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Linked References

1. American Diabetes Association, “Diagnosis and classification of diabetes mellitus,” Diabetes Care, vol. 30, pp. S42–S47, 2007. View at Publisher · View at Google Scholar · View at PubMed
2. J. R. Gavin, III, K. G. M. M. Alberti, M. B. Davidson, et al., “Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,” Diabetes Care, vol. 20, no. 7, pp. 1183–1197, 1997.
3. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, “Follow-up report on the diagnosis of diabetes mellitus,” Diabetes Care, vol. 26, no. 11, pp. 3160–3167, 2003. View at Publisher · View at Google Scholar
4. D. J. Rader, “Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus,” The American Journal of Medicine, vol. 120, no. 3, supplement 1, pp. S12–S18, 2007. View at Publisher · View at Google Scholar · View at PubMed
5. R. H. Eckel, S. M. Grundy, and P. Z. Zimmet, “The metabolic syndrome,” The Lancet, vol. 365, no. 9468, pp. 1415–1428, 2005. View at Publisher · View at Google Scholar · View at PubMed
6. S. Caprio, D. Boulware, and V. Tamborlane, “Growth hormone and insulin interactions,” Hormone Research, vol. 38, pp. 47–49, 1992.
7. E. Giovannucci, “Metabolic syndrome, hyperinsulinemia, and colon cancer: a review,” The American Journal of Clinical Nutrition, vol. 86, no. 3, pp. 836S–842S, 2007.
8. P. J. Goodwin, M. Ennis, M. Bahl, et al., “High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome,” Breast Cancer Research and Treatment. In press. View at Publisher · View at Google Scholar · View at PubMed
9. D. S. Bell, “Inflammation, insulin resistance, infection, diabetes, and atherosclerosis,” Endocrine Practice, vol. 6, no. 3, pp. 272–276, 2000.
10. B. Seriolo, C. Ferrone, and M. Cutolo, “Longterm anti-tumor necrosis factor-$\alpha$ treatment in patients with refractory rheumatoid arthritis: relationship between insulin resistance and disease activity,” The Journal of Rheumatology, vol. 35, no. 2, pp. 355–357, 2008.
11. A. Oguz, E. G. Dogan, M. Uzunlulu, and F. M. Oguz, “Insulin resistance and adiponectin levels in Behçet's syndrome,” Clinical and Experimental Rheumatology, vol. 25, no. 4, supplement 45, pp. S118–S119, 2007.
12. P. A. Sarafidis and G. L. Bakris, “Insulin resistance, hyperinsulinemia, and hypertension: an epidemiologic approach,” Journal of the CardioMetabolic Syndrome, vol. 1, no. 5, pp. 334–344, 2006. View at Publisher · View at Google Scholar
13. G. M. Reaven, “Insulin resistance, the insulin resistance syndrome, and cardiovascular disease,” Panminerva Medica, vol. 47, no. 4, pp. 201–210, 2005.
14. W. P. T. James, “The epidemiology of obesity: the size of the problem,” Journal of Internal Medicine, vol. 263, no. 4, pp. 336–352, 2008. View at Publisher · View at Google Scholar · View at PubMed
15. M. A. Sabin and J. P. Shield, “Childhood obesity,” Frontiers of Hormone Research, vol. 36, pp. 85–96, 2008. View at Publisher · View at Google Scholar
16. E. A. Enas, V. Mohan, M. Deepa, S. Farooq, S. Pazhoor, and H. Chennikkara, “The metabolic syndrome and dyslipidemia among Asian Indians: a population with high rates of diabetes and premature coronary artery disease,” Journal of the CardioMetabolic Syndrome, vol. 2, no. 4, pp. 267–275, 2007. View at Publisher · View at Google Scholar
17. D. P. Schuster, T. Gaillard, and K. Osei, “The cardiometabolic syndrome in persons of the African diaspora: challenges and opportunities,” Journal of the CardioMetabolic Syndrome, vol. 2, no. 4, pp. 260–266, 2007. View at Publisher · View at Google Scholar
18. K. C. Hoang, T. V. Le, and N. D. Wong, “The metabolic syndrome in East Asians,” Journal of the CardioMetabolic Syndrome, vol. 2, no. 4, pp. 276–282, 2007. View at Publisher · View at Google Scholar
19. M. Reimann, A. E. Schutte, and P. E. H. Schwarz, “Insulin resistance—the role of ethnicity: evidence from Caucasian and African cohorts,” Hormone and Metabolic Research, vol. 39, no. 12, pp. 853–857, 2007. View at Publisher · View at Google Scholar · View at PubMed
20. F. C. Lowell, “Immunologic studies in insulin resistance I. Report of a case exhibiting variations in resistance and allergy to insulin,” The Journal for Clinical Investigation, vol. 23, no. 2, pp. 225–231, 1944. View at Publisher · View at Google Scholar · View at PubMed
21. W. B. Sherman, “A case of coexisting insulin allergy and insulin resistance,” Journal of Allergy, vol. 21, no. 1, pp. 49–54, 1950. View at Publisher · View at Google Scholar
22. M. Krebs, M. Krssak, P. Nowotny, et al., “Free fatty acids inhibit the glucose-stimulated increase of intramuscular glucose-6-phosphate concentration in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 86, no. 5, pp. 2153–2160, 2001. View at Publisher · View at Google Scholar
23. P. J. Randle, P. B. Garland, C. N. Hales, and E. A. Newsholme, “The glucose fatty acids cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus,” The Lancet, vol. 281, no. 7285, pp. 785–789, 1963. View at Publisher · View at Google Scholar
