1. DeFronzo RA. The triumvirate: (-cell muscle, liver: a collusion responsible for NIDDM. Diabetes 37:677-687, 1988.

2. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 13: 610-630, 1990.

3. Haist RE, Campbell J. Best CH: The prevention of diabetes. N. Engl. J. Med 223: 607-615, 1940.

4. Nathan DM, Long-term complications of diabetes mellitus. N. Engl. J. Med. 328:1676-1685, 1993.

5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977-986, 1993.

6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with

sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837-853, 1998.

7. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79: 1510-1515, 1987,

8. Garvey WT, Olefsky JM, Matthaei S, Marshall S: Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. J. Biol. Chem 262: 189-197, 1987.

9. Rayfield EJ, Ault MJ, Keusch GT, Brothers MJ, Nechemias C, Smith H: Infection and diabetes: the case for glucose control. Am J. Med 72: 438-450, 1982.

10. Boulot P, Chabbert-Buffet N, d'Ercole C, Floriot M, Fontaine P, Fournier A, Gillet JY, Grandperret-Vauthier S, Geudj AM, Guionnet B, Hauguel-de-Mouzon S, Hieronimus Hoffet M, Jullien D, Lamotte MF, Lejeune V, Lepercq J, Lorenzi F, Mares P, Miton A, Penfornis A, Pfister B, Renard E, Rodier M, Roth P, Sery GA, Timsit J, Valkat S, Van A, Verier-Mine O; Diabetes and Pregnancy Group. French milticentric survey of outcome of pregnancy in women with pregestational diabetes. Diabetes Care 26: 2990-1993, 2003.

11. Savage PJ, Bennion LO, Flock EV, Nagulesparan M, Mott D, Roth J, Unger RH, Bennett PH: Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. J. Clin. Endocrinol. Metab. 48: 999-1007, 1979.

12. Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM. The acute and chronic effects of sulfonylurea therapy in type II diabetes. Diabetes 33: 346-354, 1984.

13. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG: The effect of insulin

treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34: 222-234, 1985.

14. Weir GC, Leahy JL, Bonner-Weir S: experimental reduction of beta-cell mass: implications

for the pathogenesis of diabetes. Diabetes Metab. Rev. 2: 125-161, 1986.

15. Weir GC, Clore ET, Zmachinski CJ, Bonner-Weir S: Islet secretion in a new experimental

model for non-insulin-dependent diabetes. Diabetes 30: 590-595, 1981.

16. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA: Effect of chronic hyperglycemia on in

vivo insulin secretion in partially pancreatectomized rats. J. Clin. Invest. 80: 1037-1044, 1987.

17. Leahy JL, Bonner-Weir S, Weir GC: Abnormal insulin secretion in a streptozocin model of

diabetes: effects of insulin treatment. Diabetes 34: 660-666, 1985.

18. Kergoat M, Bailbe D, Portha B: Insulin treatment improves glucose-induced insulin release in rats with NIDDM induced by streptozocin. Diabetes 36: 971-977, 1987.

19. Leahy JL, Bonner-Weir S, Weir GC: Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion after an incomplete pancreatectomy. J. Clin. Invest. 81: 1407-1414, 1988.

20. Leahy JL, Cooper HE, Weir GC: Impaired insulin secretion associated with near

normoglycemia: study in normal rats with 96-h in vivo glucose infusions. Diabetes 36: 459-464, 1987.

21. Imamura T, Koffler M, Helderman JH, Prince D, Thirlby R, Inman L, Unger RH: Severe

diabetes induced in subtotally depancreatized dogs by sustained hyperglycemia. Diabetes 37: 600-609, 1988.

22. Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A. (-cell adaptation and decompensation during the progression of diabetes. Diabetes 50 (Suppl.1) S154-S159, 2001.

23. Colella RM, May JM, Bonner-Weir S, Leahy JL, Weir GC: Glucose utilization in islets of

hyperglycemic rat models with impaired glucose-induced insulin secretion. Metabolism 36: 335-337, 1987.

24. Chan CB, MacDonald PE, Saleh MC, Johns DC, Marban E Wheeler MB. Over-expression of uncoupling protein-2 inhibits glucose-stimulated insulin secsretion from rat islets. Diabetes 48: 1482-1986, 1999.

25. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunciton, and type 2 diabetes. Cell 105: 745-755, 2001

26. Zhao, C, Rutter GA. Overexpression of lactate dehydrogenase A attenuates glucose-induced insulin secretion in stable MIN-6 beta-cell lines. FEBS. Lett. 4300:213-216, 1998.

27. Jonas J-C, Sharma A, Hasenkamp W, Ilkova H, Patane G, Laybutt R, Bonner-Weir S, Weir G. Chronic hyperglycemia triggers loss of pancreatic B-cell differentiation in an animal model of diabetes. J. Biol. Chem. 274: 14112-14121, 1999.

28. Ostenson C-G, Khan A, Abdel-Halim SM, Guenifi A, Suzuki K, Goto Y, Efendic S. Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat. Diabetologia 36: 3-8, 1993,

29. Ling Z-C, Hong-Lie C, Ostenson C-G, Efendic S, Khan A. Hyperglycemia contributes to impaired insulin response in GK rat islets. Diabetes 50 (Suppl.1) S108-S112, 2001.

30. Zawalich WS, Zawalich KC, Shulman GI, Rossetti L: Chronic in vivo hyperglycemia impairs phosphoinositide hydrolysis and insulin release in isolated perfused rat islets. Endocrinology 126: 253-260, 1990.

31. Metz SA, Meredith M, Vadakekalam J, Rabaglia ME, Kowluru A. A defect late in stimulus-secretion coupling impairs insulin secretion in (Kakizaki diabetic rats). Diabetes 48: 1754-1762, 1999.

32. Robertson RP, Type II diabetes, glucose "non-sense" and islet desensitization. Diabetes 38:

1501-1505, 1989.

33. Robertson RP, Eicosanoids asvpluripotential modulators of pancreatic islet function.

Diabetes 37: 367-379, 1988.

34. Laybutt DR, Sharma A, Sgroi DC, Gaudet J, Bonner-Weir S, Weir GC. Genetic regulation of metabolic pathways in (-cells disrupted by hyperglycemia. J. Biol. Chem. 277:10912-10921.

35. Hoppener JW, Nieuwenhuis MG, Vroom TM, Ahren B, Lips CJ. Role of islet amyloid in type 2 diabetes mellitus: consequence or cause? Mol. Cell. Endocrinol. 197: 205-212, 2002.

36. McGarrry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42: 128-138, 1999.

37. Prentki M, Corkey BE. Are the (-cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45: 273-283, 1996.

38. Prentki M, Roduit R, Lameloise N, Corkey BE, Assimacopoulos-Jeannet F. Glucotoxicity, lipotoxicity and pancreatic B-cell failure: a role for malonyl-CoA, PPAR( and altered lipid partitioning. Can. J. Diabetes Care 25:36-46, 2001.

39. Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney JT, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J. Biol. Chem. 267: 5802-5810, 1992.

40. Sako Y, Grill VE. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and (-cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127: 1580-1589, 1990.

41. Bollheimer LC, Skelly RH, Chester MW, McGarry JD, Rhodes CJ. Chronic exposure to free fatty acid reduces pancreatic (-cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis and translation. J. Clin. Invest. 101: 1094-1101, 1998.

42. Maedler K, Spinas GA, Dyntar D, Moritz W, Kaiser N, Donath MY. Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. Diabetes 50: 69-76, 2001.

43. Shimabukuro M, Higi M, Zhou YT, Wang MY, Newgard CB, Unger RH. Lipoapoptosis in (-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferance overexpression. J. Biol. Chem. 273: 32487-32490.

44. Wang M-Y, Koyama K, Shimabukuro M, Newgard CB, Unger RH. Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase and glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. USA 95:11921-11926, 1998.

45. Harmon JS, Gleason CE, Tanaka Y, Poitout V, Robertson RP. Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker diabetic fatty rats. Diabetes 50: 2481-2486, 2001.

46. Dobbins RL, Chester MW, Daniels MB, McGarry JD, Stein DT. Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes 47: 1613-1618, 1998.

47. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N. Engl. J. Med. 345:971-980, 2001.

48. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev . 15: 1763-1768, 1998.

49. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet 17: 138-13l9, 1997.

50. Gadot M, Leibowitz G, Shafrir E, Cerasi E, Gross D, Kaiser N. Hyperproinsulinemia and insulin deficiency in the diabetic Psammomys obesus. Endocrinology 135: 610-616, 1994.

