1. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes 5:117-269, 1997.

2. Grill V. A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. Ann Med 22:171-175, 1990.

3. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus. J. Clin Invest 76: 149-155, 1985.

4. DeFronzo RA. Lilly Lecture. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667-687, 1988.

5. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry. Diabetes 30:1000-1007, 1981.

6. DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 3:415-459, 1987.

7. Mari A, Wahren J, DeFronzo RA, Ferrannini E. Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods. Metabolism 43:1419-1425, 1994.

8. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis. Its importance in human glucose homeostasis. Diabetes Care 24:382-391, 2001.

9. Ekberg K, Landau BR, Wajngot A, Chandramouli V, Efendic S, Brunengraber H, Wahren J. Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. Diabetes 48:292-298, 1999.

10. Magnusson I. Katz LD. Shulman RG. Shulman GI. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 254:573-6, 1991

11. Katz LD, Glickman MG, Rapoport S, Ferrannini E, DeFronzo RA. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32:675-679, 1983.

12. Ferrannini E, Bjorkman O, Reichard GA Jr, Pilo A, Olsson M, Wahren J, DeFronzo RA. The disposal of an oral glucose load in healthy subjects. Diabetes 34:580-588, 1985.

13. Mitrakou A, Kelley D, Veneman T, Jensen T, Pangburn T, Reilly J, Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381-90, 1990.

14. Mandarino L, Bonadonna R, McGuinness O, Wasserman D. Regulation of Muscle Glucose Uptake In Vivo. In: Handbook of Physiology, Section 7, The Endocrine System, Vol. II, The Endocrine Pancreas and Regulation of Metabolism, pp 803-848, L.S. Jefferson and A.D. Cherrington, eds., Oxford University Press, 2001.

15. Del Prato S. Riccio A. Vigili de Kreutzenberg S. Dorella M. Tiengo A. DeFronzo RA. Basal plasma insulin levels exert a qualitative but not quantitative effect on glucose-mediated glucose uptake. Am J Physiol 268:E1089-95, 1995.

16. Cherrington AD. Control of glucose uptake and release by the liver in vivo. Diabetes 48:1198-1214, 1999.

17. Jansson P-A, Larsson A, Smith U, Lonroth P. Lactate release from the subcutaneous tissue in lean and obese men. J Clin Invest 93:240-246, 1994.

18. Groop LC, Bonadonna RC, Del Prato S Ratheiser K, Zych K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205-215, 1989

19. Santomauro A, Boden G, Silva M, Rocha DM, Santos RF, Ursich MJM, Strassman PG, Wajchenberg BL. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and non-diabetic subjects. Diabetes 48:1836-1841, 1999.

20. Bergman RN. Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein?. Diabetologia. 43:946-52, 2000.

21. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46:3-10, 1997.

22. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 51:7-18, 2002.

23. Baron AD. Schaeffer L. Shragg P. Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 36:274-83, 1987.

24. DeFronzo RA, Ferrannini E, Hendler R, Wahren J, and Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci 75:5173-5177, 1978.

25. Ferrannini E, Wahren J, Felig P, DeFronzo RA. Role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man. Metabolism 29:28-35, 1980.

26. Hsieh P-S, Moore MC, Neal DW, Cherrington AD. Hepatic glucose uptake rapidly decreases after removal of the portal signal in conscious dogs. Am J Physiol 275:E987-E992, 1998.

27. Adkins-Marshall B, Pagliassotti MJ, Asher JR, Connolly CC, Neal DW, Williams PE, Myers SR, Hendrick GK, Adkins RB Jr, Cherrington AD. Role of hepatic nerves in response of liver to intraportal delivery in dogs. Am J Physiol 262:E679-E686, 1992.

28. Creutzfeldt W. The incretin concept today. Diabetologia 16:75-85, 1979.

29. Drucker DJ. Glucagon-like peptides. Diabetes 47:159-169, 1998.

30. Holst JJ, Gromada J, Nauck MA. The pathogenesis of NIDDM involves a defective expression of the GIP receptor. Diabetologia 40:984-986, 1997.

31. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 334:777-783, 1996.

32. Cerasi E. Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible? Diabetologia 38:992-997, 1995.

33. Sicree RA, Zimmet P, King HO, Coventry JO. Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 years. Diabetes 36:179-186, 1987.

34. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet i:1356-1359, 1989.

35. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. The natural history of impaired glucose tolerance in the Pima Indians. New Engl J Med 319:1500-1505, 1988.

36. Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 44:1386-1391, 1995.

37. Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance. Evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 49:2094-2101, 2000.

38. Weyer C, Bogardus C, Pratley RE. Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance. Diabetes 48:2197-2203, 1999.

39. Weyer C, Tataranni PA, Bogardus C, Pratley RE. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 24:89-94, 2000.

40. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first degree NIDDM relative. JAMA 273:1855-1861, 1995.

41. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. New Engl J Med 321:337-343, 1989.

42. Reaven GM, Hollenbeck CB, Chen YDI. Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 32:52-55, 1989.

43. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41:1575-1586, 1992.

44. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn RC. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340:925-929, 1992.

45. Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WG, Knowler WC, Bennett PH, Moll P, Bogardus C. In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes 36:1329-1335, 1987.

46. Kahn SE. Clinical Review 135. The importance of ß-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 86:4047-4058, 2001.

47. Bergman RN, Finegood DT, Kahn SE. The evolution of ß-cell dysfunction and insulin resistance in type 2 diabetes. European J Clin Invest 32:35-45, 2002.

48. Hansen BC, Bodkin NH. Heterogeneity of insulin responses: phases leading to type 2 (noninsulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29:713-719, 1986.

49. Diamond MP, Thornton K, Connolly-Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Invest 2:708-715, 1995.

50. Hollenbeck CB, Reaven GM. Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab 64:1169-1173, 1987.

51. Reaven GM. Banting Lecture. Role of insulin resistance in human disease. Diabetes 37:595-607, 1988.

52. Faber OK, Damsgaard EM. Insulin secretion in type II diabetes. Acta Endocrinol 262 (suppl.):47-50, 1984.

53. Faber OK, Hagen C, Binder C, Markussen J, Naithani VK, Blix PM, Kuzuya H, Horwitz DL, Rubenstein AH, Rossing N. Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest 62: 197-203, 1978.

54. DeFronzo RA, Ferrannini E, Simonson DC. J Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387-95, 1989.

55. Hales CN. The pathogenesis of NIDDM. Diabetologia 37:S162-S168, 1994.

56. Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 37: 1020-4, 1988.

57. Garvey WT, Olefsky JM, Rubenstein AH, Kolterman OG. Day-long integrated urinary C-peptide excretion. Diabetes 37: 590-9, 1988.

58. Lillioja S, Mott DM, Howard BV,Bennett PH, Yki-Jarvinen H, Freymond D, Nyomba BL, Zurlo F, Swinburn B, Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. New Engl J Med 318: 1217-25, 1988.

59. Jallut D, Golay A, Munger R, Frascarolo P, Schutz Y, Jequier E, Felber JP. Impaired glucose tolerance and diabetes in obesity: a 6 year follow-up study of glucose metabolism. Metabolism 39:1068-1075, 1990.

60. Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennett PH, Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. N Engl J Med 329:1988-1992, 1993.

61. Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE, the American Diabetes Association GENNID Study Group. ß-cell function is a major contributor to oral glucose tolerance in high-risk relatives of our ethnic groups in the U.S. Diabetes 51:2170-2178, 2002.

62. Dowse GK, Zimmet PZ, Collins VR. Insulin levels and the natural history of glucose intolerance in Nauruans. Diabetes 45:1367-1372, 1996.

63. Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus. New Engl J Med 315: 220-4, 1986.

64. Ho LT, Chang ZY, Wang JT, Li SH, Liu YF, Chen Y-DI, Reaven GM. Insulin insensitivity in offspring of parents with type 2 diabetes mellitus. Diabet Med 7: 31-34, 1990.

65. Clement K, Pueyo ME, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa PH, Froguel PH, Robert JJ, Velho G. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia 39:82-90, 1996.