24. E. Shafrir and I. Raz, “Diabetes: mellitus or lipidus?,” Diabetologia, vol. 46, no. 3, pp. 433–440, 2003.
25. J. D. Cameron and J. K. Cruickshank, “Glucose, insulin, diabetes and mechanisms of arterial dysfunction,” Clinical and Experimental Pharmacology and Physiology, vol. 34, no. 7, pp. 677–682, 2007. View at Publisher · View at Google Scholar · View at PubMed
26. C. Lara-Castro, Y. Fu, B. H. Chung, and W. T. Garvey, “Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease,” Current Opinion in Lipidology, vol. 18, no. 3, pp. 263–270, 2007. View at Publisher · View at Google Scholar · View at PubMed
27. S. R. Kashyap and R. A. DeFronzo, “The insulin resistance syndrome: physiological considerations,” Diabetes & Vascular Disease Research, vol. 4, no. 1, pp. 13–19, 2007. View at Publisher · View at Google Scholar · View at PubMed
28. R. J. Kones and J. H. Phillips, “Insulin: fundamental mechanism of action and the heart,” Cardiology, vol. 60, no. 5, pp. 280–303, 1975.
29. G. Sesti, “Pathophysiology of insulin resistance,” Best Practice & Research in Clinical Endocrinology & Metabolism, vol. 20, no. 4, pp. 665–679, 2006. View at Publisher · View at Google Scholar · View at PubMed
30. P. Bergsten, “Pathophysiology of impaired pulsatile insulin release,” Diabetes/Metabolism Research and Reviews, vol. 16, no. 3, pp. 179–191, 2000. View at Publisher · View at Google Scholar
31. C. J. Goodner, B. C. Walike, D. J. Koerker, et al., “Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys,” Science, vol. 195, no. 4274, pp. 177–179, 1977. View at Publisher · View at Google Scholar
32. C. Simon, G. Brandenberger, and M. Follenius, “Ultradian oscillations of plasma glucose, insulin, and C-peptide in man during continuous enteral nutrition,” The Journal of Clinical Endocrinology & Metabolism, vol. 64, no. 4, pp. 669–674, 1987.
33. K. S. Polonsky, J. Sturis, and E. Van Cauter, “Temporal profiles and clinical significance of pulsatile insulin secretion,” Hormone Research, vol. 49, no. 3-4, pp. 178–184, 1998. View at Publisher · View at Google Scholar
34. E. A. Ryan, S. Imes, D. Liu, et al., “Defects in insulin secretion and action in women with a history of gestational diabetes,” Diabetes, vol. 44, no. 5, pp. 506–512, 1995. View at Publisher · View at Google Scholar
35. W. H. Herman, S. S. Fajans, M. J. Smith, K. S. Polonsky, G. I. Bell, and J. B. Halter, “Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor- 4$\alpha$/MODY1 gene,” Diabetes, vol. 46, no. 11, pp. 1749–1754, 1997. View at Publisher · View at Google Scholar
36. E. H. Hani, L. Suaud, P. Boutin, et al., “A missense mutation in hepatocyte nuclear factor-4$\alpha$, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus,” The Journal of Clinical Investigation, vol. 101, no. 3, pp. 521–526, 1998. View at Publisher · View at Google Scholar · View at PubMed
37. J.-F. Surmely, E. Guenat, J. Philippe, et al., “Glucose utilization and production in patients with maturity-onset diabetes of the young caused by a mutation of the hepatocyte nuclear factor-1$\alpha$ gene,” Diabetes, vol. 47, no. 9, pp. 1459–1463, 1998. View at Publisher · View at Google Scholar
38. R. G. Long, R. H. Albuquerque, A. Prata, et al., “Response of plasma pancreatic and gastrointestinal hormones and growth hormone to oral and intravenous glucose and insulin hypoglycaemia in Chagas's disease,” Gut, vol. 21, no. 9, pp. 772–777, 1980. View at Publisher · View at Google Scholar
39. L. F. Samos and B. A. Roos, “Diabetes mellitus in older persons,” Medical Clinics of North America, vol. 82, no. 4, pp. 791–803, 1998. View at Publisher · View at Google Scholar
40. D. A. Lang, D. R. Matthews, M. Burnett, and R. C. Turner, “Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man,” Diabetes, vol. 30, no. 5, pp. 435–439, 1981. View at Publisher · View at Google Scholar
41. S. O'Rahilly, R. C. Turner, and D. R. Matthews, “Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes,” The New England Journal of Medicine, vol. 318, no. 19, pp. 1225–1230, 1988.