51. Nesher R, Gross DJ, Donath MY, Cerasi E, Kaiser N. Interaction between genetic and dietary factors determines (-cell function in Psammomys obesus, an animal model of type 2 diabetes. Diabetes 48: 731-737, 1999.

52. Leibowitz G. Ferber S, Apelqvist A, Edlund H, Gross DJ, Cerasi E, Melloul D, Kaiser N. IPF1/PDX1 deficiency and (-Cell dysfunction in Psammomys obesus, an animal with type 2 diabetes. Diabetes 50:17989-1806, 2001.

53. Gremlich S, Bonny C, Waeber G, Thorens B. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J. Biol. Chem. 272: 30262-30269, 1997.

54. Zangen DH, Bonner-Weir S, Lee CH, Latimer JB, Miller CP, Habener JF, Weir GC. Reduced insulin, GLUT2 and IDX-1 in beta cells after partial pancreatectomy. Diabetes 46: 258-264, 1997.

55. Sharma A, Olson LK, Robertson RP, Stein R. The reduction of insulin gene transcription in HIT-T15 B cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Mol. Endocrinol. 9:1127-1134, 1995.

56. Triggs-Raine BL, Kirkpatrick RD, Kelly SL, Norquay LD, Cattini PA, Yamagata K, Hanley AJG, Zinman B, Harris SB, Barrett PH, Hegele RA, HNF1( G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc. Natl. Acad. Sci. USA 99: 4614-4619, 2002.

57. Harris SB, Gittelsohn J, Hanley A, Barnie A, Wolever TM, Gao J, Logan A, Zinman B. The prevalence of NIDDM and associated risk factors in native Canadians. Diabetes Care 20: 185-187, 1997.

58. Harmon JS, Gleason CE, Tanaka Y, Oseid EA, Hunter-Berger KK, Robertson RP. In vivo prevention of hyperglycemia also prevents glucotoxic effects on PDX-1 and insulin gene expression. Diabetes 48: 1995-2000, 1999.

59. Gleason CE, Gonzalez M, Harmon JS, Robertson RP. Determinants of glucose toxicity and its reversibility in the pancreatic islet (-cell line, HIT-T15. Am. J. Physiol. Endocrinol. Metab. 279: E997-E1002, 2000.

60. Turner RC. The UK Prospective Diabetes Study. A review. Diabetes Care. 21: Suppl. 3. C35-C38, 1998.

61. Reaven GM, Sageman WS, Swenson RS. Development of insulin resistance in normal dogs following alloxan-induced insulin deficiency. Diabetologia 13: 459-462, 1977.

62. Dall'Aglio E. Chang H, Hollenbeck CB, Mondon CE, Sims C, Reaven GM. In vivo and in vitro resistance to maximal insulin stimulated glucose disposal in insulin deficiency. Am. J. Physiol. 249: E312-E316, 1985.

63. Unger RH, Grundy S. Hyperglycemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28: 119-121, 1985.

64. Yki-Jarvinen H, Koivisto VA. Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type 1 diabetes. J. Clin. Endocrinol. Metab. 58: 659-666, 1984.

65. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method of quantifying insulin secretion and resistance. Am. J. Physiol. 232: E214-E223, 1979.

66. Richter EA, Hansen BF, Hansen SA. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. Biochem. J. 252:733-737, 1988.

67. Kurowski TG, Lin Y, Luo Z, Tsichlis PN, Buse MG, Heydrick SJ, Ruderman NB. Hyperglycemia inhibits insulin activation of Akt/protein kinase B, but not phosphatidylinositol 3-kinase in rat skeletal muscle. Diabetes 48: 658-663.

68. Tomas E, Lin Y-S, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. Hyperglycemia and insulin resistance: Possible mechanisms. Ann. N.Y. Acad. Sci. 967: 43-51, 2002.

69. Shepherd PR, Kahn BB. Glucose transporters and insulin action. N. Engl. J. Med. 341: 248-257, 1999.

70. Matthaei S, Horuk R, Olefsky JM: Blood-brain glucose transfer in diabetes mellitus decreased number of glucose transporters at blood-brain barrier. Diabetes 35:1181-1184, 1986.

