3G é uma
proteína trocadora de nucleotídeos que catalisa a troca de GDP por GTP da proteína
TC10, ativando-a. Uma vez ativada, a TC10 desencadeia um segundo sinal para a
translocação da proteína GLUT4 para a membrana celular, em paralelo à ativação da via
da PI 3-quinase(48). Recentemente foi demonstrado que a insulina estimula agudamente a
fosforilação em tirosina de Cbl e sua associação com a CAP no tecido adiposo de
animais normais, e também que essa via pode participar do controle da adiposidade em
modelos animais de resistência à insulina(49).
Diversos estudos têm demonstrado que a ativação da via da MAP quinase pela insulina
não está reduzida no diabetes do tipo 2 e em outros estados de resistência à insulina,
podendo até mesmo estar aumentada(54-56). Possivelmente assim a hiperinsulinemia
crônica, à qual os tecidos estão expostos nesses estados, exerceria efeitos deletérios
sobre o crescimento celular na vasculatura, resultando em doença cardiovascular.
Adipocinas
Além de servir como estoque de lipídios, a célula adiposa produz e secreta diversos
hormônios, chamados coletivamente de adipocinas, as quais podem influenciar
profundamente o metabolismo e o gasto energético. A expressão de fator de necrose
tumoral-alfa (TNF-a) está aumentada na gordura de roedores e de humanos obesos, e
pode promover a fosforilação do IRS-1 em serina, resultando em menor atividade
quinase do receptor de insulina e resistência à insulina(24, 112). Em roedores, anticorpos
anti-TNF-a melhoram significativamente a resistência à insulina(113), bem como a
ausência total do receptor de TNF-a(114-116). Em humanos, no entanto, a importância
desse mecanismo ainda é controversa, visto que estudos limitados com anticorpos anti-
TNF-a demonstraram pouco ou nenhum efeito sobre o estado de resistência à
insulina(117).
A leptina, um hormônio da família das citocinas, é produzida pelo tecido adiposo e age
em receptores no sistema nervoso central e em outros locais para inibir a ingesta
alimentar e promover o gasto energético(118, 119). O mecanismo molecular por meio do
qual a leptina e outros agentes anorexigênicos reduzem o apetite parece envolver a
inativação hipotalâmica da AMPK ("AMP-activated protein kinase") pela
hiperleptinemia gerada pela adiposidade excessiva, elevando os níveis locais de malonil
CoA e inibindo a fome(120). A resistência à insulina caracteriza estados de deficiência ou
resistência graves à leptina, como os camundongos ob/ob ou db/db, ou modelos
genéticos de diabetes lipoatrófico(121-123). Em alguns desses, a administração de leptina
exógena melhora a tolerância à glicose e a sensibilidade à insulina, independentemente
dos efeitos na ingesta alimentar, provavelmente afetando vias neuroendócrinas que
modulam a ação da insulina no fígado(70, 124), embora essa citocina possa também ter
efeitos diretos nos hepatócitos(125). Em humanos, a deficiência congênita de leptina ou
mutações em seu receptor ocorrem em casos extremamente raros e têm sido associadas
com obesidade grave, mas não com diabetes(126), porém os casos estudados são de
indivíduos jovens e ainda não é possível prever se eles irão desenvolver resistência à
insulina ou diabetes no futuro.
PERSPECTIVAS
Existem mais de cem resíduos de serina que podem ser fosforilados no IRS-1, e muitas
proteínas quinases fosforilam o IRS-1, incluindo JNK, PKCz, IKK-ß, mTOR, MAP
quinase e AMPK, embora a JNK tenha recebido mais atenção recentemente por ser
capaz de se associar ao IRS-1 e promover sua fosforilação no resíduo 307 de serina
(Ser307), tornando esse substrato mais refratário à associação com o receptor de insulina
e, conseqüentemente, reduzindo sua fosforilação em tirosina, o que pode contribuir para
a resistência à insulina durante situações de estresse fisiológico, como inflamação e
obesidade(142).
