Obesity and cancer, a case for insulin signaling

Cell Death and Disease

Volumn 6, Issue 12, 2015, Pages

  Poloz, Y ^a   Stambolic, V ^a,b  

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

INSULIN;

ANIMAL; HUMAN; HYPERINSULINISM; INSULIN RESISTANCE; METABOLISM; MORBID OBESITY; NEOPLASMS; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; HYPERINSULINISM; INSULIN; INSULIN RESISTANCE; NEOPLASMS; OBESITY, MORBID; SIGNAL TRANSDUCTION;

EID: 84987610993     PISSN: None     EISSN: 20414889     Source Type: Journal    
DOI: 10.1038/CDDIS.2015.381     Document Type: Review

References (192)

1. World Health Organization. Obesity and Overweight: Fact Sheet N 311 2015.
2. Stewart ST, Cutler DM, Rosen AB. Forecasting the effects of obesity and smoking on U.S. life expectancy. N Engl J Med 2009; 361: 2252–2260.
3. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625–1638.
4. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 2002; 20: 42–51.
5. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569–578.
6. World Cancer Research Fund, American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective 2007.
7. International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention: Weight Control and Physical Activity 2002.
8. Arnold M, Pandeya N, Byrnes G, Renehan AG, Stevens GA, Ezzati M et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol 2015; 16: 36–46.
9. Byers T, Sedjo RL. Does intentional weight loss reduce cancer risk? Diabetes Obes Metab 2011; 13: 1063–1072.
10. Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA 2006; 296: 193–201.
11. Sjostrom L, Gummesson A, Sjostrom CD, Narbro K, Peltonen M, Wedel H et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 2009; 10: 653–662.
12. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015; 347: 78–81.
13. Kasuga M, Hedo JA, Yamada KM, Kahn CR. The structure of insulin receptor and its subunits. Evidence for multiple nonreduced forms and a 210,000 possible proreceptor. J Biol Chem 1982; 257: 10392–10399.
14. Ebina Y, Edery M, Ellis L, Standring D, Beaudoin J, Roth RA et al. Expression of a functional human insulin receptor from a cloned cDNA in Chinese hamster ovary cells. Proc Natl Acad Sci USA 1985; 82: 8014–8018.
15. Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci USA 1989; 86: 114–118.
16. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 1985; 313:756–761.
17. Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A. Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway. Endocrinology 2012; 153: 2152–2163.
18. Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F, Scalia P et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 1999; 18: 2471–2479.
19. Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, McClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J 1990; 9: 2409–2413.
20. Vogt B, Carrascosa JM, Ermel B, Ullrich A, Haring HU. The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics. Biochem Biophys Res Commun 1991; 177: 1013–1018.
21. Yamaguchi Y, Flier JS, Yokota A, Benecke H, Backer JM, Moller DE. Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 1991; 129: 2058–2066.
22. Pandini G, Medico E, Conte E, Sciacca L, Vigneri R, Belfiore A. Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. J Biol Chem 2003; 278: 42178–42189.
23. Sciacca L, Prisco M, Wu A, Belfiore A, Vigneri R, Baserga R. Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology 2003; 144: 2650–2658.
24. Wang Y, Hua S, Tian W, Zhang L, Zhao J, Zhang H et al. Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent. Gynecol Oncol 2012; 125: 734–741.
25. Dodge JA, Laurence KM. Congenital absence of islets of Langerhans. Arch Dis Child 1977; 52: 411–413.
26. Fosel S. Transient and permanent neonatal diabetes. Eur J Pediatr 1995; 154: 944–948.
27. Hill DE. Effect of insulin on fetal growth. Semin Perinatol 1978; 2: 319–328.
28. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, de la Luz Sierra M et al. Mutations in the insulin receptor gene. Endocr Rev 1992; 13: 566–595.
29. Escribano O, Guillen C, Nevado C, Gomez-Hernandez A, Kahn CR, Benito M. Beta-cell hyperplasia induced by hepatic insulin resistance: role of a liver-pancreas endocrine axis through insulin receptor A isoform. Diabetes 2009; 58: 820–828.
30. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 2001; 29: 40–47.
31. Louvi A, Accili D, Efstratiadis A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol 1997; 189: 33–48.
32. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 1991; 352: 73–77.
33. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr., Glasheen E et al. Role of IRS-2 in insulin and cytokine signalling. Nature 1995; 377: 173–177.
34. Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM. Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 1998; 18: 1379–1387.
35. Hawkins PT, Jackson TR, Stephens LR. Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase. Nature 1992; 358: 157–159.
36. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261–269.
37. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/ PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.
38. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 2003; 278: 14599–14602.
39. Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem 1997; 272: 17269–17275.
40. 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: 785–789.
41. Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 1980; 107: 519–527.
42. He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137: 635–646.
43. Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 1999; 274: 15982–15985.
44. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 2003; 423: 550–555.
45. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 648–657.
46. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005; 15: 702–713.
47. Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 2003; 28: 573–576.
48. Yamagata K, Sanders LK, Kaufmann WE, Yee W, Barnes CA, Nathans D et al. rheb, a growth factor-and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem 1994; 269: 16333–16339.
49. Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 1996; 10: 1096–1107.
50. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8: 224–236.
51. Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277: 99–101.
52. Price DJ, Grove JR, Calvo V, Avruch J, Bierer BE. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 1992; 257: 973–977.
53. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.
54. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 2003; 278: 35959–35967.
55. Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 2002; 22: 2025–2036.
56. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231–241.
57. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12: 3499–3511.
58. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992; 70: 93–104.
59. Pronk GJ, McGlade J, Pelicci G, Pawson T, Bos JL. Insulin-induced phosphorylation of the 46-and 52-kDa Shc proteins. J Biol Chem 1993; 268: 5748–5753.
60. Sasaoka T, Draznin B, Leitner JW, Langlois WJ, Olefsky JM. Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. J Biol Chem 1994; 269: 10734–10738.
61. Sasaoka T, Rose DW, Jhun BH, Saltiel AR, Draznin B, Olefsky JM. Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. J Biol Chem 1994; 269: 13689–13694.
62. Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M et al. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 1993; 260: 1953–1955.
63. Moodie SA, Willumsen BM, Weber MJ, Wolfman A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 1993; 260: 1658–1661.
64. Warne PH, Viciana PR, Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 1993; 364: 352–355.
65. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279–3290.
66. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370: 527–532.
67. Leibiger B, Leibiger IB, Moede T, Kemper S, Kulkarni RN, Kahn CR et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell 2001; 7: 559–570.
68. Leibiger IB, Leibiger B, Moede T, Berggren PO. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell 1998; 1: 933–938.
69. Uhles S, Moede T, Leibiger B, Berggren PO, Leibiger IB. Selective gene activation by spatial segregation of insulin receptor B signaling. FASEB J 2007; 21: 1609–1621.
70. Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S et al. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia 2010; 53: 1743–1753.
71. Uhles S, Moede T, Leibiger B, Berggren PO, Leibiger IB. Isoform-specific insulin receptor signaling involves different plasma membrane domains. J Cell Biol 2003; 163: 1327–1337.
72. Cox ME, Gleave ME, Zakikhani M, Bell RH, Piura E, Vickers E et al. Insulin receptor expression by human prostate cancers. Prostate 2009; 69: 33–40.
73. Kalli KR, Falowo OI, Bale LK, Zschunke MA, Roche PC, Conover CA. Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. Endocrinology 2002; 143: 3259–3267.
74. Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL et al. Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008; 68: 10238–10246.
75. Mulligan AM, O'Malley FP, Ennis M, Fantus IG, Goodwin PJ. Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 2007; 106: 39–47.
76. Papa V, Pezzino V, Costantino A, Belfiore A, Giuffrida D, Frittitta L et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 1990; 86: 1503–1510.
77. Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 2010; 70: 741–751.
78. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999; 19: 3278–3288.
79. Moller DE, Yokota A, Caro JF, Flier JS. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol Endocrinol 1989; 3: 1263–1269.
80. Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R, Belfiore A. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 2002; 21: 8240–8250.
81. Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V et al. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metabol 2002; 87: 245–254.
82. Wang CF, Zhang G, Zhao LJ, Qi WJ, Li XP, Wang JL et al. Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth. PloS One 2013; 8: e69001.
83. Frisch CM, Zimmermann K, Zillessen P, Pfeifer A, Racke K, Mayer P. Non-small cell lung cancer cell survival crucially depends on functional insulin receptors. Endocrine-Related Cancer 2015; 22: 609–621.
84. Milazzo G, Giorgino F, Damante G, Sung C, Stampfer MR, Vigneri R et al. Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 1992; 52: 3924–3930.
85. Osborne CK, Monaco ME, Lippman ME, Kahn CR. Correlation among insulin binding, degradation, and biological activity in human breast cancer cells in long-term tissue culture. Cancer Res 1978; 38: 94–102.
86. Frittitta L, Vigneri R, Stampfer MR, Goldfine ID. Insulin receptor overexpression in 184B5 human mammary epithelial cells induces a ligand-dependent transformed phenotype. J Cell Biochem 1995; 57: 666–669.
87. Giorgino F, Belfiore A, Milazzo G, Costantino A, Maddux B, Whittaker J et al. Overexpression of insulin receptors in fibroblast and ovary cells induces a ligand-mediated transformed phenotype. Mol Endocrinol 1991; 5: 452–459.
88. Rose PP, Carroll JM, Carroll PA, DeFilippis VR, Lagunoff M, Moses AV et al. The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma. Oncogene 2007; 26: 1995–2005.
89. Zhang H, Fagan DH, Zeng X, Freeman KT, Sachdev D, Yee D. Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene 2010; 29: 2517–2527.