71. McCall AL, Fixman LB, Fleming N, Tornheim K, Chick W, Ruderman NB: Chronic hypoglycemia increases brain glucose transport. Am J. Physiol. 251: E442-E447, 1986.

72. Traxinger RR, Marshall S: Recovery of maximal insulin responsiveness and insulin sensitivity after induction of insulin resistance in primary cultured adipocytes. J. Biol. Chem. 264:8156-8163, 1989.

73. Nawano M, Ueta K, Oku A, Arakawa K, Saito A, Funaki M, Anai M, Kikuchi M, Oka Y, Asano T. Hyperglycemia impairs the insulin signaling step between PI 3-kinase and Akt/PKB activation in ZDF rat liver. Biochem. Biophys. Res. Commun. 9:252-256, 1999.

74. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 47: 859-866, 1998.

75. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 19: 257-267, 1996.

76. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820, 2001.

77. Fine E, Horal M, Chang T, Fortin G. Loeken M. Hyperglycemia is responsible for altered gene expression, apoptosis, and neural tube defects associated with diabetic pregnancy. Diabetes 48: 2454-2462, 1999.

78. Garcia-Patterson A, Erdozain L, Ginovart G, Adelantado JM, Cubero JM, Gallo G, deLeiva A, Corcoy R. In human gestational diabetes mellitus congenital malformations are related to pre-pregnancy body mass index and to severity of diabetes. Diabetologia 509-514, 2004.

79. Poitout V, Robertson RP. Minireview: Secondary (-cell failure in type 2 diabetes - A convergence of glucotoxicity and lipotoxicity. Endocrinology 143: 339-342, 2002.

80. Du Y, Miller CM, Kern TS. Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic. Biol. Med. 35: 1491-1499, 2003.

81. Purves T, Middlemas A, Agthong S, Jude EF, Bouton AJ, Fernyhough P, Tomlinson D, A role for mitogen-activated protein kinasesx in the etiology of diabetic neuropathy. FASEB J. 15: 2508-2514, 2001.

82. Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS. High glucose stimulates angiotensinogen gene expression via reactive oxygen spe4cies generation in rat kidney proximal tubular cells. Endocrinol. 143: 2975-2985, 2002.

83. Ihara Y, Toyokuni S, Uchida K, Odaka H, Tanaka T, Ikeda H, Hiai H, Seino Y, Yamada Y. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Diabetes 48: 927-932, 1999.

84. Tanaka Y, Gleason CE, Tran POT, Harmon JS, Robertson RP. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc. Natl. Acad. Sci. USA 96: 10857-10862, 1999.

85. Kaneto H, Fujii J, Myint T, Miyazawa N, Islam KN, Kawasaki Y, Suzuki K, Nakamura M, Tatsumi H, Yamasaki Y, Taniguchi N. Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction. Biochem. J. 320: 855-863, 1996.

86. Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 48: 2398-2406, 1999.

87. Tanaka Y, Tran PO, Harmon J, Robertson RP. A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Proc. Natl. Acad. Sci. USA 99: 12363-12368, 2002.

88. Tang J, Neidigh JL, Cooksey RC, McClain DA. Transgenic mice with increasesd hexosamine flux specifically targeted to beta-cells exhibit hyperinsulinemia and peripheral insulin resistance. Diabetes 49: 1492 - 1499, 2000.

89. Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC. Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J. Biol. Chem. 276: 31099-31104, 2001.

90. Konrad RJ, Kudlow JE. The role of O-linked protein glycosylation in beta cell dysfunction. Int. J. Mol. Med. 10: 535-539, 2002.

91. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Browlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc. Natl. Acad. Sci. USA 97: 12222-12226, 2000.

92. Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GI, Kikkawa R. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J. 14: 439-447, 2000.

93. Aiello LP, The potential role of PKC beta in diabetic retinopathy and macular edema. Surv. Ophthalmol. 47: Suppl. 2, S263-S269, 2002.

94. Kaneto H, Suzuma K, Sharma A, Bonner-Weir S, King GL, Weir GC. Involvement of protein kinase C (2 in c-myc induction by high glucose in pancreatic (-cells. J. Biol. Chem. 277: 3680-3685, 2002.