66. Polonsky KS. Lilly Lecture 1994. The beta cell in diabetes: from molecular genetics to clinical research. Diabetes 44:705-717, 1995.

67. Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in ß-cell function. Nature 414:788-791, 2001.

68. McCarthy MI, Froguel P. Genetic approaches to the molecular understanding of type 2 diabetes. Am J Physiol 283:E217-E225, 2002.

69. Bell GI, Zian K, Newman M, Wu S, Wright L, Fajans S., Spielman RS, Cox NJ. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc. Natl. Acad. Sci. 88:1484-1488, 1991.

70. Froguel PH, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passap P. Familial hyperglycaemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 328:697-702, 1993.

71. Menzel S, Yamagata K, Trabb JB, Nerup J, Permutt MA, Fajans SS, Menzel R, Iwasaki N, Omori Y, Cox N, Bell GI. Localization of MODY3 to a 5-cM Region of Human Chromosome 12. Diabetes 44:1408-1413, 1995.

72. Zhang Y, Warren-Perry M, Saker PJ, Hattersley AT, Mackie ADR, Baird JD, Greenwood RH, Stoffel M, Bell GI, Turner RC. Candidate gene studies in pedigrees with maturity-onset diabetes of the young not lined with glucokinase. Diabetologia 38:1055-1066, 1995.

73. Weng J, Macfarlane WM, Lehto M, Gu HF, Shepherd LM, Ivarsson SA, Wibell L, Smith T, Groop LC. Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. Diabetologia 44:249-258, 2001.

74. Sturis J, Kurland IJ, Byrne MM, Mosekilde E, Froguel P, Pilkis SJ, Bell GI, Polonsky KS. Compensation in pancreatic ß-cell function in subjects with glucokinase mutations. Diabetes 43:718-723, 1994.

75. Beck-Nielsen H, Nielsen OH, Pedersen O, Bak J, Faber O, Schmitz O. Insulin action and insulin secretion in identical twins with MODY: evidence for defects in both insulin action and insulin secretion. Diabetes 37:730-735, 1988.

76. Mohan V, Sharp PS, Aber VR, Mather HM, Kohner EM. Insulin resistance in maturity-onset diabetes of the young. Diabetes Metab 13:193-197, 1988.

77. Elbein SC, Hoffman M, Qin H, Chiu K, Tanizawa Y, Permutt MA. Molecular screening of the glucokinase gene in familial type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia37:182-187, 1994.

78. Efendic S, Grill V, Luft R, Wajngot A. Low insulin response: a marker of pre-diabetes. Adv Exp Med Biol 246:167-174, 1988.

79. Davies MJ, Metcalfe J, Gray IP, Day JL, Hales CN. Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. Diabetic Med 10:305-312, 1993.

80. Chen K-W, Boyko EJ, Bergstrom RW, Leonetti DL, Newell-Morris L, Wahl PW, Fujimoto WY. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 18:747-753, 1995.

81. Arner P, Pollare T, Lithell H. Different etiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia 34:483-487, 1991.

82. Ferrannini E. Natali A. Bell P. Cavallo-Perin P. Lalic N. Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). [Journal Article] Journal of Clinical Investigation. 100(5):1166-73, 1997

83. Banjeri MA, Lebovitz HE. Insulin action in black Americans with NIDDM. Diates Care 15:1295-1302, 1992.

84. Mbanya J-CN, Pani LN, Mbanya DNS, Sobngwi E, Ngogang J. Reduced insulin secretion in offspring of African type 2 diabetic patients. Diabetes Care 23:1761-1765, 2000.

85. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 6: E214-23, 1979.

86. Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83: 572-584, 1968.

87. Temple R, Clark PMS, Hales CN. Measurement of insulin secretion in type 2 diabetes: problems and pitfalls. Diab Med 9:503-512, 1992.

88. Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, Porte D. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol 46: 222-229, 1976.

89. Vague P, Moulin J-P. The defective glucose sensitivity of the B cell in insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 31: 139-142, 1982.

90. Kosaka K, Kuzuya T, Akanuma Y, Hagura R. Increase in insulin response after treatment of overt maturity onset diabetes mellitus is independent of the mode of treatment. Diabetologia 18: 23-28, 1980.

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

92. Prentki M, Corkey BE. Are the beta 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.

93. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863-870, 1995.

94. Shimabukuro M, Zhou Y-T, Levi M, Unger RH. Fatty acid induced ß cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci 95:2498-2502, 1998.

95. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW. Physiological importance of deficiency in early prandial insulin secretion in non-insulin dependent diabetes. Diabetes 37: 736-744, 1988.

96. Luzi L. Effect of the loss of first phase insulin secretion on glucose production and disposal in man. Am J Physiol 257: E241-E246, 1989.

97. Bonner-Weir S. ß-cell turnover. Its assessment and implications. Diabetes 50:S20-S24, 2001.

98. Haffner SM, Miettinen H, Stern MP. Insulin secretion and resistance in nondiabetic Mexican Americans and non-Hispanic whites with a parental history of diabetes. J Clin Endocrinol Metab 81:1846-1851, 1996.

99. Gautier J-F, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, Polonsky KS, Bogardus C, Pratley RE. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 50:1828-1833, 2001.

100. Vauhkonen N, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 100:86-96, 1997.

101. Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 95:690-698, 1995.

102. Barnett AH, Spilipoulos AJ, Pyke DA, Stubbs WA, Burrin J, Alberti KGMM. Metabolic studies in unaffected co-twins of non-insulin-dependent diabetics. Brit Med J 282:1656-1658, 1981.

103. Watanabe RM. Valle T. Hauser ER. Ghosh S. Eriksson J. Kohtamaki K. Ehnholm C. Tuomilehto J. Collins FS. Bergman RN. Boehnke M. Familiality of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators. Human Heredity. 49(3):159-68, 1999.

104. Mahtani MM. Widen E. Lehto M. Thomas J. McCarthy M. Brayer J. Bryant B. Chan G. Daly M. Forsblom C. Kanninen T. Kirby A. Kruglyak L. Munnelly K. Parkkonen M. Reeve-Daly MP. Weaver A. Brettin T. Duyk G. Lander ES. Groop LC. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nature Genetics. 14:90-4, 1996.

105. 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.

106. Leahy JL, Bonner-Weir S, Weir GC. Abnormal glucose regulation of insulin secretion in models of reduced beta-cell mass. Diabetes 33: 667-73, 1984.

107. 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: 1407-14, 1988.

108. Leahy JL, Cooper HE, Weir GC. Impaired insulin secretion associated with near normoglycemia. Diabetes 36: 459-464, 1987.

109. Robertson RP, Olson IK, Zhang H-J. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes 43:1085-1089, 1994.

110. Newgard CB, McGarry JD. Metabolic coupling factors in pancreatic beta cell signal transduction. Annu Rev Biochem 64:689-719, 1995.

111. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607-614, 1992.

112. Zhou YP, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 93:870-876,1994.

113. Shimabukuro M. Higa M. Zhou YT. Wang MY. Newgard CB. Unger RH. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem. 273:32487-90, 1998.

114. Fehmann HC. Goke R. Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocrine Reviews. 16:390-410, 1995.

115. Drucker DJ. Minireview: the glucagon-like peptides. Endocrinology. 142:521-527, 2001

116. Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W: Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 76:912-917, 1993

117. D'Alessio DA. Vogel R. Prigeon R. Laschansky E. Koerker D. Eng J. Ensinck JW. Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest 97:133-138, 1996.

118. Schirra J. Sturm K. Leicht P. Arnold R. Goke B. Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest 101:1421-30, 1998

119. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 Amide] but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest 91:301-307, 1993.

120. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609-613, 2001.

121. Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:473-478, 1997.

122. Nanauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:741-744, 1993.

123. Xu G. Stoffers DA. Habener JF. Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 48:2270-2276, 1999.

124. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid. A long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48:241-253, 1999.

125. Johnson KH, O'Brien TD, Betysholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. New Engl J Med 321: 513-518, 1989.

126. Ohsawa H, Kanatsuka A, Yamaguchi T, Makino H, Yoshida S. Islet amyloid polypeptide inhibits glucose-stimulated insulin secretion from isolated rat pancreatic islets. Biochem Biophys Res Comm 160: 961-967, 1989.

