Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach

Journal of Clinical Endocrinology and Metabolism

Volumn 89, Issue 2, 2004, Pages 463-478

  Bays, Harold ^b   Mandarino, Lawrence ^a   DeFronzo, Ralph A ^a  

^a UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^b Louisville Metab Atherosclerosis R   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLATION STIMULATING PROTEIN; ADIPONECTIN; ADIPSIN; ANGIOTENSINOGEN; FAT; FATTY ACID; GLUCOSE; INSULIN; INTERLEUKIN 6; LEPTIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PLASMINOGEN ACTIVATOR INHIBITOR 1; RESISTIN; TUMOR NECROSIS FACTOR ALPHA;

ADIPOCYTE; CELL FUNCTION; CLINICAL FEATURE; ENDOCRINE SYSTEM; GLUCONEOGENESIS; GLUCOSE INTOLERANCE; GLUCOSE METABOLISM; GLUCOSE TRANSPORT; HUMAN; HYPERGLYCEMIA; HYPOTHESIS; IMMOBILIZATION; INFLAMMATION; INSULIN RELEASE; INSULIN RESISTANCE; MOLECULAR BIOLOGY; NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS ISLET BETA CELL; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RISK FACTOR; WEIGHT GAIN;

ADIPOCYTES; ANIMALS; DIABETES MELLITUS, TYPE 2; FATTY ACIDS, NONESTERIFIED; HUMANS; LIPID METABOLISM; OBESITY; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANSCRIPTION FACTORS;

EID: 1442352339     PISSN: 0021972X     EISSN: None     Source Type: Journal    
DOI: 10.1210/jc.2003-030723     Document Type: Review

References (334)

1. DeFronzo RA 1988 Lilly Lecture. The triumvirate: β cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667-687
2. DeFronzo RA 1997 Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 4:177-269
3. Kelley DE 1995 Effects of weight loss on glucose homeostasis in NIDDM. Diabetes Rev 3:366-377
4. Schneider SH, Morgado A 1995 Effects of fitness and physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes. Diabetes Rev 3:378-407
5. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA 1992 The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41:1575-1586
6. Tripathy D, Carlsson M, Almgren P, Isomaa B, Taskinen M-R, Tuomi T, Groop LC 2000 Insulin secretion and insulin sensitivity in relation to glucose tolerance. Lessons from the Botnia Study. Diabetes 49:975-980
7. Pratipanawatr W, Pratipanawatr T, Cusi K, Berria R, Adams JM, Jenkinson CP, Maezono K, DeFronzo RA, Mandarino LJ 2001 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
8. Jackson S, Bagstaff SM, Lynn S, Yeaman SJ, Turnbull DM, Walker M 2000 Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant nondiabetic relatives of type 2 diabetic families. Diabetes 49:1169-1177
9. Yalow RS, Berson SA 1960 Immunoassay of endogenous plasma insulin in man. J Clin Invest 39:1157-1175
10. Diamond MP, Jacobs R, Connolly-Howard M, DeFronzo RA 1993 Glucose metabolism during the menstrual cycle: assessment by the euglycemic, hyperinsulinemic clamp technique. J Reprod Med 38:417-421
11. Reaven GM, Hollenbeck CB, Chen YDI 1989 Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 32:52-55
12. Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M 1997 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
13. Weyer C, Bogardus C, Pratley RE 1999 Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance. Diabetes 48:2197-2203
14. Mirrakou A, Kelly D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J 1992 Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22-29
15. Polonsky KS, Sturis J, Bell GI 1996 Non-insulin-dependent diabetes mellitus: a genetically programmed failure of the β cell to compensate for insulin resistance. N Engl J Med 334:777-783
16. Kahn SE 2001 The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 86:4047-4058
17. Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE, and the American Diabetes Association GENNID Study Group 2002 β-Cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 51:2170-2178
18. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D 1984 Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest 74:1238-1246
19. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH 1989 Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet 1:1356-1359
20. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J 1985 Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin-dependent (type II) diabetes mellitus. J Clin Invest 76:149-155
21. Groop LC, Bonadonna RC, Del Prato S, Ratheiser K, Zyck K, DeFronzo RA 1989 Effect of insulin on oxidative and non-oxidative pathways of glucose and FFA metabolism in NIDDM. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205-213