95. Kaneto H, Sharma A, Suzuma K Laybutt DR, Xu G, Bonner-Weir S, Weir GC. Induction of c-Myc expression suppresses insulin gene transcription by inhibiting neuroD/BETA2-mediated transcriptional activation. J. Biol. Chem. 277:12998-13006, 2002.

96. Goldberg HJ, Whiteside CI, Fantus IG. The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-(I and -(. J. Biol. Chem. 277: 33833-33841, 2002.

97. Marshall S, Garvey WT, Taxinger RR. New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids. FASEB J. 5: 3031-3036, 1991.

98. Hresko RC, Heimberg H, Chi MM, Mueckler M. Glucosamine-induced insulin resistance in 3T3-L1 adipocytes is caused by depletion of intracellular ATP. J. Biol. Chem. 273: 20658-20668, 1998.

99. Vosseller K, Wells L, Lane MD, Hart GW. Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance assocaited with defects in Akt activation in 3T3-L1 adipocytes. Proc. Natl. Acad. Sci. USA 99: 5313-5318, 2002.

100. Herbert LF, Daniels MC, Zhou J, Crook ED, Turner RL, Simmons ST, Neidigh JL, Zhu J-S, Baron AD, McClain DA. Overexpression of glutamine: fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance. J. Clin. Invest. 98: 930-936, 1996.

101. Rossetti L, Hawkins M, Chen W, Gindi J, Barzilai N. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J. Clin. Invest. 96: 132-140, 1995.

102. Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes 48: 1562-1571, 1999.

103. Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Invest. 103: 931-943, 1999.

104. Carvalho E, Eliasson B, Wesslan C, Smith U. Impaired phosphorylation and insulin-stimulated translocation to the plasma membrane of protein kinase B/Akt in adipocytes from type II diabetic subjects. Diabetologia 43: 1107-1115, 2000.

105. Oku A, Nawano M, Ueta K, Fuijita T, Umebayashi I, Arakawa K, Kano-Ishihara T, Saito A, Anai M, Funaki M, Kikuchi M, Oka Y, Asano T. Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 280: E816-E824, 2001.

106. Pillay TS, Xiao S, Olefsky JM. Glucose-induced phosphorylation of the insulin receptor: functional effects and characterization of phosphorylation sites. J. Clin. Invest. 97: 613-620, 1996.

107. Muller HK, Kellerer M, Ermel B, Muhlhofer A, Obermaier-Kusser B, Vogt B, Haring HU. Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. Diabetes 40: 1440-1448, 1991.

108. Avignon A, Yamada K, Zhou X, Spencer B, Cardona O, Saba-Siddique S, Galloway L, Standaert ML, Farese RV. Chronic activation of protein kinase C in soleus muscles and other tissues of insulin-resistant type II diabetic Goto-Kakizaki (GK), obese/aged, and obese/Zucker rats. A mechanism for inhibiting glycogen synthesis. Diabetes 45: 1396-1404, 1996.

109. Bollag GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland DEJ. Protein kinase C directly phosphorylates the insulin receptor in vivo and reduces its protein-tyrosine kinase activity. Proc. Natl. Acad. Sci. USA 83: 5822-5824, 1987.

110. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H. Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J. Clin. Invest. 97: 1471-1477, 1996.

111. Peraldi P, Spiegelman B. TNF-alpha and insulin resistance: summary and future prospects. Mol. Cell. Biochem. 182: 169-175, 1998.

112. Kellerer M, Mushack J, Seffer E, Mischak H, Ullrich A, Haring HU. Protein kinase C isoforms (, ( and ( require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells). Diabetologia 41: 833-838,1998.

113. Newton AC. Protein kinase C: structure, function and regulation. J. Biol. Chem. 270: 28495-28498, 1995.

114. Chen KS, Heydrick SJ, Brown ML, Friel JC, Ruderman NB. Insulin increases a biochemically distinct pool of diacylglycerol in the rat soleus muscle. Am. J. Physiol. 266: E479-E485, 1994.

115. Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277:42394-42398, 2002.

116. Cazzolli R, Carpenter L, Biden TJ, Schmitz-Peiffer C. A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate. Diabetes 50: 2210-2218, 2001.

117. Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin stimulted PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J. Biol. Chem. 274: 24202 - 24210, 1999.