127. Howard CF. Longitudinal studies on the development of diabetes in individual macaca nigra. Diabetologia 29: 301-306, 1986.

128. Hartter E, Svoboda T, Ludvik B, Schuller M, Lell B, Kuenburg E, Brunnbauer M, Woloszczuk W, Prager R. Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans. Diabetologia 34:52-54, 1991.

129. Eriksson J, Nakazato M, Miyazato M, Shiomi K, Matsukura S, Groop L. Islet amyloid polypeptide: plasma-concentrations in individuals at increased risk of developing type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35:292-293, 1992.

130. Westermark GT, Christmanson L, Terenghi G, Permerth J, Betsoltz C, Larsson J, Polak JM, Westermark P. Islet amyloid polypeptide: demonstration of mRNA in human pancreatic islets by in situ hybridization in islets with and without amyloid deposits. Diabetologia 36:323-328,1993.

131. Ghatei MA, Datta HK, Zaidi M, BrethertonWatt D, Wimalawansa SJ, Maclntyre 1, Bloom SR. Amylin and amylin-amide lack an acute effect on blood glucose and insulin. J. Endocrinol 124: R9-R11, 1990.

132. Bretherton-Watt D, Gilbey SG, Ghatei MA, Beacham J, Bloom SR. Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man. Diabetologia 33: 115-117, 1990.

133. Hoppener JWM, Verbeek JS, de Koning EJP, Oosterwijk C, van Hulst KL, Visser-Vernooy HJ, Hofhuis FMA, van Gaalen S, Berends MJH, Hackeng WHL, Jansz HS, Morris JF, Clark A, Capel PJA, Lipis CJM. Chronic overproduction of islet amyloid polypeptide-amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia. Diabetologia 36:1258-1265, 1993.

134. Gebre-Medhin S, Olofsson C, Mulder H. Islet amyloid polypeptide in the islets of Langerhans: friend or foe? Diabetologia 43:687-695, 2000.

135. Westermark P, Wilander E. The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 15: 417-421, 1978.

136. Gepts W, Lecompte PM. The pancreatic islets in diabetes. Am J Med 70: 105-114, 1981.

137. Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of type I and type 2 diabetes mellitus revisited. Surv Synth Path Res 4: 110-25, 1985.

138. Clark A, Wells CA, Buley ID , Cruickshank JK, Vanhegan RI, Matthews DR, Cooper GJ, Holman RR, Turner RC. Islet amyloid, increased alpha-cells, reduced beta-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 9: 151-159, 1988.

139 Butler AE, Janson J, Bonner-Weir S, Ritzel RA, Butler PC. Decreased ?-cell mass inpatients with type-2 diabetes mellitus. Diabetes 51(suppl 2):A367, 2002.

140. Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger R. Quantitation of endocrine cell content in the pancreas of non-diabetic and diabetic humans. Diabetes 31: 694-700, 1982.

141. Rahier J, Sempoux C, Moulin P, Guiot Y. No decrease of the B cell mass in type 2 diabetic patients. Diabetologia 43(Suppl 1):A65, 2000.

142. Janson J, Butler AE, Bonner-Weir S, Ritzel RA, Sultana C, Butler PC. Failure of compensatory increase in new islet formation in humans with type-2 diabetes mellitus. Diabetes 51(suppl 2): A377, 2002.

143. Hales CN, Barker DJP, Clark PM, Cox J, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64 years. BMJ 303:1019-1022, 1991.

144. Eriksson UJ. Lifelong consequences of metabolic adaptations in utero? Diabetologia 39:1123-1125, 1996.

145. Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35:595-601, 1993.

146. Phillips DIW. Insulin resistance as a programmed response to fetal under nutrition. Diabetologia 39:1119-1122, 1996.

147. Strauss W, Hales C. Plasma insulin in minor abnormalities of glucose tolerance: a 5 year follow-up. Diabetologia 10:237-243, 1974.

148. Hara H, Egusa G Yamakido M, Kawate R. The high prevalence of diabetes mellitus and hyperinsulinemia among the Japanese-Americans living in Hawaii and Los Angeles. Diabetes Res Clin Pract 24:(Suppl. 1):S37-S42, 1994.

149. Berrish TS, Hetherington CS, Alberti KGMM, Walker M. Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance. Diabetologia 38:699-704, 1995.

150. Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH, Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab 73:866-876, 1991.

151. Himsworth HP, Kerr RB. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci 4: 120-152, 1939.

152. Ginsberg H, Kimmerling G, Olefsky JM, Reaven GM. Demonstration of insulin resistance in untreated adult-onset diabetic subjects with fasting hyperglycemia. J Clin Invest 55: 454-461, 1975.

153. Butterfield WJH, Whichelow MJ. Peripheral glucose metabolism in control subjects and diabetic patients during glucose, glucose-insulin, and insulin sensitivity tests. Diabetologia 1:43-53, 1965.

154. Katz H, Homan M, Jensen M, Caumo A, Cobelli C, Rizza R. Assessment of insulin action in NIDDM in the presence of dynamic changes in insulin and glucose concentration. Diabetes 43:289-296, 1994.

155. Wangot A, Roovete A, Vranic M. Luft R, Efendic S. Insulin resistance and decreased insulin response to glucose in lean type II diabetes. Proc Natl Acad Sci USA 79:4432-4437, 1982.

156. Bergman RN. Lilly Lecture. Toward physiological understanding of glucose tolerance- minimal-model approach. Diabetes 38:1512-26, 1989.

157. DeFronzo RA, Deibert D, Hendler R, Felig P. Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J Clin Invest 63: 939-946, 1982.

158. DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature in non-insulin-dependent and insulin-dependent diabetes. Diabetologia 23: 313-319, 1982.

159. Golay A, DeFronzo RA, Ferrannini E, Simonson DC, Thorin D, Acheson K, Thiebaud D, Curchod B, Jequier E, Felber JP. Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin dependent) diabetic patients. Diabetologia 31:585-591, 1988.

160. 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.

161. Vuorinen-Markkola H, Koivisto VA, Yki-Järvinen H: Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type 1 diabetic patients. Diabetes 41:571-580, 1992.

162. Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E. Metabolic basis of obesity and noninsulin-dependent diabetes mellitus. Diabetes Metab Rev 4:727-747, 1988.

163. DeFronzo RA, Sherwin RS, Hendler R, and Felig P. Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest 62:204-213, 1978.

164. Firth R, Bell P, Rizza R. Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism 36:1091 -1095, 1987.

165. Campbell PJ, Mandarino LJ, Gerich JE. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin dependent diabetes mellitus. Metabolism 37: 15-21, 1988.

166. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and noninsulin-dependent subjects. J Clin Invest 74:1238-46, 1984.

167. Del Prato S, Simonson DC, Sheehan P, Cardi F, DeFronzo RA. Studies on the mass effect of glucose in diabetes. Evidence for glucose resistance. Diabetologia 40:687-697, 1997.

168. Nielsen MF, Basu R, Wise S, Caumo A, Cobelli C, Rizza RA. Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes. Evidence for a concentration-dependent defect in uptake. Diabetes 47:1735-1747, 1998.

169. Huang SC, Phelps ME, Hoffman EJ, Sideris K, Selin CJ, Kuhl DE. Non-invasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol 238:E69-E82, 1980.

170. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin dependent diabetes mellitus. Diabetes 35: 990-998, 1986.

171. Best JD, Judzewitsch RG, Pfeiffer MA, Beard JC, Halter JB, Porte D. The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes mellitus. Diabetes 31:333-338, 1982.

172. Tayek JA, Katz J. Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C] glucose study. Am J Physiol 270:E709-E717, 1996.

173. Fery F. Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in Type 2 diabetes: normalization of glucose kinetics by short-term fasting. J Clin Endocrinol Metab 78:536-542, 1994.

174. Jeng C-Y, Sheu WHH, Fuh MM-T, Chen I, Reaven GM. Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 43:1440-1444, 1994.

175. DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J, Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia. Diabetes 32: 35-45, 1983.