22. DeFronzo RA, Ferrannini E, Simonson DC 1989 Fasting hyperglycemia in non-insulin dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38:387-395
23. Ferrannini E, Simonson DC, Katz LD, Reichard G, Bevilacqua S, Barrett EJ, Olsson M, DeFronzo RA 1988 The disposal of an oral glucose load in patients with non-insulin dependent diabetes. Metabolism 37:79-85
24. 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322:223-228
25. 13C nuclear magnetic resonance study. J Clin Invest 90:1323-1327
26. Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS 2000 Diabetes trends in the United States, 1990-1998. Diabetes Care 23:1278-1283
27. Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI 1988 Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 37:1020-1024
28. Boden G, Shulman GI 2002 Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β cell dysfunction. Eur J Clin Invest 32(Suppl 3):14-23
29. Reaven GM 1995 The fourth musketeer - from Alexandre Dumas to Claude Bernard. Diabetologia 38:3-13
30. Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E 1988 Metabolic basis of obesity and noninsulin-dependent diabetes mellitus. Diabetes Metab Rev 4:727-747
31. Boden G 1997 Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46:3-10
32. McGarry JD 2002 Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51:7-18
33. Kashyap S, Belfort R, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K 2002 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
34. Goodpaster BH, Thaete FL, Kelley BE 2000 Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 71:885-892
35. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E 2002 Insulin resistance in morbid obesity. Reversal with intramyocellular fat depletion. Diabetes 51:144-151
36. Seppala-Lindroos A, Vehkavaara S, Hakkinen A-M, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H 2002 Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023-3028
37. Miyazaki Y, Hardies LJ, Wajcberg E, Glass L, Triplitt C, Bajaj M, Cersosimo E, Mandarion LJ, DeFronzo RA 2002 Effect of pioglitazone on liver fat content, abdominal fat distribution, and insulin sensitivity in patients with type 2 diabetes mellitus. Diabetes 51(Suppl 2):A69
38. Prentki M, Corkey BE 1996 Are the B-cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45:273-283
39. Unger RH 1996 Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 45:273-283
40. Shimabukuro M, Zhou YT, Levi M, Unger RH 1998 Fatty acid induced β cell apoptosis. Free Natl Acad Sci USA 95:2498-2502
41. Matschinsky FM 1996 Banting Lecture 1995: a lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223-241
42. Newgard CB, McGarry JD 1995 Metabolic coupling factors in pancreatic β cell signal transduction. Annu Rev Biochem 64:689-719
43. McGarry JD, Dobbins RL 1999 Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128-138
44. Warnotte C, Gilon P, Nenquin M, Henquin JC 1994 Mechanisms of the stimulation of insulin release by saturated fatty acids: a study of palmitate effects of mouse B-cells. Diabetes 43:703-711
45. Stein DT, Esser V, Stevenson BE, Lane KE, Whiteside JH, Daniels MB, Chen S, McGarry JD 1996 Essentially of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest 97:2728-2735
46. Zhou UP, Grill VE 1994 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
47. Sako Y, Grill VE 1990 A 48-h lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and β cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127:1580-1589
48. Mason TM, Goh T, Tchipashvili V, Sandhu H, Gupta N, Lewis GF, Giacca A 1999 Prolonged elevation of plasma free fatty acids desensitizes the insulin secretory response to glucose in vivo in rats. Diabetes 48:524-530
49. Zhou YP, Grill V 1995 Long term exposure to fatty acids and ketones inhibits b-cell function in human pancreatic islets of Langerhans. J Clin Endocrinol Metab 80:1584-1590
50. Unger RH 1997 How obesity causes diabetes in Zucker diabetic fatty rats. Trends Endocrinol Metab 7:276-282
51. Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P 2002 Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets. Evidence that β cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51:1437-1442
52. Carpentier A, Mittelman SD, Lamarche B, Bergman RN, Giacca A, Lewis GF 1999 Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am J Physiol 276:E1055-E1066