118. Straczkowski M, Kowalska I, Kikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baran M. Zendzian-Piotrowska M, Brzezinska Z, Gorski J. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 53: 1215-1221, 2004.

119. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 39: 357-363, 1996.

120. Paolisso G, D'Amore A, Volpe C, Balbi V, Saccomanno F, Galzerano D, Giugliano D, Varricchio M, D'Onofrio F. Evidence for a relationship between oxidative stress and insulin action in non-insulin dependent (type 2) diabetic patients. Metabolism 43: 1426-1429, 1994.

121. Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 47: 1562-1569, 1998.

122. Tirosh A, Potashnik R, Bashan N, Rudich A. Oxidative stress disrupts insulin-induced cellular redistribution of inuslin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. J. Biol. Chem. 274: 10595-10602, 1999.

123. Jain SK, Levine SN, Duett J, Hollier B. Elevated lipid peroxidation levels in red blood cells of streptozotocin-treated diabetic rats. Metabolism 39: 971-975, 1990.

124. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48: 1-9, 1999.

125. Lu B, Ennis D, Lai R, Bogdanovic E, Nikolov R, Salamon L, Fantus C, Le-Tien H, Fantus IG. Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). J. Biol. Chem. 276: 35589-35598, 1001.

126. Haber CA, Lam TKT, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus IG. N-acetylcysteine (NAC) and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stess. Am J. Physiol. Endocrinol. Metab. 285:E744-E753, 2003.

127. Paolisso G, D'Amore A, Giugliano D, Ceriello A, Varricchio M, D'Onofrio F. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am J. Clin. Nutr. 57: 650-656, 1993.

128. Paolisso G, D'Amore A, Balbi V, Volpe C, Galzerano D, Giuliano D, Sgambato S, Varricchio M, D'Onofrio F. Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am. J. Physiol. 266: E261-E268, 1994.

129. Powis G, Gasdaska JR, Baker A. Redox signaling and the control of cell growth and death. Adv. Pharmacol. 38: 329-359, 1997.

130. Guyton KZ, Liu Y, Gorospe M, Xu Q, Holbrook NJ. Activation of mitogen-activated protein kinase by H2O2: Role in cell survival following oxidant injury. J. Biol. Chem. 271: 4138-4142, 1996.

131. Blair AS, Hajduch E, Litherland GJ, Hundal HS. Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress. Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways. J. Biol. Chem. 274: 36293-36299, 1999.

132. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nichizuka Y. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2 . Proc. Natl. Acad. Sci. USA 94: 11223-11237, 1997.

133. Palmer HJ, Paulson KE. Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr. Rev. 55: 353-361, 1997.

134. Hunt J.V., Dean RT, Wolff SP. Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and aging. Biochem. J. 256: 205-212, 1988.

135. Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and deoxyglucosone in the glycation of proteins by glucose. Biochem. J. 344: 109-116, 1999.

136. Nishikawa T, Edelstein D, Du XL, Yamagishi S-I, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes H-P, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404: 787-790, 2000.

137. Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13: 23-30, 1999.

138. Wu G, Haynes TE, Li H, Yan W, Meininger CJ. Gutamine metabolism to glucosamine is necessary for glutamine inhibition of endothelial nitric oxide synthesis. Biochem. J. 353: 245-252, 2001.

139. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol.186: 1-85, 1990

140. Hodgkinson AD, Bartlett T, Oates PJ, Millward BA, Demaine AG. The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Diabetes 52: 846-851, 2003.

141. Hammes H-P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus

A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med.1 - 6, 2003.

142. Cowell RM, Russell JW. Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy. J. Investig. Med. 52: 33-44, 2004.

143. Van Dam PS, Van Asbeck S, Erkelens DW, Marx JJ, Gispen WH, Bravenboer B. The role of oxidative stress in neuropathy and other diabetic complications. Diabets Metab. Rev. 11: 181-192, 1995.

144. Kowlura RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 50: 1938-1942, 2001.

145. Hugay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, Groner Y. Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide disminutase in transgenic mouse embryos. Am. J. Obstet. Gynecol. 173: 1036-1041, 1995.

146. Wentzel P, Eriksson UJ. Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro. Diabetes 47: 677-684, 1998.

147. Yki Jarvinen H, Koivisto VA. Natural course of insulin resistance in type 1 diabetes. N. Engl. J. Med. 315: 224-230, 1986.