42. E. Van Cauter, K. S. Polonsky, J. D. Blackman, et al., “Abnormal temporal patterns of glucose tolerance in obesity: relationship to sleep-related growth hormone secretion and circadian cortisol rhythmicity,” The Journal of Clinical Endocrinology & Metabolism, vol. 79, no. 6, pp. 1797–1805, 1994. View at Publisher · View at Google Scholar
43. U. B. Andersen, H. Dige-Petersen, E. K. Frandsen, H. Ibsen, and A. Vølund, “Basal insulin-level oscillations in normotensive individuals with genetic predisposition to essential hypertension exhibit an irregular pattern,” Journal of Hypertension, vol. 15, no. 10, pp. 1167–1173, 1997. View at Publisher · View at Google Scholar
44. J. M. W. van den Ouweland, P. Maechler, C. B. Wollheim, G. Attardi, and J. A. Maassen, “Functional and morphological abnormalities of mitochondria harbouring the tRNA(Leu(UUR)) mutation in mitochondrial DNA derived from patients with maternally inherited diabetes and deafness (MIDD) and progressive kidney disease,” Diabetologia, vol. 42, no. 4, pp. 485–492, 1999. View at Publisher · View at Google Scholar
45. H. Sakura, S. J. H. Ashcroft, Y. Terauchi, T. Kadowaki, and F. M. Ashcroft, “Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice,” Diabetologia, vol. 41, no. 6, pp. 654–659, 1998. View at Publisher · View at Google Scholar
46. R. N. Kulkarni, J. C. Brüning, J. N. Winnay, C. Postic, M. A. Magnuson, and C. R. Kahn, “Tissue-specific knockout of the insulin receptor in pancreatic $\beta$ cells creates an insulin secretory defect similar to that in type 2 diabetes,” Cell, vol. 96, no. 3, pp. 329–339, 1999. View at Publisher · View at Google Scholar
47. A. Dresner, D. Laurent, M. Marcucci, et al., “Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity,” The Journal of Clinical Investigation, vol. 103, no. 2, pp. 253–259, 1999. View at Publisher · View at Google Scholar · View at PubMed
48. D. R. Matthews, “Oscillatory insulin secretion: a variable phenotypic marker,” Diabetic Medicine, vol. 13, no. 9, supplement 6, pp. S53–S58, 1996.
49. B. Gumbiner, E. Van Cauter, W. F. Beltz, et al., “Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction,” The Journal of Clinical Endocrinology & Metabolism, vol. 81, no. 6, pp. 2061–2068, 1996. View at Publisher · View at Google Scholar
50. A. Ullrich, J. R. Bell, E. Y. Chen, et al., “Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes,” Nature, vol. 313, no. 6005, pp. 756–761, 1985. View at Publisher · View at Google Scholar
51. C. A. Baumann, V. Ribon, M. Kanzaki, et al., “CAP defines a second signalling pathway required for insulin-stimulated glucose transport,” Nature, vol. 407, no. 6801, pp. 202–207, 2000. View at Publisher · View at Google Scholar · View at PubMed
52. T. Noguchi, T. Matozaki, K. Inagaki, et al., “Tyrosine phosphorylation of $\text{p}{62}^{\text{Dok}}$ induced by cell adhesion and insulin: possible role in cell migration,” The EMBO Journal, vol. 18, no. 7, pp. 1748–1760, 1999. View at Publisher · View at Google Scholar · View at PubMed
53. T. Pawson and J. D. Scott, “Signaling through scaffold, anchoring, and adaptor proteins,” Science, vol. 278, no. 5346, pp. 2075–2080, 1997. View at Publisher · View at Google Scholar
54. M. F. White, “IRS proteins and the common path to diabetes,” American Journal of Physiology, vol. 283, no. 3, pp. E413–E422, 2002.
55. J. P. Whitehead, P. Humphreys, A. Krook, et al., “Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif,” Diabetes, vol. 47, no. 5, pp. 837–839, 1998. View at Publisher · View at Google Scholar
56. S. F. Previs, D. J. Withers, J.-M. Ren, M. F. White, and G. I. Shulman, “Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo,” Journal of Biological Chemistry, vol. 275, no. 50, pp. 38990–38994, 2000. View at Publisher · View at Google Scholar · View at PubMed
57. P. Gual, Y. Le Marchand-Brustel, and J. F. Tanti, “Positive and negative regulation of glucose uptake by hyperosmotic stress,” Diabetes & Metabolism, vol. 29, no. 6, pp. 566–575, 2003. View at Publisher · View at Google Scholar
58. L. Rui, T. L. Fisher, J. Thomas, and M. F. White, “Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2,” Journal of Biological Chemistry, vol. 276, no. 43, pp. 40362–40367, 2001.