53. Paolisso G, Gambardella A, Amato L, Tortoriello R, D'Amore A, Varricchio M, D'Onofrio F 1995 Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia 38:1295-1299
54. Carpentier A, Mittelman SD, Bergman RN, Giacca A, Lewis GF 2000 Prolonged elevation of plasma free fatty acids impair pancreatic B-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 49:399-408
55. 2 gene. Diabetes 50:1143-1148
56. Paolisso G, Tagliamonte MR, Rizzo MR, Gualdiero P, Saccomanno F, Gambardella A, Giugliano D, D'Onofrio F, Howard BV 1998 Lowering fatty acids potentiates acute insulin response in first degree relatives of people with type II diabetes. Diabetologia 41:1127-1132
57. Qvigstad E, Mostad IL, Bjerve KS, Grill VE 2003 Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects. Am J Physiol 284:E129-E137
58. Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, Porte Jr D, Schwartz MW 1999 Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. Am J Physiol 277:E659-E667
59. Bergman RN, Ader M 2000 Free fatty acids and pathogenesis of type 2 diabetes mellitus. TEM 11:351-356
60. Charles MA, Eschwege E, Thibult N, Claude JR, Warnet JM, Rosselin GE, Girard J, Balkau B 1997 The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 40:1101-1106
61. Knowler WC, Pettitt DJ, Saad MF, Bennett PH 1990 Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diab Metab Rev 6:1-27
62. Unger RH 2002 Lipotoxic diseases. Annu Rev Med 53:319-336
63. Randle PJ, Garland PB, Hales CN, Newsholme EA 1963 The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785-789.
64. Wititsuwannakul D, Kim K 1977 Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. J Biol Chem 252:7812-7817
65. Felber JP, Meyer HU, Curchod B, Iselin HU, Rousselle J, Maeder E, Pahud P, Jequier E 1981 Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia 20:39-44
66. Golay A, Felber JP, Meyer HU, Curchod B, Maeder E, Jequier E 1984 Study on lipid metabolism in obesity diabetes. Metabolism 33:111-116
67. Thiebaud D, DeFronzo RA, Jacot E, Golay A, Acheson K, Maeder E, Jequier E, Felber JP 1982 Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism 21:1128-1136
68. Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Furnsinn C, Moser E, Waldhausl W 1999 Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48:358-364
69. Boden G 1999 Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 111:241-248
70. Boden G, Chen X, Ruiz J, White JV, Rossetti L 1994 Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93:2438-2446
71. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH 1997 Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46:983-988
72. 1HNMR spectroscopy study. Diabetologia 42:113-116
73. Jacobs S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Hearing H-U 1999 Association of increased intramyocellular lipid content with insulin resistance in lean non-diabetic offspring of type 2 diabetic subjects. Diabetes 48:1113-1119
74. Martin WH 1996 Effects of acute and chronic exercise on fat metabolism. Exercise Sport Sci Rev 24:203-231
75. Abernethy PJ, Thaver R, Taylor AW 1990 Acute and chronic responses of skeletal muscle to endurance and sprint exercise. A review. Sports Med 10:365-389
76. Kelley DE, He J, Menshikova EV, Ritov VB 2002 Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944-2950
77. Kelley DE, Mandarino LJ 2000 Fuel selection in human skeletal muscle in insulin resistance. Diabetes 49:677-683
78. Itani SI, Ruderman NB, Schmieder F, Boden G 2002 Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes 51:2005-2011
79. Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, Cooney GJ 2000 Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol 279:E554-E560
80. De Fea K, Roth RA 1997 Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939-12947
81. Ravichandran LV, Esposito DL, Chen J, Quon MJ 2001 PKC-ζ phosphorylates 1RS-1 and impairs its ability to activate P-3-kinase in response to insulin. J Biol Chem 276:3543-3549
82. Faergeman NJ, Knudsen J 1997 Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signaling. Biochem J 323:1-12
83. Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G, Olefsky JM 2002 Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. J Clin Endocrinol Metab 87:226-234
84. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline SW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI 1999 Effects of free fatty acids on glucose transport and IRS-1 associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253-259