90. Clemmons DR, Underwood LE. Nutritional regulation of IGF-I and IGF binding proteins. Ann Rev Nutr 1991; 11: 393–412.
91. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metabol 2000; 85: 4712–4720.
92. Ferguson RD, Novosyadlyy R, Fierz Y, Alikhani N, Sun H, Yakar S et al. Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. Breast Cancer Res 2012; 14: R8.
93. Gallagher EJ, Alikhani N, Tobin-Hess A, Blank J, Buffin NJ, Zelenko Z et al. Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. Diabetes 2013; 62: 3553–3560.
94. Rostoker R, Abelson S, Bitton-Worms K, Genkin I, Ben-Shmuel S, Dakwar M et al. Highly specific role of the insulin receptor in breast cancer progression. Endocrine-Related Cancer 2015; 22: 145–157.
95. Jensen EV, Jacobson HI, Walf AA, Frye CA. Estrogen action: a historic perspective on the implications of considering alternative approaches. Physiol Behav 2010; 99: 151–162.
96. Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metabol 1988; 67: 460–464.
97. Weaver JU, Holly JM, Kopelman PG, Noonan K, Giadom CG, White N et al. Decreased sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP-1) in extreme obesity. Clin Endocrinol 1990; 33: 415–422.
98. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metabol 1983; 57: 304–310.
99. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95: 1218–1226.
100. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E et al. Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrin Metab 1996; 81: 881–886.
101. Belanger C, Luu-The V, Dupont P, Tchernof A. Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm Metab Res 2002; 34: 737–745.
102. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973; 36: 207–214.
103. Schindler AE, Ebert A, Friedrich E. Conversion of androstenedione to estrone by human tissue. J Clin Endocrinol Metab 1972; 35: 627–630.
104. Henderson BE, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer. Cancer Res 1982; 42: 3232–3239.
105. Bosco JL, Antonsen S, Sorensen HT, Pedersen L, Lash TL. Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev 2011; 20: 101–111.
106. Choi Y, Kim TY, Oh DY, Lee KH, Han SW, Im SA et al. The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat 2015 [e-pub ahead of print].
107. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res 2010; 3: 1451–1461.
108. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304–1305.
109. Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat 2011; 126: 215–220.
110. Vissers PA, Cardwell CR, van de Poll-Franse LV, Young IS, Pouwer F, Murray LJ. The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res Treat 2015; 150: 427–437.
111. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275: 223–228.
112. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117: 1422–1431.
113. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 1996; 271: 27879–27887.
114. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 1642–1646.
115. Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 2015; 107: djv006.
116. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167–1174.
117. Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR et al. Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res 2015; 17: 32.
118. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen–induced lung tumorigenesis. Cancer Prev Res 2010; 3: 1066–1076.
119. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer 2008; 8: 501–505.
120. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007; 67: 10804–10812.
121. Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S et al. Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol 2013; 6: 649–659.
122. Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010; 123: 271–279.
123. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10269–10273.
124. Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S, Viollet B et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11: 390–401.
125. Stambolic V, Woodgett JR, Fantus IG, Pritchard KI, Goodwin PJ. Utility of metformin in breast cancer treatment, is neoangiogenesis a risk factor? Breast Cancer Res Treat 2009; 114: 387–389.
126. Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat ("USA-Fat"): description on 18F-FDG PET/CT. J Nucl Med 2003; 44: 170–176.
127. Bluher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 2015; 64: 131–145.
128. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.
129. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546–549.
130. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002; 415: 339–343.
131. Andreev VP, Paz-Filho G, Wong ML, Licinio J. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-h standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 2009; 41: 142–151.
132. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.
133. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155–1161.
134. Myers MG Jr., Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metabol 2010; 21: 643–651.
135. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26746–26749.
136. 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: 1875–1881.
137. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288–1295.
138. Awazawa M, Ueki K, Inabe K, Yamauchi T, Kubota N, Kaneko K et al. Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway. Cell Metab 2011; 13: 401–412.
139. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947–953.
140. Fu Y, Luo N, Klein RL, Garvey WT. Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J Lipid Res 2005; 46: 1369–1379.
141. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–946.
142. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79–83.
143. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595–1599.
144. 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.