59. S. Schinner, W. A. Scherbaum, S. R. Bornstein, and A. Barthel, “Molecular mechanisms of insulin resistance,” Diabetic Medicine, vol. 22, no. 6, pp. 674–682, 2005. View at Publisher · View at Google Scholar · View at PubMed
60. D. R. Alessi and P. Cohen, “Mechanism of activation and function of protein kinase B,” Current Opinion in Genetics & Development, vol. 8, no. 1, pp. 55–62, 1998. View at Publisher · View at Google Scholar
61. R. Meier, D. R. Alessi, P. Cron, M. Andjelković, and B. A. Hemmings, “Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase B$\beta$,” Journal of Biological Chemistry, vol. 272, no. 48, pp. 30491–30497, 1997. View at Publisher · View at Google Scholar
62. J. T. Brozinick, Jr., B. R. Roberts, and G. L. Dohm, “Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance,” Diabetes, vol. 52, no. 4, pp. 935–941, 2003. View at Publisher · View at Google Scholar
63. M. Björnholm, Y. Kawano, M. Lehtihet, and J. R. Zierath, “Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation,” Diabetes, vol. 46, no. 3, pp. 524–527, 1997. View at Publisher · View at Google Scholar
64. U. Smith, M. Axelsen, E. Carvalho, B. Eliasson, P.-A. Jansson, and C. Wesslau, “Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes,” Annals of the New York Academy of Sciences, vol. 892, no. 1, pp. 119–126, 1999. View at Publisher · View at Google Scholar
65. Y.-B. Kim, S. E. Nikoulina, T. P. Ciaraldi, R. R. Henry, and B. B. Kahn, “Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes,” The Journal of Clinical Investigation, vol. 104, no. 6, pp. 733–741, 1999. View at Publisher · View at Google Scholar · View at PubMed
66. A. Krook, R. A. Roth, X. J. Jiang, J. R. Zierath, and H. Wallberg-Henriksson, “Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects,” Diabetes, vol. 47, no. 8, pp. 1281–1286, 1998. View at Publisher · View at Google Scholar
67. A. Krook, M. Björnholm, D. Galuska, et al., “Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients,” Diabetes, vol. 49, no. 2, pp. 284–292, 2000. View at Publisher · View at Google Scholar
68. M. Beeson, M. P. Sajan, M. Dizon, et al., “Activation of protein kinase C-$\zeta$ by insulin and phosphatidylinositol-3,4,5-${({\text{PO}}_4)}_3$ is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise,” Diabetes, vol. 52, no. 8, pp. 1926–1934, 2003. View at Publisher · View at Google Scholar
69. Y.-B. Kim, K. Kotani, T. P. Ciaraldi, R. R. Henry, and B. B. Kahn, “Insulin-stimulated protein kinase $\text{C}\lambda /\zeta$ activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction,” Diabetes, vol. 52, no. 8, pp. 1935–1942, 2003. View at Publisher · View at Google Scholar
70. M. P. Sajan, M. L. Standaert, A. Miura, et al., “Impaired activation of protein kinase C-$\zeta$ by insulin and phosphatidylinositol-3,4,5-${({\text{PO}}_4)}_3$ in cultured preadipocyte-derived adipocytes and myotubes of obese subjects,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 8, pp. 3994–3998, 2004. View at Publisher · View at Google Scholar · View at PubMed
71. M. Elchebly, P. Payette, E. Michaliszyn, et al., “Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene,” Science, vol. 283, no. 5407, pp. 1544–1548, 1999. View at Publisher · View at Google Scholar
72. B. A. Zinker, C. M. Rondinone, J. M. Trevillyan, et al., “PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11357–11362, 2002. View at Publisher · View at Google Scholar · View at PubMed
73. F. Ahmad, R. V. Considine, T. L. Bauer, J. P. Ohannesian, C. C. Marco, and B. J. Goldstein, “Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue,” Metabolism, vol. 46, no. 10, pp. 1140–1145, 1997. View at Publisher · View at Google Scholar
74. J. F. Youngren, B. A. Maddux, S. Sasson, et al., “Skeletal muscle content of membrane glycoprotein PC-1 in obesity. Relationship to muscle glucose transport,” Diabetes, vol. 45, no. 10, pp. 1324–1328, 1996. View at Publisher · View at Google Scholar
75. S. Clément, U. Krause, F. Desmedt, et al., “The lipid phosphatase SHIP2 controls insulin sensitivity,” Nature, vol. 409, no. 6816, pp. 92–97, 2001, erratum in Nature, vol. 431, no. 7010, p. 878, 2004. View at Publisher · View at Google Scholar · View at PubMed
76. M. Butler, R. A. McKay, I. J. Popoff, et al., “Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice,” Diabetes, vol. 51, no. 4, pp. 1028–1034, 2002. View at Publisher · View at Google Scholar
77. J. R. Zierath, L. He, A. Gumà, E. Odegaard Wahlström, A. Klip, and H. Wallberg-Henriksson, “Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM,” Diabetologia, vol. 39, no. 10, pp. 1180–1189, 1996. View at Publisher · View at Google Scholar
78. J. B. Buse, K. Yasuda, T. P. Lay, et al., “Human GLUT4/muscle-fat glucose-transporter gene: characterization and genetic variation,” Diabetes, vol. 41, no. 11, pp. 1436–1445, 1992. View at Publisher · View at Google Scholar
79. P. R. Shepherd and B. B. Kahn, “Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus,” The New England Journal of Medicine, vol. 341, no. 4, pp. 248–257, 1999. View at Publisher · View at Google Scholar
80. B. Cheatham, C. J. Vlahos, L. Cheatham, L. Wang, J. Blenis, and C. R. Kahn, “Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation,” Molecular and Cellular Biology, vol. 14, no. 7, pp. 4902–4911, 1994.