85. Kashyap S, Belfort R, Finlayson J, Barrentine A, Mandarino L, DeFronzo RA, Cusi K 2002 A chronic physiologic increase in FFA in healthy subjects causes insulin signaling defects similar to those of insulin-resistant non-diabetic subjects with a strong family history of T2DM. Diabetes 51(Suppl 2):A24
86. Thompson AL, Cooney GJ 2000 Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes 49:1761-1764
87. Tippett PS, Neet KE 1982 An allosteric model for the inhibition of glucokinase by long chain acyl coenzyme A. J Biol Chem 257:14846-14852
88. 12 skeletal muscle cells pretreated with palmitate. J Biol Chem 274:24202-24210
89. Chavez JA, Knotts TA, Wang LP, Lit G, Dobrowsky RT, Florant GL, Summers SA 2003 A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 278:10297-10303
90. DeFronzo RA, Ferrannini E, Hendler R, Wahren J, Felig P 1978 Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 75:5173-5177
91. DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J 1983 Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia. Diabetes 32:35-45
92. Cherrington AD 1999 Banting Lecture. Control of glucose uptake and release by the liver in vivo. Diabetes 48:1198-1214
93. Exton JH, Corbin JG, Park CR 1969 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
94. Bahl JJ, Matsuda M, DeFronzo RA, Bressler R 1997 In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. Biochem Pharmacol 53:67-74
95. Williamson JR, Kreisberg RA, and Felts PW 1966 Mechanisms for the stimulation of gluconeogenesis by fatty acids in perfused rat liver. Proc Natl Acad Sci USA 56:247-254
96. Massillon D, Barzailai N, Hawkins M, Prus-Wetheimer D, Rossetti L 1997 Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion. Diabetes 46:153-157
97. Chen X, Iqbal N, Boden G 1999 The effect of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest 103:365-372
98. Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR, Nowotny P, Waldhausl W, Shulman GI 2000 Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49:701-707
99. Puhakainen I, Yki-Jarvinen H 1993 Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose production in NIDDM. Diabetes 42:1694-1699
100. Mittelman SD, Bergman RN 2000 Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. Am J Physiol 279:E630-E637
101. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA 1983 Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72:1737-1747
102. Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F, Giorico MA, Ferrannini E 1987 Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 36:502-506
103. Golay A, Swislocki ALM, Chen Y-DI, Reaven GM 1987 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
104. Boden G, Chen X, Capulong E, Mozzoli M 2001 Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes 50:810-816
105. Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, DeFronzo RA 1991 The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 72:96-107
106. Seppala-Lindroos A, Vehkavaara S, Hakkinen A-M, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H 2002 Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023-3028
107. Lam TKT, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A 2003 Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol 284:E863-E873
108. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI 2001 Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98:7522-7527
109. Baron AD, Schaeffer L, Shragg P, Kolterman OG 1987 Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36:274-283
110. Matsuda M, DeFronzo RA, Consoli A, Bressler P, Del Prato S 2002 Dose response curve relating plasma glucagon to hepatic glucose production and glucose disposal in type 2 diabetes mellitus. Metabolism 51:1111-1119
111. Waldhausl W, Bratusch-Marrain P, Gasic S, Korn A, Nowotny P 1982 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
112. Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA 2001 The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol 280:E827-E847
113. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE 2001 The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947-953
114. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L 2001 Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108:1875-1881
115. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941-946
116. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930-1935
117. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y 2001 Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126-1133
118. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79-83
119. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595-1599
120. Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, Miyazaki Y, DeFronzo RA 2003 Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes mellitus. Diabetes 52:1364-1370
121. Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, Pratipanawatr, T, Miyazaki Y, DeFronzo RA 2004 Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 89:200-206
122. Krakoff J, Funahashi T, Stehouwer CDA, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC, Lindsay RS 2003 Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care 26:1745-1751
123. Yang W-S, Jeng C-Y, Wu T-J, Tanaka S, Funahashi T, Matsuzawa Y, Wang J-P, Chen C-L, Tai T-Y, Chuang L-M 2002 Synthetic peroxisome proliferators- activated receptor-γ agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25:376-380
124. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746-26749
125. Hunter SJ, Garvey WT 1998 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
126. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307-312
127. Lazar MA 2002 Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 13:18-23
128. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S 2001 Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans. Diabetes 50:2199-2202
129. Wang H, Chu WS, Hemphill C, Elbein SC 2002 Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J Clin Endocrinol Metab 87:2520-2524
130. McTernan PG, McTernan CL, Chetty R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S 2002 Increased resistin gene and protein expression in human abdominal adipose tissue. J Clin Endocrinol Metab 87:2407
131. Vidal-Puig A, O'Rahilly S 2001 Resistin: a new link between obesity and insulin resistance? Clin Endocrinol (Oxf) 55:437-438
132. McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S 2002 Resistin, central obesity, and type 2 diabetes. Lancet 359:46-47
133. McTernan PG, Fisher FM, McTernan CL, Chetty R, Valsamakis G, Harte AL, Lauer MN, Smith SA, Barnett AH, Kumar S 2002 Depot-specific expression of resistin in human adipose tissue and regulation of resistin secretion by insulin and rosiglitazone in human subcutaneous adipocytes in vitro. Diabetologia 45(Suppl 2):A66-A67
134. Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G 2003 A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52:1611-1618
135. Rajala MW, Obici S, Scherer PE, Rossetti L 2003 Adipose-derived resistin and gut-derived resistin-like molecule-β selectively impair insulin action on glucose production. J Clin Invest 111:225-230
136. Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu GD, Lazar MA 2001 A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA 98:502-506
137. Haugen F, Jorgenson A, Drevon CA, Trayhurn P 2001 Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett 507:105-108
138. Hartman HB, Xu X, Tyler KX, Dalal CK, Lazar MA 2002 Mechanisms regulating adipocyte expression of resistin. J Biol Chem 277:19754-19761
139. Shojima N, Sakoda FL, Ogihara T, Fujishiro M, Katagiri H, Anai M, Onishi Y, Ono H, Inukai K, Abe M, Fukushima Y, Kikuchi M, Oka Y, Asano T 2002 Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes 51:1737-1744
140. Saye JA, Cassis LA, Sturgill TW, Lynch KR, Peach MJ 1989 Angiotensinogen gene expression in 3T3-L1 cells. Am J Physiol 256:C448-C451
141. Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM 1998 Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 83:3925-3929
142. Hainault I, Nebout G, Turban S, Ardouin B, Ferre P, Quignard-Boulange A 2002 Adipose tissue-specific increase in angiotensinogen expression and secretion in the obese (fa/fa) Zucker rat. Am J Physiol 282:E59-E66
143. Hsueh WA, Law RE 1999 Insulin signaling in the arterial wall. Am J Cardiol 84:21J-24J
144. Goetze S, Xi XP, Graf K, Fleck E, Hsueh WA, Law RE 1999 Troglitazone inhibits angiotensin II-induced extracellular signal-regulated kinase 1/2 nuclear translocation and activation in vascular smooth muscle cells. FEBS Lett 452:277-282
145. Yudkin JS 1999 Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? Diabetes Care 22(Suppl 3):C25-C30
146. Juhan-Vague I, Alessi MC 1997 PAI-I, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 78:656-660
147. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I 1997 Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 46:860-867
148. Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I 2000 Plasminogen activator inhibitor 1, transforming growth factor-β1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374-1380
149. Birgel M, Gottschling-Zeller H, Rohrig K, Hauner H 2000 Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes. Arterioscler Thromb Vasc Biol 20:1682-1687
150. McCall JL, Tuckey JA, Parry BR 1992 Serum tumour necrosis factor α and insulin resistance in gastrointestinal cancer. Br J Surg 79:1361-1363
151. Van der Poll T, Romijn JA, Endert E, Borm JJ, Buller HR, Sauerwein HP 1991 Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 261:E457-E465
152. Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Amer P 2002 Mapping of early signaling events in tumor necrosis factor-α-mediated lipolysis in human fat cells. J Biol Chem 277:1085-1091
153. Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259:87-91
154. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A 1993 Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 268:26055-26058
155. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665-668
156. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 95:2409-2415
157. Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA 2003 Tumor necrosis factor α and insulin resistance in obese type 2 diabetic patients. Int J Obesity 27:88-94
158. Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H 1998 Relation between plasma tumor necrosis factor-α and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 18:1199-1202
159. Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG 1999 Circulating tumor necrosis factor-α concentrations in a native Canadian population with high rates of type 2 diabetes mellitus. J Clin Endocrinol Metab 84:272-278
160. Spiegelman BM 1998 PPAR-γ: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507-514
161. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW 1997 Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 82:4196-200
162. Van Snick J 1990 Interleukin 6: an over-view. Annu Rev Immunol 8:253-278
163. Sandler S, Bendtzen K, Eizirik DL, Welsh M 1990 Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. Endocrinology 126:1288-1294
164. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM 2001 C-Reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327-334
165. Pickup JC, Chusney GD, Thomas SM, Burt D 2000 Plasma interleukin-6, tumour necrosis factor and blood cytokine production in type 2 diabetes. Life Sci 67:291-300
166. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-432
167. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543-546
168. Zierath JR, Frevert EU, Ryder JW, Berggren PO, Kahn BB 1998 Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes. Diabetes 47:1-4
169. Montague CT, Prins JB, Sanders L, Zhang J, Sewter CP, Digby J, Byrne CD, O'Rahilly S 1998 Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes 47:1384-1391
170. Ceddia RB, William Jr WN, Curi R 1999 Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. Int J Obesity Related Metab Disord 23:75-82
171. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ 1997 Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374-377
172. Muoio DM, Dohm GL 2002 Peripheral metabolic actions of leptin. Best Practice Res Clin Endocrinol Metab 16:653-666
173. Ranganathan S, Ciaraldi TP, Henry RR, Mudaliar S, Kern PA 1998 Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells. Endocrinology 139:2509-2513
174. Mantzoros CS, Flier JS 2000 Editorial: leptin as a therapeutic agent-trials and tribulations. J Clin Endocrinol Metab 85:4000-4002
175. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398-401
176. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879-884
177. Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, Nicola NA, Alexander WS, Hilton DJ 1996 Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci USA 93:14564-14568
178. + mouse. Discrepancies between in vitro and in vivo immunological assays. J Clin Invest 61:243-250
179. Chandra RK 1980 Cell-mediated immunity in genetically obese C57BL/6J ob/ob mice. Am J Clin Nutr 33:13-16
180. Pickup JC, Crook MA 1998 Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41:1241-1248
181. Choy LN, Rosen BS, Spiegelman BM 1992 Adipsin and an endogenous pathway of complement from adipose cells. J Biol Chem 267:12736-12741