CONCLUSÕES
Houve um progresso científico considerável na compreensão dos mecanismos
moleculares de ação da insulina e nas alterações protéicas que levam à resistência à
insulina. No entanto, muitas lacunas não foram preenchidas. É necessário definir
algumas das etapas das vias de transmissão do sinal, elucidar os mecanismos de "cross-
talk" com outros hormônios, e determinar a suscetibilidade genética da resistência à
insulina e as interações entre os genes e o ambiente. Esses estudos provavelmente irão
propiciar uma abordagem terapêutica individualizada para os pacientes portadores da
síndrome de resistência à insulina, bem como fornecer medidas para sua prevenção.
REFERÊNCIAS
1. Banting FG, Best CH. Pancreatic extracts. 1922. J Lab Clin Med. 1990;115:254-72.
3. Berson SA, Yalow RS. Some current controversies in diabetes research. Diabetes.
1965;14:549-72.
4. Yalow RS, Berson SA. Plasma insulin concentrations in nondiabetic and early
diabetic subjects. Determinations by a new sensitive immuno-assay technique. Diabetes.
1960;9:254-60.
6. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis
nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294:739-45.
8. Olefsky J, Farquhar JW, Reaven G. Relationship between fasting plasma insulin level
and resistance to insulin-mediated glucose uptake in normal and diabetic subjects.
Diabetes. 1973;22:507-13.
9. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded
definition. Annu Rev Med. 1993;44:121-31.
10. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease —
1988. Nutrition. 1997;13:65.
11. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of
insulin resistance. J Clin Invest. 2000;106:165-9.
12. Ebina Y, Ellis L, Jarnagin K, et al. The human insulin receptor cDNA: the structural
basis for hormone-activated transmembrane signaling. Cell. 1985;40:747-58.
13. White MF, Haring HU, Kasuga M, Kahn CR. Kinetic properties and sites of
autophosphorylation of the partially purified insulin receptor from hepatoma cells. J
Biol Chem. 1984;259:255-64.
14. 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 Chem. 1988;263:2969-80.
15. Patti ME, Kahn CR. The insulin receptor — a critical link in glucose homeostasis
and insulin action. J Basic Clin Physiol Pharmacol. 1998;9:89-109.
16. White MF. The IRS-signaling system: a network of docking proteins that mediate
insulin action. Mol Cell Biochem. 1998;182:3-11.
17. Carvalheira JB, Siloto RM, Ignacchitti I, et al. Insulin modulates leptin-induced
STAT3 activation in rat hypothalamus [letter]. FEBS. 2001;500:119-24.
18. Rojas FA, Carvalho CR, Paez-Espinosa V, Saad MJ. Regulation of cardiac Jak-2 in
animal models of insulin resistance. IUBMB Life. 2000;49:501-9.
19. Velloso LA, Carvalho CR, Rojas FA, Folli F, Saad MJ. Insulin signaling in heart
involves insulin receptor substrates-1 and -2, activation of phosphatidylinositol 3-kinase
and the JAK 2-growth related pathway. Cardiovasc Res. 1998;40:96-102.
20. Araki E, Lipes MA, Patti ME, et al. Alternative pathway of insulin signaling in mice
with targeted disruption of the IRS-1 gene. Nature. 1994;372:186-90.
21. Withers DJ, Gutierrez JS, Towery H, et al. Disruption of IRS-2 causes type 2
diabetes in mice. Nature. 1998;391:900-4.
22. Liu SC, Wang Q, Lienhard GE, Keller SR. Insulin receptor substrate 3 is not
essential for growth or glucose homeostasis. J Biol Chem. 1999;274:18093-9.
23. Fantin VR, Wang Q, Lienhard GE, Keller SR. Mice lacking insulin receptor
substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J
Physiol Endocrinol Metab. 2000;278:E127-E133.
24. 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. Science. 1996;271:665-8.
25. Carvalheira JB, Ribeiro EB, Araujo EP, et al. Selective impairment of insulin
signaling in the hypothalamus of obese Zucker rats. Diabetologia. 2003;46:1629-40.
26. Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by
salicylate. J Clin Invest. 2001;108:437-46.
27. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced
insulin resistance with salicylates or targeted disruption of Ikkbeta. Science.
2001;293:1673-7.
29. Folli F, Saad MJ, Backer JM, Kahn CR. Insulin stimulation of phosphatidylinositol
3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of
the intact rat. J Biol Chem. 1992;267:22171-7.