81. Q. Wang, R. Somwar, P. J. Bilan, et al., “Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts,” Molecular and Cellular Biology, vol. 19, no. 6, pp. 4008–4018, 1999.
82. G. Bandyopadhyay, M. L. Standaert, M. P. Sajan, et al., “Dependence of insulin-stimulated glucose transporter 4 translocation on 3-phosphoinositide-dependent protein kinase-1 and its target threonine-410 in the activation loop of protein kinase C-$\zeta$,” Molecular Endocrinology, vol. 13, no. 10, pp. 1766–1772, 1999. View at Publisher · View at Google Scholar
83. J. T. Brozinick, Jr., B. R. Roberts, and G. L. Dohm, “Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance,” Diabetes, vol. 52, no. 4, pp. 935–941, 2003. View at Publisher · View at Google Scholar
84. H. Cho, J. Mu, J. K. Kim, et al., “Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB$\beta$),” Science, vol. 292, no. 5522, pp. 1728–1731, 2001. View at Publisher · View at Google Scholar · View at PubMed
85. S. George, J. J. Rochford, C. Wolfrum, et al., “A family with severe insulin resistance and diabetes due to a mutation in AKT2,” Science, vol. 304, no. 5675, pp. 1325–1328, 2004. View at Publisher · View at Google Scholar · View at PubMed
86. J. C. Pickup, “Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes,” Diabetes Care, vol. 27, no. 3, pp. 813–823, 2004. View at Publisher · View at Google Scholar
87. G. S. Hotamisligil, “Inflammatory pathways and insulin action,” International Journal of Obesity, vol. 27, pp. S53–S55, 2003. View at Publisher · View at Google Scholar · View at PubMed
88. S. Perrier, F. Darakhshan, and E. Hajduch, “IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde?,” FEBS Letters, vol. 580, no. 27, pp. 6289–6294, 2006. View at Publisher · View at Google Scholar · View at PubMed
89. J. Jager, T. Grémeaux, M. Cormont, Y. Le Marchand-Brustel, and J.-F. Tanti, “Interleukin-1$\beta$-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression,” Endocrinology, vol. 148, no. 1, pp. 241–251, 2007. View at Publisher · View at Google Scholar · View at PubMed
90. E. Somm, P. Cettour-Rose, C. Asensio, et al., “Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents,” Diabetologia, vol. 49, no. 2, pp. 387–393, 2006. View at Publisher · View at Google Scholar · View at PubMed
91. C. Lagathu, L. Yvan-Charvet, J.-P. Bastard, et al., “Long-term treatment with interleukin-1$\beta$ induces insulin resistance in murine and human adipocytes,” Diabetologia, vol. 49, no. 9, pp. 2162–2173, 2006. View at Publisher · View at Google Scholar · View at PubMed
92. C. A. Dinarello, “The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1,” The New England Journal of Medicine, vol. 343, no. 10, pp. 732–734, 2000. View at Publisher · View at Google Scholar
93. C. M. Larsen, M. Faulenbach, A. Vaag, et al., “Interleukin-1-receptor antagonist in type 2 diabetes mellitus,” The New England Journal of Medicine, vol. 356, no. 15, pp. 1517–1526, 2007. View at Publisher · View at Google Scholar · View at PubMed
94. J. He, I. Usui, K. Ishizuka, et al., “Interleukin-1$\alpha$ inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes,” Molecular Endocrinology, vol. 20, no. 1, pp. 114–124, 2006. View at Publisher · View at Google Scholar · View at PubMed
95. J.-A. Kim, D. C. Yeh, M. Ver, et al., “Phosphorylation of ${\text{Ser}}^{24}$ in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance,” Journal of Biological Chemistry, vol. 280, no. 24, pp. 23173–23183, 2005. View at Publisher · View at Google Scholar · View at PubMed
96. G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-$\alpha$: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993. View at Publisher · View at Google Scholar
97. K. T. Uysal, S. M. Wiesbrock, M. W. Marino, and G. S. Hotamisligil, “Protection from obesity-induced insulin resistance in mice lacking TNF-$\alpha$ function,” Nature, vol. 389, no. 6651, pp. 610–614, 1997. View at Publisher · View at Google Scholar · View at PubMed
98. H. Kanety, R. Feinstein, M. Z. Papa, R. Hemi, and A. Karasik, “Tumor necrosis factor $\alpha$-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1,” Journal of Biological Chemistry, vol. 270, no. 40, pp. 23780–23784, 1995. View at Publisher · View at Google Scholar
99. A. Steensberg, C. Keller, R. L. Starkie, T. Osada, M. A. Febbraio, and B. K. Pedersen, “IL-6 and TNF-$\alpha$ expression in, and release from, contracting human skeletal muscle,” American Journal of Physiology, vol. 283, no. 6, pp. E1272–E1278, 2002.