182. Cianflone K, Maslowska M, Sniderman AD 1999 Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Semin Cell Dev Biol 10:31-41
183. Maslowska M, Vu H, Phelis S, Sniderman AD, Rhode BM, Blank D, Cianflone K 1999 Plasma acylation stimulating protein, adipsin and lipids in non-obese and obese populations. Eur J Clin Invest 29:679-686
184. Festa A, D'Agostino Jr R, Howard G, Mykkanen L, Tracy RP, Haffner SM 2000 Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102:42-47
185. Blake GJ, Ridker PM 2001 High sensitivity C-reactive protein for predicting cardiovascular disease: an inflammatory hypothesis. Eur Heart J 22:349-352
186. DeFronzo RA, Ferrannini E 1991 Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care Rev 14:173-194
187. Reaven GM 1988 Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595-1607
188. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM 1998 Leptin regulates proinflammatory immune responses. FASEB J 12:57-65
189. Luster AD 1998 Chemokines: chemotactic cytokines that mediate inflammation. N Engl J Med 338:436-445
190. Gomez-Ambrosi J, Fruhbeck G 2001 Do resistin and resistin-like molecules also link obesity to inflammatory diseases? Ann Intern Med 135:306-307
191. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y 2000 Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723-1732
192. Collins T, Cybulsky MI 2001 NF-κB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 107:255-264
193. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI 2001 Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108:437-446
194. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE 2001 Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Iκκβ. Science 293:1673-1677
195. Stevenson MA, Zhao MJ, Asea A, Coleman CN, Calderwood SK 1999 Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-κB-responsive genes. J Immunol 163:5608-5616
196. Osman A, Pendergrass M, Cusi K, Christ CY, Adams JM, DeFronzo RA, Mandarino LJ, RKS2 (p90 rks) activity is increased in skeletal muscle in type 2 diabetes mellitus. Biochem Biophys Acta, in press
197. Mora S, Pessin JE 2002 An adipocentric view of signaling and intracellular trafficking. Diabetes Metab Res Rev 18:345-356
198. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD 1998 Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care 21:518-524
199. Pi-Sunyer F 1996 Weight and non-insulin-dependent diabetes mellitus. Am J Clin Nutr 63(Suppl 3):426S-429S
200. Knowler WC, Pettitt DJ, Savage PJ, Bennett PH 1981 Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 113:144-156
201. Carey V, Walters E, Colditz G, Solomon C, Willett W, Rosner B, Speizer F, Manson J 1997 Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses' Health Study. Am J Epidemiol 45:614-619
202. Wannamethee SG, Shaper AG 1999 Weight change and duration of overweight and obesity in the incidence of type 2 diabetes. Diabetes Care 22:1266-1272
203. Perry IJ, Wannamethee SG, Shaper AG, Alberti KG 1999 Serum true insulin concentration and the risk of clinical non-insulin dependent diabetes during long-term follow-up. Int J Epidemiol 28:735-741
204. Burke JP, Williams K, Haffner SM, Villalpando CG, Stern MP 2001 Elevated incidence of type 2 diabetes in San Antonio, Texas, compared with that of Mexico City, Mexico. Diabetes Care 24:1573-158
205. DeFronzo RA, Sherwin RS, Hendler R, Felig P 1978 Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest 62:204-213
206. Kolterman OG, Insel J, Saekow M, Olfesky JM 1980 Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest 65:1272-1284
207. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G, for the European Group for the Study of Insulin Resistance (EGIR) 1997 Insulin resistance and hypersecretion in obesity. J Clin Invest 100:1166-1173
208. Bjorntorp P 1991 Metabolic implications of body fat distribution. Diabetes Care 14:1132-1143
209. Chan JM, Rimm EB, Colditz GA, Stapfer MJ, Willett WC 1994 Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17:961-969
210. Rabinowitz D, Zierler KL 1962 Forearm metabolism in obesity and its response to intraarterial insulin. Characterization of insulin resistance and evidence for adaptive hyperinsulinism. J Clin Invest 41:2173-2181
211. Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, Landau BR, Ferrannini E 2000 Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49:1367-1373
212. Kashiwagi A, Verso MA, Andrews J, Vasquez B, Reavan GM, Foley JE 1983 In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus. J Clin Invest 72:1246-1254