176. Cherrington AD, Stevenson RW, Steiner KE, Davis MA, Myers SR, Adkins BA, Abumrad NN, Williams PE. Insulin, glucagon, and glucose as regulators of hepatic glucose uptake and production in vivo. Diabetes Metab Rev 3:307-332, 1987.

177. Bergman RN, Bucolo RJ. Interaction of insulin and glucose in the control of hepatic glucose balance. Am J Physiol 227:1314-1322, 1974.

178. Mevorach M, Giacca A, Aharon Y, Hawkins M, Shamoon H, Rossetti L. Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus. J Clin Invest 102:744-753, 1998.

179. Basu R, Basu A, Nielsen M, Shah P, Rizza RA. Effect of overnight restoration of euglycemia on glucose effectiveness in type 2 diabetes mellitus. J Cin Endocrinol Metab 84:2314-2319, 1999.

180. Waldhausl W, Bratusch-Marrain P, Gasic S, Korn A, Nowotny P. Insulin production rate, hepatic insulin retention, and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinemic type II (non-insulin dependent) diabetes mellitus. Diabetologia 23: 6-15, 1982.

181. Consoli A, Nurjahn N, Capani F, Gerich J. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38: 550-556, 1989.

182. Nurjhan N, Consoli A, Gerich J. Increased lipolysis and its consequences on gluconeogenesis in noninsulin-dependent diabetes mellitus. J Clin Invest 89:169-175, 1992.

183. Magnusson I, Rothman D, Katz L, Shulman R, Shulman G. Increased rate of gluconeogenesis in type II diabetes: a 13C nuclear magnetic resonance study. J Clin Invest 90:1323-1327, 1992.

184. Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, Landau BR, Ferrannini E. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49:1367-1373, 2000.

185. Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Qinones-Galvan A, Sironi AM, Natali A, Ferrannini E. Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Diabetes 50:1807-1812, 2001.

186. Stumvoll M, Perriello G, Nurjhan N, Bucci A, Welle S, Jansson P-A, Dailey G, Bier D, Jenssen T, Gerich J. Glutamine and alanine metabolism in NIDDM. Diabetes 45:863-868, 1996.

187. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36:274-283, 1987.

188. Felig P, Wahren J, Hendler R. Influence of maturity-onset diabetes on splanchnic balance after oral glucose ingestion. Diabetes 27: 121-126, 1978.

189. Foley JE. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care 15:773-784, 1992.

190. Matsuda M, DeFronzo RA, Glass L, Consoli A, Giordano M, Bressler P, DelPrato S. Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism 51:1111-1119, 2002.

191. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. J Clin Endocrinol Metab 81:4059-4067, 1996.

192. Clore JN, Stillman J, Sugerman H. Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes 49:969-974, 2000.

193. O'Brien RM, Granner DK. PEPCK gene as model of inhibitory effects of insulin on gene transcription. Diabetes Care 13:327-339, 1990.

194. Sutherland C, O'Brien RM, Granner DK. New connections in the regulation of PEPCK gene expression by insulin. Phil Trans R Soc Long B 351:191-199, 1996.

195. Cersosimo E, Garlick P, Ferretti J. Regulation of splanchnic and renal substrate supply by insulin in humans. Metabolism 49:676-683, 2000.

196. Moller N. Rizza RA. Ford GC. Nair KS. Assessment of postabsorptive renal glucose metabolism in humans with multiple glucose tracers. Diabetes. 50:747-751, 2001

197. Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 102:619-624, 1998.

198. Bjorntorp P, Berchtold P, Holm J. The glucose uptake of human adipose tissue in obesity. Eur J Clin Invest 1:480-485, 1971.

199. Frayn KN, Coppack SW, Humphreys SM, Whyte PL. Metabolic characteristics of human adipose tissue in vivo. Clin Sci 76:509-516, 1989.

200. Campbell P, Mandarino L, Gerich J. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose intake in non-insulin-dependent diabetes mellitus. Metabolism 37:1 5-22, 1988.

201. Capaldo B, Napoli R, Dimarino L, Picardi A, Riccardi G, Sacca L. Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type 2 diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance. J Clin Endocrinol Metab 67:893-898, 1988.

202. Jackson RA, Perry G, Rogers J, Advoni U, Pilkington TRE. Relationship between the basal glucose concentration, glucose tolerance, and forearm glucose uptake in maturity onset diabetes. Diabetes 22:751-761, 1973.

203. Utriainen T. Takala T. Luotolahti M. Ronnemaa T. Laine H. Ruotsalainen U. Haaparanta M. Nuutila P. Yki-Jarvinen H. Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia. 41:555-559, 1998.

204. Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA. Postprandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 77:1525-1532, 1986.

205. Ferrannini E, Simonson DC, Katz LD, Reichard G Jr, Bevilacqua S, Barrett EJ, Olsson M, DeFronzo RA. The disposal of an oral glucose load in patients with non-insulin dependent diabetes. Metabolism 37:79-85, 1988.

206. Huang SC, Phelps ME, Hoffman EJ, Sideris K, Selin CJ, Kuhl DE. Non-invasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol 238:E69-E82, 1980.

207. Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg G, Arcangeli M, Aoki T, Sorensen J, Berger M, Sonksen P, Gerich J. Skeletal muscle glycolysis oxidation, and storage of an oral glucose load. J Clin Invest 81:1563-1571,1988.

208. Jackson RA, Roshania RD, Hawa MI, Sim BM, DiSilvio L. Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 63:541-549, 1986.

209. Jackson RA, Perry G, Rogers J, Advoni U, Pilkington TRE. Relationship between the basal glucose concentration, glucose tolerance, and forearm glucose uptake in maturity onset diabetes. Diabetes 22:751-761, 1973.

210. Shimazu T. Neuronal regulation of hepatic glucose metabolism in mammals. Diabetes Metab Rev 3:185-206, 1987.

211. McMahon V, Marsh HM, Rizza RA. Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM. Diabetes 38:291-303, 1989.

212. Basu A, Basu R, Shah P, Vella A, Johnson M, Nair KS, Jensen MD, Schwenk WF, Rizza RA. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism. Evidence for a defect in hepatic glucokinase activity. Diabetes 49:272-283, 2000.

213. Ludvik B, Nolan JJ, Roberts A, Baloga J, Joyce M, Bell Jo M, Olefsky JM. Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin-dependent diabetes mellitus. J Clin Invest 100:2354-2361, 1997.

214. Reaven GM, Brand RJ, Ida Chen Y-D, Mathur AK, Goldfine I. Insulin resistance and insulin secretion are determinants of oral glucose tolerance in normal individuals. Diabetes 42:1324-1332, 1993.

215. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. New Engl J Med 322:223-228, 1990.

216. Bonadonna RC, Bonora E. Glucose and free fatty acid metabolism in human obesity: relationships to insulin resistance. Diabetes Rev 5:21-51, 1997.

217. Reaven GM, Chen Y-DI, Donner CC, Fraze E, Hollenbeck CB. How insulin resistant are patients with non-insulin-dependent diabetes mellitus? J Clin Endocrinol Metab 61:32-36, 1985.

218. Lillioja A, Mott DM, Zawadzki JK, Young AA, Abbott WG, Bogardus C. Glucose storage is a major determinant of in vivo 'insulin resistance' in subjects with normal glucose tolerance. J Clin Endocrinol Metab 62: 922-927, 1986.

219. Tripathy D, Carlsson M, Almgren P, Osomaa B, Raskinen M-R, Tuomi T, Groop LC. Insulin secretion and insulin sensitivity in relation to glucose tolerance. Lessons from the Botnia Study. Diabetes 49:975-980, 2000.

220. Zimmet PZ. The pathogenesis and prevention of diabetes in adults. Diabetes Care 18:1050-1064, 1995.

221. Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS: Diabetes trends in the United States, 1990-1998. Diabetes Care 23:1278-1283, 2000.

222. Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI: Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 37:1020-1024, 1988.

223. Thiebaud D, DeFronzo RA, Jacot E, Golay A, Acheson K, Maeder E, Jequier E, Felber JP. Effect of long-chain triglyceride infusion on glucose metabolism in man. Metabolism 31:1128-1136, 1982.