145. Juge-Aubry CE, Somm E, Giusti V, Pernin A, Chicheportiche R, Verdumo C et al. Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 2003; 52: 1104–1110.
146. Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100: 7265–7270.
147. Torti FM, Dieckmann B, Beutler B, Cerami A, Ringold GM. A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science 1985; 229: 867–869.
148. Bullo M, Garcia-Lorda P, Peinado-Onsurbe J, Hernandez M, Del Castillo D, Argiles JM et al. TNFalpha expression of subcutaneous adipose tissue in obese and morbid obese females: relationship to adipocyte LPL activity and leptin synthesis. Int J Obes Relat Metab Disord 2002; 26: 652–658.
149. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389: 610–614.
150. Bouzakri K, Zierath JR. MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem 2007; 282: 7783–7789.
151. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274: 1377–1379.
152. 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: 665–668.
153. Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 2001; 98: 4640–4645.
154. Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A et al. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 2001; 107: 181–189.
155. Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 2008; 283: 35375–35382.
156. Stephens JM, Lee J, Pilch PF. 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 1997; 272: 971–976.
157. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494–1505.
158. Tang X, Guilherme A, Chakladar A, Powelka AM, Konda S, Virbasius JV et al. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci USA 2006; 103: 2087–2092.
159. Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM et al. Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 1996; 10: 1457–1466.
160. Li P, Fan W, Xu J, Lu M, Yamamoto H, Auwerx J et al. Adipocyte NCoR knockout decreases PPARgamma phosphorylation and enhances PPARgamma activity and insulin sensitivity. Cell 2011; 147: 815–826.
161. Oakes ND, Kennedy CJ, Jenkins AB, Laybutt DR, Chisholm DJ, Kraegen EW. A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat. Diabetes 1994; 43: 1203–1210.
162. Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R et al. From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 2004; 53: 1285–1292.
163. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821–1830.
164. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–1808.
165. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11: 191–198.
166. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333–336.
167. Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 2007; 6: 386–397.
168. Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr Pract 2012; 18: 826–833.
169. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008; 31: 289–294.
170. Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci 2008; 1: 36–43.
171. Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M et al. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 2009; 58: 95–103.
172. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sc USA 1998; 95: 7987–7992.
173. Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J et al. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 2006; 341: 549–556.
174. Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Archiv 2007; 455: 479–492.
175. Unger RH. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrin Metab 2003; 14: 398–403.
176. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270–1274.
177. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005–2011.
178. Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW et al. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 1997; 46: 169–178.
179. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidyli-nositol 3-kinase activity in muscle. J Biol Chem 2002; 277: 50230–50236.
180. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M et al. Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673–1677.
181. Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B et al. Life without white fat: a transgenic mouse. Genes Dev 1998; 12: 3168–3181.
182. Sovik O, Vestergaard H, Trygstad O, Pedersen O. Studies of insulin resistance in congenital generalized lipodystrophy. Acta Paediatr 1996; 413: 29–37.
183. Arioglu E, Rother KI, Reitman ML, Premkumar A, Taylor SI. Lipoatrophy syndromes: when 'too little fat' is a clinical problem. Pediatr Diabetes 2000; 1: 155–168.
184. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346: 570–578.
185. Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metabol 2015; 100: 1802–1810.
186. Lipscombe LL, Hux JE, Booth GL. Reduced screening mammography among women with diabetes. Arch Intern Med 2005; 165: 2090–2095.
187. Wee CC, McCarthy EP, Davis RB, Phillips RS. Screening for cervical and breast cancer: is obesity an unrecognized barrier to preventive care? Ann Intern Med 2000; 132: 697–704.
188. Chang IH, Ahn SH, Han JH, Kim TH, Kim YS, Myung SC. The clinical significance in healthy men of the association between obesity related plasma hemodilution and tumor marker concentration. J Urol 2009; 181: 567–572 discussion 72-73.
189. Uppot RN, Sahani DV, Hahn PF, Gervais D, Mueller PR. Impact of obesity on medical imaging and image-guided intervention. Am J Roentgenol 2007; 188: 433–440.
190. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 2005; 165: 1267–1273.
191. Qi D, Rodrigues B. Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism. Am J Physiolo Endocrinol Metab 2007; 292: E654–E667.
192. Yamauchi H, Cristofanilli M, Nakamura S, Hortobagyi GN, Ueno NT. Molecular targets for treatment of inflammatory breast cancer. Nature Rev Clinical Oncol 2009; 6: 387–394.