30. Saad MJ, Araki E, Miralpeix M, Rothenberg PL, White MF, Kahn CR. Regulation
of insulin receptor substrate-1 in liver and muscle of animal models of insulin
resistance. J Clin Invest. 1992;90:1839-49.
31. Saad MJ, Folli F, Kahn JA, Kahn CR. Modulation of insulin receptor, insulin
receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of
dexamethasone-treated rats. J Clin Invest. 1993;92:2065-72.
32. 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 J. 1995;305:25-8.
33. Czech MP, Corvera S. Signaling mechanisms that regulate glucose transport. J Biol
Chem. 1999;274:1865-8.
34. Backer JM, Myers MG Jr, Shoelson SE, et al. Phosphatidylinositol 3"-kinase is
activated by association with IRS-1 during insulin stimulation. EMBO J. 1992;11:3469-
79.
37. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-
dependent protein kinase which phosphorylates and activates protein kinase Balpha.
Curr Biol. 1997;7:261-9.
38. Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB. Normal insulin-
dependent activation of Akt/protein kinase B, with diminished activation of
phosphoinositide 3-kinase, in muscle in type 2 diabetes. [see comments.]. J Clin Invest.
1999;104:733-41.
39. Kitamura T, Ogawa W, Sakaue H, et al. Requirement for activation of the serine-
threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but
not of glucose transport. Mol Cell Biol. 1998;18:3708-17.
41. Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively
active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose
transporter 4 translocation. J Biol Chem. 1996;271:31372-8.
43. Pessin JE, Thurmond DC, Elmendorf JS, Coker KJ, Okada S. Molecular basis of
insulin-stimulated GLUT4 vesicle trafficking. J Biol Chem. 1999;274:2593-6.
44. Rea S, James DE. Moving GLUT4: the biogenesis and trafficking of GLUT4
storage vesicles. Diabetes. 1997;46:1667-77.
45. Ribon V, Saltiel AR. Insulin stimulates tyrosine phosphorylation of the proto-
oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J. 1997;324(Pt 3):839-45.
46. Ribon V, Printen JA, Hoffman NG, Kay BK, Saltiel AR. A novel, multifuntional c-
Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. Mol Cell Biol.
1998;18:872-9.
47. Baumann CA, Ribon V, Kanzaki M, et al. CAP defines a second signaling pathway
required for insulin-stimulated glucose transport. Nature. 2000;407:202-7.
49. Thirone AC, Carvalheira JB, Hirata AE, Velloso LA, Saad MJ. Regulation of Cbl-
associated protein/Cbl pathway in muscle and adipose tissues of two animal models of
insulin resistance. Endocrinology. 2004;145:281-93.
50. Paez-Espinosa EV, Rocha EM, Velloso LA, Boschero AC, Saad MJ. Insulin-
induced tyrosine phosphorylation of Shc in liver, muscle and adipose tissue of insulin
resistant rats. Mol Cell Endocrinol. 1999;156:121-9.
51. Boulton TG, Nye SH, Robbins DJ, et al. ERKs: a family of protein-serine/threonine
kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
Cell. 1991;65:663-75.
52. Lazar DF, Wiese RJ, Brady MJ, et al. Mitogen-activated protein kinase kinase
inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem.
1995;270:20801-7.
53. Miron M, Verdu J, Lachance PE, Birnbaum MJ, Lasko PF, Sonenberg N. The
translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in
Drosophila. Nat Cell Biol. 2001;3:596-601.
54. Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI
3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest.
2000;105:311-20.
55. Jiang ZY, Lin YW, Clemont A, et al. Characterization of selective resistance to
insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest.
1999;104:447-57.
56. Zecchin HG, Bezerra RM, Carvalheira JB, et al. Insulin signaling pathways in aorta
and muscle from two animal models of insulin resistance — the obese middle-aged and
the spontaneously hypertensive rats. Diabetologia. 2003;46:479-91.
57. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of
glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature.
1995;378:785-9.
58. Brady MJ, Nairn AC, Saltiel AR. The regulation of glycogen synthase by protein
phosphatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in
insulin action. J Biol Chem. 1997;272:29698-703.
59. Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic
gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885-909.
60. Sutherland C, OBrien RM, Granner DK. New connections in the regulation of
PEPCK gene expression by insulin. Philos Trans R Soc Lond B Biol Sci. 1996;351:191-
9.