224. Kelley De, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance. A reexamination. Diabetes 49:677-683, 2000.

225. Kashyap S, Belfort R, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K: Chronic elevation in plasma free fatty acids impairs insulin secretion in non-diabetic offspring with a strong family history of T2DM. Diabetes 51(Suppl 2):A12, 2002.

226. Carpentier A. Mittelman SD. Bergman RN. Giacca A. Lewis GF. Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes. 49:399-408, 2000.

227. Reaven GM. The fourth Musketeer - from Alexandre Dumas to Calude Bernard. Diabetologia 38:3-13, 1995.

228. Goodpaster BH, Thaete FL, Kelley BE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 71:885-892, 2000.

229. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E. Insulin resistance in morbid obesity. Reversal with intramyocellular fat depletion. Diabetes 51:144-151, 2002.

230. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H: Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749-758, 2000.

231. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 87:2784-2791, 2002.

232. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1785-789, 1963.

233. Wititsuwannakul D, Kim K. Mechanism of palmityl coenzyme A inhibition or liver glycogen synthase. J Biol Chem 252:7812-7817, 1977.

234. Golay A, Felber JP, Meyer HU, Curchod B, Maeder E, Jequier E. Study on lipid metabolism in obesity diabetes. Metabolism 33:111-116, 1984.

235. Felber JP, Meyer HU, Curchod B, Iselin HU, Rousselle J, Maeder E, Pahud P, Jequier E.. Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia 20: 39-44, 1981.

236. Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Furnsinn C, Moser E, Waldhausl W. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48:358-364, 1999.

237. Bonadonna RC, Groop LC, Zych K, Shank M, and DeFronzo RA. Dose dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans. Am J Physiol 22:736-750, 1990.

238. Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 111:241-248, 1999.

239. Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93:2438-2446, 1994.

240. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1HNMR spectroscopy study. Diabetologia 42:113-116, 1999.

241. Jacobs S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Hearing H-U. Association of increased intramyocellular lipid content with insulin resistance in lean non-diabetic offspring of type 2 diabetic subjects. Diabetes 48:1113-1119, 1999.

242. Kelley De, Goodpaster BH. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care 24:933-941, 2001.

243. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance. Diabetes 49:677-683, 2000.

244. 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 IkB-a. Diabetes 51:2005-2011, 2002.

245. Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, Cooney GJ. Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol 279:E554-E560, 2000.

246. De Fea K, Roth RA. Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939-12947, 1997.

247. Ravichandran LV, Esposito DL, Chen J, Quon MJ. PKC-zeta phosphorylates IRS-1 and impairs its ability to activate P-3-kinase in response to insulin. J Biol Chem 276:3543-3549, 2001.

248. Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G, Olefsky JM. Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. J Clin Endocrinol Metab 87:226-234, 2002.

249. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline SW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1 associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253-259, 1999.

250. Thompson AL, Cooney GJ. Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes 49:1761-1764, 2000.

251. Tippett PS, Neet KE. An allosteric model for the inhibition of glucokinase by long chain acyl coenzyme A. J Biol Chem 257:14846-14852, 1982.

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

253. Baron AD. Hemodynamic actions of insulin. Am J Physiol 267:E187-E202, 1994.

254. Mather K, Laakso M, Edelman S, Hook G, Baron A. Evidence for physiological coupling of insulin-mediated glucose metabolism and limb blood flow. Am J Physiol Endocrinol Metab 279:E1264-E1270, 2000.

255. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 94:1172-1179, 1994.

256. Utriainen T, Nuutila P, Takala T, Vicini P, Ruotsalainen U, Ronnemaa T, Tolvanen T, Raitakari M, Haaparanta M, Kirvela O, Cobelli C, Yki-Jarvinen H. Intact stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus. J Clin Invest 100:777-785, 1997.

257. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 49:1231-1238, 2000.

258. Kreutzenberg SV, Crepaldi C, Marchetto S, Calo L, Tiengo A, Del Prato S, Avogaro A. Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 85:793-798, 2000.

259. Davda RK, Chandler LJ, Guzman NJ. Protein kinase C modulates receptor-independent activation of endothelial nitric oxide synthase. Eur J Pharmacol 266:237-244, 1994.

260. Zeng G, Quon MJ. Insulin stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 98:894-898, 1996.

261. Exton JH, Corbin JG, Park CR. Control of gluconeogenesis in liver. IV. Differential effects of fatty acids and glucagon on ketogenesis and gluconeogenesis in the perfused rat liver. J Biol Chem 244:4095-4102, 1969.

262. Bahl JJ, Matsuda M, DeFronzo RA, Bressler R. In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. Biochem Pharmacol 53:67-74, 1997.

263. Massillon D, Barzailai N, Hawkins M, Prus-Wetheimer D, Rossetti L. Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion. Diabetes 46:153-157, 1997.

264. Chen X, Iqbal N, Boden G. The effect of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest 103:365-372, 1999.

265. Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR, Nowotny P, Waldhausl W, Shulman GI. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49:701-707, 2000.

266. Lewis GF. Vranic M. Harley P. Giacca A. Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes. 46:1111-11119, 1997.

267. Rebrin K. Steil GM. Getty L. Bergman RN. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes. 44:1038-45, 1995.

268. Ferrannini E, Barrett EJ, Bevilacqua S, and DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72:1737-1747, 1983.

269. Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F, Giorico MA, Ferrannini E: Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 36:502-506, 1987.

270. Golay A, Swislocki ALM, Chen Y-DI, Reaven GM: Relationships between plasma free fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non-insulin-dependent diabetic individuals. Metabolism 36:692-696, 1987.

271. Baron AD, Schaeffer L, Shragg P, Kolterman OG: Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36:274-283, 1987.

272. Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care 14:1132-1143, 1991.

273. Arner P. Regional adipocity in man. J Endocrinol 155:191-192, 1997.

274. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414:799-806, 2001.

275. 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.

276. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 106:165-169, 2000.

277. Whitehead JP, Clark SF, Urso B, James DE. Signalling through the insulin receptor. Current Opinion in Cell Biology 12:222-228, 2000.

278. Wilden PA, Kahn CR. The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. Mol Endo 8:558-567, 1994.

279. Haring HU, Mehnert H. Pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: candidates for a signal transmitter defect causing insulin resistance of the skeletal muscle. Diabetologia 36:176-182, 1993.

280. Wajtaszewski JFP, Hansen BF, Kiens B, Richter EA. Insulin signaling in human skeletal muscle. Time course and effect of exercise. Diabetes 46:1775-1781, 1997.

281. Shepherd PR, Kahn BB. Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248-257, 1999.

282. Garvey WT. Insulin action and insulin resistance: diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system. Am J Med 105:331-345, 1998.

283. Chou DK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A, Rosen OM. Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem 262:1842-1847, 1987.

284. Ebina Y, Araki E, Tiara F, Shimada F, Mari M, Craik CS, Siddle K, Pierce SB, Roth RA, Rutter WJ. Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin and antibody-stimulated glucose uptake and receptor kinase activity. Proc Natl Acad Sci USA 84:704-708, 1987.

285. Ellis LE, Clauser E, Morgan ME, Roth RA, Rutter WJ. Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-dexoyglucose. Cell 45:721-732, 1986.

286. White MF, Livingston JN, Backer JM, Lauria V, Duli TJ, Ullrich A, Kahn DR. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell 54:641-649, 1992.

287. Kerouz, N.J., Horsch, D., Pons, S., Kahn, C.R. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest 100:3164-3172, 1997

288. Baumann CA. Ribon V. Kanzaki M. Thurmond DC. Mora S. Shigematsu S. Bickel PE. Pessin JE. Saltiel AR. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature. 407:202-207, 2000.

289. Chiang SH. Baumann CA. Kanzaki M. Thurmond DC. Watson RT. Neudauer CL. Macara IG. Pessin JE. Saltiel AR. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature. 410:944-948, 2001.

290. Backer JM, Myers Jr MG, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M., Hu P, Margolis B., Skoinik EY, Schlessinger J, White, MF. The phosphatidylinositol 3' kinase is activated by association with IRS-1 during insulin stimulation. EMBO J 11:3469-3479, 1992.