100. G. van Hall, A. Steensberg, M. Sacchetti, et al., “Interleukin-6 stimulates lipolysis and fat oxidation in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 88, no. 7, pp. 3005–3010, 2003. View at Publisher · View at Google Scholar
101. C. Weigert, A. M. Hennige, K. Brodbeck, H. U. Häring, and E. D. Schleicher, “Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of ${\text{Ser}}^{473}$ of Akt,” American Journal of Physiology, vol. 289, no. 2, pp. E251–E257, 2005. View at Publisher · View at Google Scholar · View at PubMed
102. L. S. Quinn, L. Strait-Bodey, B. G. Anderson, J. M. Argilés, and P. J. Havel, “Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway,” Cell Biology International, vol. 29, no. 6, pp. 449–457, 2005. View at Publisher · View at Google Scholar · View at PubMed
103. I. Shimomura, R. E. Hammer, S. Ikemoto, M. S. Brown, and J. L. Goldstein, “Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy,” Nature, vol. 401, no. 6748, pp. 73–76, 1999. View at Publisher · View at Google Scholar · View at PubMed
104. E. A. Oral, V. Simha, E. Ruiz, et al., “Leptin-replacement therapy for lipodystrophy,” The New England Journal of Medicine, vol. 346, no. 8, pp. 570–578, 2002. View at Publisher · View at Google Scholar · View at PubMed
105. C. M. Steppan, S. T. Bailey, S. Bhat, et al., “The hormone resistin links obesity to diabetes,” Nature, vol. 409, no. 6818, pp. 307–312, 2001. View at Publisher · View at Google Scholar · View at PubMed
106. A. R. Shuldiner, R. Yang, and D.-W. Gong, “Resistin, obesity, and insulin resistance—the emerging role of the adipocyte as an endocrine organ,” The New England Journal of Medicine, vol. 345, no. 18, pp. 1345–1346, 2001. View at Publisher · View at Google Scholar
107. B. Moon, J. J.-M. Kwan, N. Duddy, G. Sweeney, and N. Begum, “Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation,” American Journal of Physiology, vol. 285, no. 1, pp. E106–E115, 2003.