61. Bergman RN. New concepts in extracellular signaling for insulin action: the single
gateway hypothesis. Recent Prog Horm Res. 1997;52:359-85.
62. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol
metabolism by proteolysis of a membrane-bound transcription factor. Cell.
1997;89:331-40.
63. Edwards PA, Tabor D, Kast HR, Venkateswaran A. Regulation of gene expression
by SREBP and SCAP. Biochim Biophys Acta. 2000;1529:103-13.
68. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL.
Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-
induced diabetes. Proc Natl Acad Sci USA. 1999;96:13656-61.
70. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses
insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature.
1999;401:73-6.
72. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL.
Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and
sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell. 2000;6:77-86.
75. Taylor SI, Kadowaki T, Accili D, et al. Mutations in the insulin receptor gene in
genetic forms of insulin resistance. Recent Prog Horm Res. 1990;46:185-213.
76. Stern MP. Strategies and prospects for finding insulin resistance genes. J Clin
Invest. 2000;106:323-7.
77. Ogg S, Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin
receptor-like metabolic signaling pathway. Mol Cell. 1998;2:887-93.
78. Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR. Development
of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null
alleles. Cell. 1997;88:561-72.
79. Kido Y, Burks DJ, Withers D, et al. Tissue-specific insulin resistance in mice with
mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000;105:199-205.
81. Fruman DA, Mauvais-Jarvis F, Pollard DA, et al. Hypoglycaemia, liver necrosis and
perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat
Genet. 2000;26:379-82.
82. Terauchi Y, Tsuji Y, Satoh S, et al. Increased insulin sensitivity and hypoglycaemia
in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet.
1999;21:230-5.
84. Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Knockout models are useful tools to
dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol. (Oxf)
2002;57:1-9.
85. Mauvais-Jarvis F, Ueki K, Fruman DA, et al. Reduced expression of the murine
p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and
ameliorates diabetes. J Clin Invest. 2002;109:141-9.
86. Bruning JC, Michael MD, Winnay JN, et al (1998) A muscle-specific insulin
receptor knockout exhibits features of the metabolic syndrome of NIDDM without
altering glucose tolerance. Mol.Cell. 1998;2:559-69.
87. Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of
body weight and reproduction. Science. 2000;289:2122-5.
88. Kulkarni RN, Winnay JN, Daniels M, et al. Altered function of insulin receptor
substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest.
1999;104:R69-R75.
89. Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes
leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell.
2000;6:87-97.
90. Abel ED, Peroni O, Kim JK, et al. Adipose-selective targeting of the GLUT4 gene
impairs insulin action in muscle and liver. Nature. 2001;409:729-33.
91. Zisman A, Peroni OD, Abel ED, et al. Targeted disruption of the glucose transporter
4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med.
2000;6:924-8.
92. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue
abnormalities but not diabetes in mice deficient in GLUT4. Nature 1995;377:151-5.
93. Kim JK, Michael MD, Previs SF, et al. Redistribution of substrates to adipose tissue
promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest.
2000;105:1791-7.
94. Wojtaszewski JF, Hansen BF, Gade, et al. Insulin signaling and insulin sensitivity
after exercise in human skeletal muscle. Diabetes. 2000;49:325-31.
95. Wojtaszewski JF, Higaki Y, Hirshman MF, et al. Exercise modulates postreceptor
insulin signaling and glucose transport in muscle-specific insulin receptor knockout
mice. J Clin Invest. 1999;104:1257-64.
96. Thorell A, Hirshman MF, Nygren J, et al. Exercise and insulin cause GLUT-4
translocation in human skeletal muscle. Am J Physiol. 1999;277:E733-E741.
97. Kennedy JW, Hirshman MF, Gervino EV, et al. Acute exercise induces GLUT4
translocation in skeletal muscle of normal human subjects and subjects with type 2
diabetes. Diabetes. 1999;48:1192-7.
98. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu
Rev Med. 1998;49:235-61.
99. Perseghin G, Price TB, Petersen KF, et al. Increased glucose transport-
phosphorylation and muscle glycogen synthesis after exercise training in insulin-
resistant subjects. N Engl J Med. 1996;335:1357-62.