291. Sun XJ, Miralpeix M, Myers Jr MG, Glasheen EM, Backer JM, Kahn CR, White MF. The expression and function of IRS-1 in insulin signal transmission. J Biol Chem 267-22662-22672, 1992.

292. Cross DA. Alessi DR. Cohen P. Andjelkovich M. Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 378:785-789, 1995.

293. Brady MJ. Nairn AC. Saltiel AR. The regulation of glycogen synthase by protein phosphatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in insulin action. J Biol Chem. 272:29698-703, 1997.

294. Okada T, Sakuma L, Fukui Y, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. J Biol Chem 269:3568-3573, 1994.

295. Cross D, Alessi D, Vandenheed J, McDowell H, Hundal H, and Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not rapamycin. Biochem J 303:21-26, 1994.

296. Osawa H, Sutherland C, Robey R, Printz R, Granner D. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem 271:16690-16694, 1996.

297. Thomas G. Hall MN. TOR signalling and control of cell growth. Current Opinion in Cell Biology. 9:782-7, 1997.

298. Nave BT. Ouwens M. Withers DJ. Alessi DR. Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 344(Pt 2):427-31, 1999

299. Miron M. Verdu J. Lachance PE. Birnbaum MJ. Lasko PF. Sonenberg N. The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Nature Cell Biology. 3:596-601, 2001

300. Shimomura I. Bashmakov Y. Ikemoto S. Horton JD. Brown MS. Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Nat Acad Sci USA. 96:13656-61, 1999

301. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase and MAP kinase-mediated signaling in human muscle. J Clin Invest 105:311-320, 2000.

302. Hsueh WA, Law RE. Insulin signaling in the arterial wall. Am J Cardiol 84:21J-24J, 1999.

303. Xi X-P, Graf K, Goetze S, HsuehWA, Law RE. Inhibition of MAP kinase blocks insulin-mediated DNA synthesis and transcriptional activation of c-fos by Elk-1 in vascular smooth muscle cells. FEBS Lett 417:283-286, 1997.

304. Boulton TG. Nye SH. Robbins DJ. Ip NY. Radziejewska E. Morgenbesser SD. DePinho RA. Panayotatos N. Cobb MH. Yancopoulos GD. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 65:663-75, 1991.

305. Lazar DF. Wiese RJ. Brady MJ. Mastick CC. Waters SB. Yamauchi K. Pessin JE. Cuatrecasas P. Saltiel AR. Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem. 270:20801-7, 1995.

306. Dorrestijn J, Ouwens DM, Van den Berghe N, Box JL, Maassen JA. Expression of dominant-negative Ras mutant does not affect stimulation of glucose uptake and glycogen synthesis by insulin. Diabetologia 39:558-563, 1996.

307. Dent P, Lavoinne A, Nakielny S, Caudwell FB, Watt P, Cohen F. The molecular mechanisms by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature 348:302-307, 1990.

308. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem 58:453-508, 1989.

309. Newgard CB, Brady MJ, O'Doherty RB, Saltiel AR. Organizing glucose disposal. Emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes 49:1967-1977, 2000.

310. Sheperd PR, Nave BT, Siddle K. Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3L1 adipocytes: evidence for the involvement of phosphoinositide 3 kinase and p70 ribosomal protein S6 kinase. Biochem J 305:25-28, 1995.

311. Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic studies. J Clin Invest 79:240-250, 1987.

312. Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG, Meelheim D, Dohm GL. Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin dependent diabetes. J Clin Invest 1987;79:1330-7.

313. Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, Jenquin M, Silverman JF, Khazanie PG, Sinha MK. Studies on the mechanism of insulin resistance in the liver from humans with non-insulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 78: 249-58, 1986.

314. Molina JM, Ciaraldi TP, Brady D, Olefsky JM. Decreased activation rate of insulin-mediated glucose transport in adipocytes from obese and NIDDM subjects. Diabetes 38:991-995, 1989.

315. Trichitta V, Brunetti A, Chiavetta A, Benzi L, Papa V, Vigneri R. Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients. Diabetes 38:1579-1584, 1989.

316. Comi RJ, Grunberger G, Gorden P. Relationship of insulin binding and insulin-stimulated tyrosine kinase activity is altered in type II diabetes. J Clin Invest 79: 453-462, 1987.

317. Klein HH, Vestergaard H, Kotzke G, Pedersen O. Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM. Diabetes 344:1310-1317, 1995.

318. Obermaier-Kusser B, White MF, Pongratz DE, Su Z, Ermel B, Muhlbacher C, Haring HU. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem 264:9497-9503, 1989.

319. Arner P, Einarsson K, Ewerth S, Livingston J, Studies on the human liver insulin receptor in non-insulin-dependent diabetes mellitus. J Clin Invest 77: 1716-1718, 1986.

320. Kashiwagi A, Verso MA, Andrews J, Vasquez B, Reaven G, Foley JE. In vitro insulin resistance of human adipocytes isolated from subjects with non-insulin-dependent diabetes mellitus. J Clin Invest 72: 1246-1254, 1983.

321. Lonnroth P, Digirolamo M, Krotkiewski M, Smith U. Insulin binding and responsiveness in fat cells from patients with reduced glucose tolerance and type II diabetes. Diabetes 32:748-754, 1983.

322. Olefsky JM, Reaven GM. Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity. Diabetes 26:680-688, 1977.

323. Cocozza S, Procellini A, Riccardi G, Monticelli A, Condorelli G, Ferrara A, Pianese L, Miele C, Capaldo B, Beguinot F, Varrone S. NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene. Diabetes 41:521-526, 1992.

324. Moller DE, Yakota A, Flier JS. Normal insulin receptor cDNA sequence in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetes 38:1496-1500, 1989.

325. Kusari J, Verma US, Buse JB, Henry RR, Olefsky JM. Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT4) in patients with common-type non-insulin-dependent diabetes mellitus. J Clin Invest 88:1323-1330, 1991.

326. Nyomba BL, Ossowski VM, Bogardus C, Mott DM. Insulin-sensitive tyrosine kinase relationship with in vivo insulin action in humans. Am J Physiol 258: E964-E974, 1990.

327. Nolan JJ, Friedenberg G, Henry R, Reichart D, Olefsky JM. Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes and obesity. J Clin Endocrinol Metab 78:471-477, 1994.

328. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Wallberg-Henriksson H, Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284-292, 2000.

329. Bak JF, Moller N, Schmitz O, Saaek A, Pedersen O. In vivo insulin action and muscle glycogen synthase activity in type 2 (non insulin dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35:777-794, 1992.

330. Freidenberg GR, Reichart D, Olefsky JM, Henry RR. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest 82:1398-1406, 1988.

331. Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn L, Mosthaf L, Haring H. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 43:447-453, 1994.

332. Pratipanawatr W, Pratipanawatr T, Cusi K, Berria R, Adams JM, Jenkinson CP, Maezono K, DeFronzo RA, Mandarino LJ. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 50:2572-2578, 2001.

333. Laville M, Auboeuf D, Khalfallah Y, Vega N, Riou JP, Vidal H. Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase in mRNA levels in human muscle. J Clin Invest 98:43-49,1996.

334. Kim Y-B, Nikoulina S, Ciaraldi TP, Henry RR, Kahn BB. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104:733-741, 1999.

335. Andreelli F, Laville M, Ducluzeau P-H, Vega N, Vallier P, Khalfallah Y, Riou J-P, Vidal H. Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. Diabetologia 42:358-364, 1999.

336. Folli F, Saad JA, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest 92:1787-1794, 1993.

337. Imai Y, Philippe N, Accili D, Taylor SI. Expression of variant forms of insulin receptor substrate-1 identified in patients with noninsulin dependent diabetes mellitus. J Clin Endocrinol Metab 82:4201-4207, 1997.

338. Hitman GA, Hawrammi K, McCarthy MI, Viswanathan M, Snehalatha C, Ramachandran A, Tuomilehto J, Tumilehto-Wolf E, Nissenen A, Pedersen O. Insulin receptor substrate-1 gene mutations in NIDDM: implication for the study of polygenic disease. Diabetologia 38:481-486, 1995.