108. M. Pravenec, L. Kazdová, V. Landa, et al., “Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat,” Journal of Biological Chemistry, vol. 278, no. 46, pp. 45209–45215, 2003. View at Publisher · View at Google Scholar · View at PubMed
109. M. W. Rajala, S. Obici, P. E. Scherer, and L. Rossetti, “Adipose-derived resistin and gut-derived resistin-like molecule-$\beta$ selectively impair insulin action on glucose production,” The Journal of Clinical Investigation, vol. 111, no. 2, pp. 225–230, 2003. View at Publisher · View at Google Scholar
110. Y. Okamoto, E. J. Folco, M. Minami, et al., “Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis,” Circulation Research, vol. 102, no. 2, pp. 218–225, 2008. View at Publisher · View at Google Scholar · View at PubMed
111. S. Steffens and F. Mach, “Adiponectin and adaptive immunity: linking the bridge from obesity to atherogenesis,” Circulation Research, vol. 102, no. 2, pp. 140–142, 2008. View at Publisher · View at Google Scholar · View at PubMed
112. N. Kubota, Y. Terauchi, T. Yamauchi, et al., “Disruption of adiponectin causes insulin resistance and neointimal formation,” Journal of Biological Chemistry, vol. 277, no. 29, pp. 25863–25866, 2002. View at Publisher · View at Google Scholar · View at PubMed
113. N. Maeda, I. Shimomura, K. Kishida, et al., “Diet-induced insulin resistance in mice lacking adiponectin/ACRP30,” Nature Medicine, vol. 8, no. 7, pp. 731–737, 2002. View at Publisher · View at Google Scholar · View at PubMed
114. A. H. Berg, T. P. Combs, X. Du, M. Brownlee, and P. E. Scherer, “The adipocyte-secreted protein ACRP30 enhances hepatic insulin action,” Nature Medicine, vol. 7, no. 8, pp. 947–953, 2001. View at Publisher · View at Google Scholar · View at PubMed
115. T. Yamauchi, J. Kamon, H. Waki, et al., “The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity,” Nature Medicine, vol. 7, no. 8, pp. 941–946, 2001. View at Publisher · View at Google Scholar · View at PubMed
116. H. Sell and J. Eckel, “Monocyte chemotactic protein-1 and its role in insulin resistance,” Current Opinion in Lipidology, vol. 18, no. 3, pp. 258–262, 2007. View at Publisher · View at Google Scholar · View at PubMed
117. Q. Yang, T. E. Graham, N. Mody, et al., “Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes,” Nature, vol. 436, no. 7049, pp. 356–362, 2005. View at Publisher · View at Google Scholar · View at PubMed
118. T. E. Graham, Q. Yang, M. Blüher, et al., “Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects,” The New England Journal of Medicine, vol. 354, no. 24, pp. 2552–2563, 2006. View at Publisher · View at Google Scholar · View at PubMed
119. S. Kralisch, J. Klein, U. Lossner, et al., “Proinflammatory adipocytokines induce TIMP-1 expression in 3T3-L1 adipocytes,” FEBS Letters, vol. 579, no. 28, pp. 6417–6422, 2005. View at Publisher · View at Google Scholar · View at PubMed
120. W. L. Holland, T. A. Knotts, J. A. Chavez, L.-P. Wang, K. L. Hoehn, and S. A. Summers, “Lipid mediators of insulin resistance,” Nutrition Reviews, vol. 65, pp. 39–46, 2007. View at Publisher · View at Google Scholar
121. E. W. Kraegen, G. J. Cooney, J. Ye, and A. L. Thompson, “Triglycerides, fatty acids and insulin resistance—hyperinsulinemia,” Experimental and Clinical Endocrinology and Diabetes, vol. 109, no. 4, pp. 516–526, 2001. View at Publisher · View at Google Scholar
122. V. Poitout, D. Hagman, R. Stein, I. Artner, R. P. Robertson, and J. S. Harmon, “Regulation of the insulin gene by glucose and fatty acids,” Journal of Nutrition, vol. 136, no. 4, pp. 873–876, 2006.
123. C. Rask-Madsen and G. L. King, “Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 3, pp. 487–496, 2005. View at Publisher · View at Google Scholar · View at PubMed
124. Z. Gao, X. Zhang, A. Zuberi, et al., “Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes,” Molecular Endocrinology, vol. 18, no. 8, pp. 2024–2034, 2004. View at Publisher · View at Google Scholar · View at PubMed
125. P. Kovacs and M. Stumvoll, “Fatty acids and insulin resistance in muscle and liver,” Best Practice & Research in Clinical Endocrinology & Metabolism, vol. 19, no. 4, pp. 625–635, 2005. View at Publisher · View at Google Scholar · View at PubMed
126. P. J. Grant, “The genetics of atherothrombotic disorders: a clinician's view,” Journal of Thrombosis and Haemostasis, vol. 1, no. 7, pp. 1381–1390, 2003. View at Publisher · View at Google Scholar
127. J. Amar, L. Perez, R. Burcelin, and B. Chamontin, “Arteries, inflammation and insulin resistance,” Journal of Hypertension, vol. 24, pp. S18–S20, 2006. View at Publisher · View at Google Scholar · View at PubMed
128. P. Theuma and V. A. Fonseca, “Inflammation, insulin resistance, and atherosclerosis,” Metabolic Syndrome and Related Disorders, vol. 2, no. 2, pp. 105–113, 2004. View at Publisher · View at Google Scholar · View at PubMed
129. F. Montecucco, G. Bianchi, M. Bertolotto, G. Viviani, F. Dallegri, and L. Ottonello, “Insulin primes human neutrophils for CCL3-induced migration: crucial role for JNK 1/2,” Annals of the New York Academy of Sciences, vol. 1090, pp. 399–407, 2006. View at Publisher · View at Google Scholar · View at PubMed
130. K. Kappert, H. Meyborg, M. Clemenz, et al., “Insulin facilitates monocyte migration: a possible link to tissue inflammation in insulin-resistance,” Biochemical and Biophysical Research Communications, vol. 365, no. 3, pp. 503–508, 2008. View at Publisher · View at Google Scholar · View at PubMed
131. I. Tabas, T. Seimon, J. Arellano, et al., “The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis,” Novartis Foundation Symposium, vol. 286, pp. 99–109, 2007.