100. DeFronzo RA, Sherwin RS, Kraemer N. Effect of physical training on insulin
action in obesity. Diabetes. 1987;36:1379-85.
101. Koivisto VA, Yki-Jarvinen H, DeFronzo RA. Physical training and insulin
sensitivity. Diabetes Metab Rev. 1986;1:445-81.
103. Zinker BA, Mohr T, Kelly P, Namdaran K, Bracy DP, Wasserman DH. Exercise-
induced fall in insulin: mechanism of action at the liver and effects on muscle glucose
metabolism. Am J Physiol. 1994;266:E683-E689.
104. Begum N, Terjung RL, Tepperman HM, Tepperman J. Effect of acute exercise on
insulin generation of pyruvate dehydrogenase activator by rat liver and adipocyte
plasma membranes. Diabetes. 1986;35:785-90.
106. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu
Rev Med. 1998;49:235-61.
107. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu
Rev Med. 1998;49:235-61.
108. Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes
mellitus. Trends Endocrinol Metab. 2000;11:351-6.
110. Hwang JH, Pan JW, Heydari S, Hetherington HP, Stein DT. Regional differences
in intramyocellular lipids in humans observed by in vivo 1H-MR spectroscopic
imaging. J Appl Physiol. 2001;90:1267-74.
111. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein
lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA. 2001;98:7522-
7.
112. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor
necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science.
1993;259:87-91.
114. Sethi JK, Xu H, Uysal KT, Wiesbrock SM, Scheja L, Hotamisligil GS.
Characterization of receptor-specific TNF-alpha functions in adipocyte cell lines
lacking type 1 and 2 TNF receptors [letter]. FEBS. 2000;469:77-82.
115. Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis
factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity.
Endocrinology. 1998;139:4832-8.
116. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-
induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610-4.
117. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human
anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in
patients with NIDDM. Diabetes. 1996;45:881-5.
118. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals.
Nature. 1998;395:763-70.
119. Halaas JL, Friedman JM. Leptin and its receptor. J Endocrinol. 1997;155:215-6.
121. Asilmaz E, Cohen P, Miyazaki M, et al. Site and mechanism of leptin action in a
rodent form of congenital lipodystrophy. J Clin Invest. 2004;113:414-24.
122. Cohen P, Zhao C, Cai X, et al. Selective deletion of leptin receptor in neurons
leads to obesity. J Clin Invest. 2001;108:1113-21.
124. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma
protein encoded by the obese gene. Science. 1995;269:543-6.
125. Lee Y, Wang MY, Kakuma T, et al. Liporegulation in diet-induced obesity. The
antisteatotic role of hyperleptinemia. J Biol Chem. 2001;276:5629-35.
126. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is
associated with severe early-onset obesity in humans. Nature. 1997;387:903-8.
127. Fruebis J, Tsao TS, Javorschi S, et al. 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 USA. 2001;98:2005-10.
130. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose
production is inhibited by the adipose-derived protein Acrp30. J Clin Invest.
2001;108:1875-81.
131. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted
protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947-53.
132. Vionnet N, Hani E, Dupont S, et al. Genomewide search for type 2 diabetes-
susceptibility genes in French whites: evidence for a novel susceptibility locus for early-
onset diabetes on chromosome 3q27-qter and independent replication of a type 2-
diabetes locus on chromosome 1q21-q24. Am J Hum Genet. 2000;67:1470-80.
133. Steppan CM, Brown EJ, Wright CM, et al. A family of tissue-specific resistin-like
molecules. Proc Natl Acad Sci USA. 2001;98:502-6.
134. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin
expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun.
2001;285:561-4.
136. Duncan BB, Schmidt MI. Chronic activation of the innate immune system may
underlie the metabolic syndrome. São Paulo Med J. 2001;119:122-7.
137. Reid J, MacDougall AI, Andrews MM. Aspirin and diabetes mellitus. Br Med J.
1957;33:1071-4.
138. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and
salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998;396:77-80.
139. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87:13-20.
140. Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation
of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting
multiple serine kinases. J Biol Chem. 2003;278:24944-50.
141. Birnbaum MJ. Turning down insulin signaling. J Clin Invest. 2001;108:655-9.
142. Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal Kinase (JNK) mediates
feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003;278:2896-902.