339. Pratley RE. Thompson DB. Prochazka M. Baier L. Mott D. Ravussin E. Sakul H. Ehm MG. Burns DK. Foroud T. Garvey WT. Hanson RL. Knowler WC. Bennett PH. Bogardus C. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest. 101:1757-64, 1998.

340. Jiang ZY. Lin YW. Clemont A. Feener EP. Hein KD. Igarashi M. Yamauchi T. White MF. King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 104:447-57, 1999.

341. 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 269:10734-8, 1994.

342. De Fea K. Roth RA. Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J Biol Chem 272:31400-6, 1997.

343. Dunaif A. Xia J. Book CB. Schenker E. Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 96:801-10, 1995.

344. Kono T, Robinson FW, Blevins TL, Ezaki O. Evidence that translocation of the glucose transport activity is the major mechanism of insulin action on glucose transport fat cells. J Biol Chem 257: 10942-10947, 1982.

345. Bell Gl, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fikomoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care 13:198-200, 1990.

346. Joost H-G, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, Doege H, James DE, Lodish HF, Moley KH, Moley JF, Mueckler M, Rogers S, Schurmann A, Seino S, Thorens B. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab 282:E974-E976, 2002.

347. Colowick SP. The hexokinases. In Boyer PD (ed.) The Enzymes, vol. 9. New York: Academic Press, pp 1-48, 1973.

348. Printz RL, Koch S, Potter LR, O'Doherty RM, Tiesinga JJ, Moritz S, Granner DK. Hexokinase II mRNA and gene structure, regulation by insulin, and evolution. J Biol Chem 268:5209-5219, 1993.

349. Rogers PA, Fisher RA, Harris H. An electrophoretic study of the distribution and properties of human hexokinases. Biochem Genet 13:857-866, 1975.

350. Magnuson MA, Andreone IL, Printz RL, Koch S, Granner DK. The glucokinase gene: structure and regulation by insulin. Proc Natl Acad Sci USA 86: 4838-4842, 1989.

351. Matchinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223-241, 1996.

352. Mandarino LJ, Campbell PJ, Gottesman IS, Gerich JE. Abnormal coupling of insulin receptor binding in non-insulin-dependent diabetes. Am J Physiol 247: E688-E692, 1984.

353. Garvey WT, Huecksteadt TP, Mattaei S, Olefsky JM. Role of glucose transporters in the cellular insulin resistance of type II non-insulin dependent diabetes mellitus. J Clin Invest 81:1528-1536, 1988.

354. Zierath JR, He L, Guma A, Odegoard Wahlstrom E, Klip A, Wallenberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 39:1180-1189, 1996.

355. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Wallenberg-Henriksson H, Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284-282, 2000.

356. Andreasson K, Galuska D, Thorne T, Sonnenfeld T, Wallberg-Henriksson H. Decreased insulin-stimulated 3-O-methylglucose transport in in vitro incubated muscle strips from type II diabetic subjects. Acta Physiol Scan 142:255-260, 1991.

357. Kahn BB, Shulman GI, DeFronzo RA, Cushman SW, Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest 87:561-570, 1991.

358. Pedersen O, Bak J, Andersen P, Lund S, Moller DE, Flier JS, Kahn BB. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 39:865-870, 1990.

359. Eriksson J, Koranyi L, Bourey R, Schalin-Jantti C, Widen E, Mueckler M, Permutt AM, Groop LC. Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle. Diabetologia 35:143-147, 1992.

360. Schalin-Jantti C, Yki-Jarvinen H, Koranyi L, Bourey R, Lindstrom J, Nikula-Ijas P, Franssila-Kallunki A, Groop LC. Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives. Diabetologia 37:401-407, 1994.

361. Garvey WT, Maianu L, Hancock JA, Golichowski AM, Baron A. Gene expression of glut4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes 41:465-475, 1992.

362. Kusari J, Verma US, Buse JB, Henry RR, Olefsky JM. Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT 4) in patients with common type non insulin dependent diabetes mellitus. J Clin Invest 88:1323-1330, 1991.

363. Choi WH, O'Rahilly S, Rees A, Morgan R, Flier JS, Moller DE. Molecular scanning of the insulin-responsive glucose transporter (GLUT 4) gene in patients with non-insulin dependent diabetes mellitus. Diabetes 40:1712-1718, 1991.

364. Sinha M, Raineri-Maldonado C, Buchanan C, Pories W, Carter-Su C, Pilch P, Caro J. Adipose tissue glucose transporters in NIDDM: decreased levels of muscle/fat isoform. Diabetes 40:474-477, 1991.

365. Guma A, Zierath JR, Wallberg-Henriksson H, Klip A. Insulin induces translocation of GLUT-4 glucose transporters in human skeletal muscle. Am J Physiol 268:E613-E622, 1995.

366. Goodyear LJ, Hirschman MF, Napoli R, Calles J, Markuns JF, Ljungqvist O, Horton ES. Glucose ingestion causes GLUT4 translocation in human skeletal muscle. Diabetes 45:1051-1056, 1996.

367. Kelley DE, Mintun MA, Watkins SC, Simoneau J-A, Jadali F, Fredrickson A. The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J Clin Invest 97:2705-2713, 1996.

368. Bonadonna RC, Saccomani MP, Seely L, Zych KS, Ferrannini E, Cobelli C, DeFronzo RA. Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes 42:191-198 1993.

369. Bonadonna RC, Del Prato S, Saccomani MP, Bonora E, Gulli G, Ferrannini E, Bier D, Cobelli C, DeFronzo RA. Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. J Clin Invest 92:486-494, 1993.

370. Bonadonna RC, Del Prato S, Bonora E, Saccomani MP, Gulli G, Natali A, Frascerra S, Pecro N, Ferrannini E, Bier D, Cobelli C, DeFronzo RA. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 45:915-925, 1996.

371. Napoli R, Hirschman MF, Horton FS. Mechanisms of increased skeletal muscle glucose transport activity after an oral glucose load in rats. Diabetes 44:1362-1368, 1995.

372. Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, Shulman GI. Impaired glucose transport as a cause of decreased insulin stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 341:240-246, 1999.

373. Williams KV, Price JC, Kelley DE. Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance. A dose-response assessment using positron emission tomography. Diabetes 50:2069-2079, 2001.

374. Perriott LM, Kono T, Whitesell RR, Knobel SM, Piston DW, Granner DK, Powers AC, May JM. Glucose uptake and metabolism by cultured human skeletal muscle cells: rate-limiting steps. Am J Physiol Endocrinol Metab 281:E72-E80, 2001.

375. Printz RL, Ardehali H, Koch S, Granner DK. Human hexokinase II mRNA and gene structure. Diabetes 44:290-294, 1995.

376. Postic CA, Leturque A, Rencurel F, Printz R, Forest C, Granner D, Girard J. The effects of hyperinsulinemia and hyperglycemia on GLUT4 and hexokinase II mRNA and protein in rat skeletal muscle and adipose tissue. Diabetes 42:922-929, 1993.

377. Jones JP, Dohn GL. Regulation of glucose transporter GLUT-4 and hexokinase II gene transcription by insulin and epinephrine. Am J Physiol (Endocrinol Metab 36):E682-E687, 1997.

378. Mandarino LJ, Printz RL, Cusi KA, Kinchington P, O'Doherty RM, Osawa H, Sewell C, Consoli A, Granner DK, DeFronzo RA. Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Physiol 269:E701-E708, 1995.

379. Kruszynska YT, Mulford MI, Baloga J, Yu JG, Olefsky JM. Regulation of skeletal muscle hexokinase II by insulin in nondiabetic and NIDDM subjects. Diabetes 47:1107-1113, 1998.

380. Vogt C, Ardehali H, Iozzo P, Yki-Jarvinen H, Koval J, Maezono K, Pendergrass M, Printz R, Granner D, DeFronzo R, Mandarino L. Regulation of hexokinase II expression in human skeletal muscle in vivo. Metabolism 49:814-818, 2000.

381. Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R, Pendergrass M, Koval J, Ardehali H, Printz R, Granner D, DeFronzo RA, Mandarino L. Effects of insulin on subcellular localization of hexokinase II in human skeletal muscle in vivo. J Clin Endocrinol Metab 83:230-234, 1998.