132. C. K. Roberts, D. Won, S. Pruthi, et al., “Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors,” Journal of Applied Physiology, vol. 100, no. 5, pp. 1657–1665, 2006. View at Publisher · View at Google Scholar · View at PubMed
133. B. Głowińska-Olszewska and M. Urban, “Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents,” Metabolism, vol. 56, no. 6, pp. 799–805, 2007. View at Publisher · View at Google Scholar · View at PubMed
134. G. Boden, W. Song, L. Pashko, and K. Kresge, “In vivo effects of insulin and free fatty acids on matrix metalloproteinases in rat aorta,” Diabetes, vol. 57, no. 2, pp. 476–483, 2008. View at Publisher · View at Google Scholar · View at PubMed
135. A. Ceriello, “Thiazolidinediones as anti-inflammatory and anti-atherogenic agents,” Diabetes/Metabolism Research and Reviews, vol. 24, no. 1, pp. 14–26, 2008. View at Publisher · View at Google Scholar · View at PubMed
136. S. M. Haffner, A. S. Greenberg, W. M. Weston, H. Chen, K. Williams, and M. I. Freed, “Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus,” Circulation, vol. 106, no. 6, pp. 679–684, 2002. View at Publisher · View at Google Scholar
137. G. Anfossi, I. Russo, and M. Trovati, “Platelet resistance to the anti-aggregating agents in the insulin resistant states,” Current Diabetes Reviews, vol. 2, no. 4, pp. 409–430, 2006.
138. J. D. McGarry, “Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes,” Diabetes, vol. 51, no. 1, pp. 7–18, 2002. View at Publisher · View at Google Scholar
139. S. N. Leroyer, J. Tordjman, G. Chauvet, et al., “Rosiglitazone controls fatty acid cycling in human adipose tissue by means of glyceroneogenesis and glycerol phosphorylation,” Journal of Biological Chemistry, vol. 281, no. 19, pp. 13141–13149, 2006. View at Publisher · View at Google Scholar · View at PubMed
140. E. E. Kershaw, M. Schupp, H.-P. Guan, N. P. Gardner, M. A. Lazar, and J. S. Flier, “PPAR$\gamma$ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo,” American Journal of Physiology, vol. 293, no. 6, pp. E1736–E1745, 2007. View at Publisher · View at Google Scholar · View at PubMed
141. I. F. Charo, “Macrophage polarization and insulin resistance: PPAR$\gamma$ in control,” Cell Metabolism, vol. 6, no. 2, pp. 96–98, 2007. View at Publisher · View at Google Scholar · View at PubMed
142. M. Bajaj, S. Suraamornkul, T. Pratipanawatr, et al., “Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes,” Diabetes, vol. 52, no. 6, pp. 1364–1370, 2003. View at Publisher · View at Google Scholar
143. Y. Miyazaki, A. Mahankali, M. Matsuda, et al., “Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients,” The Journal of Clinical Endocrinology & Metabolism, vol. 87, no. 6, pp. 2784–2791, 2002. View at Publisher · View at Google Scholar
144. A. B. Mayerson, R. S. Hundal, S. Dufour, et al., “The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes,” Diabetes, vol. 51, no. 3, pp. 797–802, 2002. View at Publisher · View at Google Scholar
145. M. Tiikkainen, A.-M. Häkkinen, E. Korsheninnikova, T. Nyman, S. Mäkimattila, and H. Yki-Järvinen, “Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes,” Diabetes, vol. 53, no. 8, pp. 2169–2176, 2004. View at Publisher · View at Google Scholar
146. L. L. Lipscombe, T. Gomes, L. E. Lévesque, J. E. Hux, D. N. Juurlink, and D. A. Alter, “Thiazolidinediones and cardiovascular outcomes in older patients with diabetes,” Journal of the American Medical Association, vol. 298, no. 22, pp. 2634–2643, 2007. View at Publisher · View at Google Scholar · View at PubMed
147. S. E. Nissen and K. Wolski, “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes,” The New England Journal of Medicine, vol. 356, no. 24, pp. 2457–2471, 2007. View at Publisher · View at Google Scholar · View at PubMed
148. M. Bajaj, S. Suraamornkul, L. J. Hardies, L. Glass, N. Musi, and R. A. DeFronzo, “Effects of peroxisome proliferator-activated receptor (PPAR)-$\alpha$ and PPAR-$\gamma$ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus,” Diabetologia, vol. 50, no. 8, pp. 1723–1731, 2007. View at Publisher · View at Google Scholar · View at PubMed
149. S. H. Han, M. J. Quon, and K. K. Koh, “Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-$\alpha$ activators,” Hypertension, vol. 46, no. 5, pp. 1086–1092, 2005. View at Publisher · View at Google Scholar · View at PubMed