382. Pendergrass M, Fazioni E, Saccomani MP, Collins D, Bonadonna R, Gulli G. In vivo glucose transport and phosphorylation in skeletal muscle is impaired in insulin resistant, normal glucose tolerant offspring of two NIDDM parents. Diabetes 44(suppl 1):197A, 1995.

383. Rothman DL, Shulman RG, Shulman GI. 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest 89:1069-1075, 1992.

384. Halseth AE, Bracy DP, Wasserman DH. Overexpression of hexokinse II increases insulin- and exercise-stimulated muscle glucose uptake in vivo. Am J Physiol 276:E70-E77, 1999.

385. Pendergrass M, Koval J, Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R, Ardehali H, Printz R, Granner D, DeFronzo RA, Mandarino L. Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes 47:387-394, 1998.

386. Vestergaard H, Bjorbaek C, Hansen T, Larsen FS, Granner DK, Pedersen O. Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients. J Clin Invest 96:2639-2645, 1995.

387. Ducluzeau P-H, Perretti N, Laville M, Andreelli F, Vega N, Riou J-P, Vidal H. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50:1134-1142, 2001.

388. Lehto M, Huang X, Davis EM, Le Beau MM, Laurila E, Eriksson KF, Bell GI, Groop L. Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity. Diabetologia 38:1466-1474, 1995.

389. Laakso M, Malkki M, Kekalainen P, Kuusito J, Deeb SS. Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. Diabetologia 38:617-622, 1995.

390. Echwald SM, Bjorbaek C, Hansen T, Clausen JO, Vestergaard H, Zierath JR, Printz RL, Granner DK, Pedersen O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 44:347-353, 1995.

391. Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E, Felber JP. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 31: 957-963, 1982.

392. Young A, Bogardus C, Wolfe-Lopez D, Mott D. Muscle glycogen synthesis and disposition of infused glucose in humans with reduced rates of insulin-mediated carbohydrate storage. Diabetes 37:303-307, 1988.

393. Avogaro A, Toffolo G, Miola M, Valerio A, Tiengo A, Cobelli C, Del Prato S. Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals. J Clin Invest 98:108-115, 1996.

394. Del Prato S, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, DeFronzo RA. Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Invest 91:484-494, 1993.

395. Bonadonna RC, Groop L, Kraemer N. Ferrannini E, Del Prato S, DeFronzo RA. Obesity and insulin resistance in man. A dose response study. Metabolism 39: 452-459, 1990.

396. Mandarino LJ, Consoli A, Kelley DE, Reilly JP, Nurjhan N. Fasting hyperglycemia normalizes oxidative and nonoxidative pathways of insulin-stimulated glucose metabolism in non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 71:1544-1551, 1990.

397. Kelley DE, Mandarino LJ. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest 86:1999-2007, 1990.

398. Bogardus C, Lillioja A, Stone K, Mott D. Correlation of muscle glycogen synthase activity and in vivo insulin action in man. J. Clin Invest 1984; 73: 1185-90.

399. Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 92:983-987, 1995.

400. Vaag A, Henriksen JE, Beck-Nielsen. Decreased insulin activation of glycogen synthase in skeletal muscles in young non-obese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. J Clin Invest 89:782-788, 1992.

401. Yki-Jarvinen H, Mott D, Young AA, Stone K, Bogardus C. Regulation of glycogen synthase and phosphorylase activity by glucose and insulin in human skeletal muscle. J Clin Invest 80: 95-100, 1987.

402. Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359(Pt 1):1-16, 2001.

403. Cohen P. The Croonian Lecture 1999. Identification of a protein kinase cascade of major importance in insulin signal transduction. Phil Trans Royal Soc London Series B: Biological Sciences 354:485-495, 1999.

404. Stralfors P, Hiraga A, Cohen P. The protein phosphatases involved in cellular regulation: purification and characterization of the glycogen-bound form of protein phosphatase-1 from rabbit skeletal muscle. Eur J Biochem 149:295-303, 1985.

405. Sutherland C, Campbell DG, Cohen P. Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rsk-mo-2. Eur J Biochem 212:581-588, 1993.

406. Damsbo P, Vaag A, Hother-Nielsen O, Beck-Nielsen H. Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 34:239-245, 1991.

407. Mandarino LJ, Wright KS, Verity LS, Nichols J, Bell JM, Kolterman OG, Beck-Nielsen H. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative glucose metabolism. J Clin Invest 80: 655-63, 1987.

408. Thorburn AW. Gumbiner B. Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest 85: 522-9, 1990.

409. Mandarino LJ, Consoli A, Jain A, Kelley DE. Interaction of carbohdyrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM. Am J Physiol 270:E463-E470, 1996.

410. Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49:263-271, 2000.

411. Henry RR, Ciaraldi TP, Abrams-Carter L, Mudaliar S, Park KS, Nikoulina SE. Glycogen synthase activity is redued in cultured skeletal muscle cells of non-insulin-dependent diabetes mellitus subjects. J Clin Invest 98:1231-1236, 1996.

412. Wells AM, Sutcliffe IC, Johnson AB, Taylor R. Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Evidence for an abnormality specific to glucose metabolism. Diabetes 42:583-589, 1993.

413. Nyomba BL, Freymond D, Raz I, Stone K, Mott DM, Bogardus C. Skeletal muscle glycogen synthase activity in subjects with non-insulin-dependent diabetes mellitus after glyburide therapy. Metabolism 39:1204-1210, 1990.

414. Pratipanawatr T, Cusi K, Ngo P, Pratipanawatr W, Mandarino LJ, DeFronzo RA. Normalization of plasma glucose concentration by insulin therapy improves insulin-stimulated glycogen synthesis in type 2 diabetes. Diabetes 51:462-468, 2002.

415. Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O. Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest 91:2342-2350, 1993.

416. Vestergaard H, Bjocbaek C, Andersen PH, Bak JF, Pedersen O. Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients. Diabetes 40:1740-1745, 1991.

417. Browner MF, Nakano K, Bang AG, Fleffenzk RJ. Human muscle glycogen synthase with DNA sequence: anegatively charged protein with ansymmetric charge distribution. Proc Natl Acad Sci USA 86:1443-1447, 1989.

418. Majer M, Mott DM, Mochizuki H, Rowles JC, Pederson O, Knowler WC, Bogardus C, Prochazka M. Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. Diabetologia 39:314-321, 1996.

419. Orho M, Nikua-Ijas P, Schalin-Jantti C, Permutt MA, Groop LC. Isolatation and characterization of the human muscle glycogen synthase gene. Diabetes 44:1099-1105, 1995.

420. Bjorbaek C, Echward SM, Hubricht P, Vestergaard H, Hansen T, Zierath J, Pedersen O. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin-responsive GLUT4 genes in NIDDM. Diabetes 43:976-983, 1994.

421. Bjorbaek C, Fik TA, Echward SM, Yang P-Y, Vestergaard H, Wang JP, Webb GC, Richmond K, Hansen T, Erikson RL, Miklos GLG, Cohen PTW, Pedersen O. Cloning of human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regiions and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients. Diabetes 44:90-97, 1995.

422. Procharzka M, Michizuki H, Baier LJ, Cohen PTW, Bogardus C. Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its mjaor role in insulin resistance in Pima Indians. Diabetologia 38:461-466, 1995.

423. Schalin-Jantti C, Harkonen M, Groop LC. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 41:598-604, 1992.

424. Falholt K, Jensen I, Lindkaer Jensen S, MortensenHB, Volund A, Heding LG,Norskov Petersen P, Falholt W. Carbohydrate and lipid metabolism of skeletal muscle in type 2 diabetic patients. Diab Med 5:27-31, 1988.

425. Mandarino LJ, Madar Z, Kolterman OG, Bell JM, Olefsky JM. Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic patients. Am J Physiol 251:E489-E496, 1986.

426. Kelley D, Mokan M, Mandarino L. Intracellular defects in glucose metabolism in obese patients with noninsulin-dependent diabetes mellitus. Diabetes 41:698-706, 1992.