213. Groop L, Bonadonna R, Simonson DC, Petrides A, Hasan S, DeFronzo RA 1992 Effect of insulin on oxidative and non-oxidative pathways of glucose and free fatty acid metabolism in human obesity. Am J Physiol 263:E79-E84
214. Clausen JO, Borch-Johnsen K, Ibsen H, Bergman RN, Hougaard P, Winther K, Pedersen O 1996 Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors. J Clin Invest 98:1195-1209
215. Kissebah AH, Peiris AN 1989 Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5:83-109
216. Despres JP, Lemieux S, Lamarche B, Prud'homme D, Moorjani S, Brun LD, Gagne C, Lupien PJ 1995 The insulin resistance-dyslipidemic syndrome: contribution of visceral obesity and therapeutic implications. Int J Obes Related Metab Disord 19(Suppl 1):S76-S86
217. Banerji MA, Chaiken RL, Gordon D, Krai JG, Lebovitz HE 1995 Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive? Diabetes 44:141-146
218. Bonora E, Del Prato S, Bonadonna RC, Gulli G, Solini A, Shank ML, Ghiatas AA, Lancaster JL, Kilcoyne RF, Alyassin AM, DeFronzo RA 1992 Total body fat content and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women. Diabetes 41:1151-1159
219. Albu JB, Kovera AJ, Johnson JA 2000 Fat distribution and health in obesity. Ann NY Acad Sci 904:491-501
220. Arner P 1997 Regional adipocity in man. J Endocrinol 155:191-192
221. Zierath JR, Livingston JN, Thorne A, Bolinder J, Reynisdottir S, Lonnqvist F, Arner P 1998 Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signaling through the insulin receptor substrate-1-pathway. Diabetologia 41:1343-1354
222. Bjorntorp P 1990 "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 10:493-496
223. Arner P 2001 Regional differences in protein production by human adipose tissue. Biochem Soc Trans 29:72-75
224. Motoshima H, Wu X, Sinha MK, Hardy VE, Rosato EL, Barbot DJ, Rosato FE, Goldstein BJ 2002 Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 87:5662-5667
225. Sewter CP, Blows F, Vidal-Puig A, O'Rahilly S 2002 Regional differences in the response of human pre-adipocytes to PPARγ and RXRα agonists. Diabetes 51:7218-723
226. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH 1997 Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46:983-988
227. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT 1999 Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 276:E977-E989
228. 13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 48:1600-1606
229. Krssak M, Falk Petersen K, Dresner A, DiPletro L, Vogel SM, Rothman DL, Roden M, Shulman GI 1999 Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113-116
230. Stein DT, Szczepanik L, Dobbins R, McGarry JD 1999 Increasing intramyocellular triglyceride stores are associated with impaired glucose tolerance and NIDDM. Diabetes 48(Suppl 1):A287
231. Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE 1997 Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 46:1579-1585
232. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL 1999 Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 48:839-847
233. Kelley DE, Goodpaster B, Wing RR, Simoneau JA 1999 Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol 277:E1130-E1141
234. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E 2002 Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 51:144-151
235. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H 2000 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
236. Robbins DC, Horton ES, Tulp O, Sims EA 1982 Familial partial lipodystrophy: complications of obesity in the non-obese? Metabolism 31:445-452
237. Arioglu E, Duncan-Morin D, Sebring N, Rother KI, Gottlieb N, Lieberman J, Herion D, Kleiner DE, Reynolds J, Premkumar A, Sumner AE, Hoofnagle J, Reitman ML, Taylor SI 2000 Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 133:263-274
238. Tansey JT, Sztalryd C, Gruia-Gray J, Roush DL, Zee JV, Gavrilova O, Reitman ML, Deng CX, Li C, Kimmel AR, Londos C 2001 Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci USA 98:6494-6499
239. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI 2002 Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345-1350
240. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578
241. Reitman ML, Mason MM, Moitra J, Gavrilova O, Marcus-Samuels B, Eckhaus M, Vinson C 1999 Transgenic mice lacking white fat: models for understanding human lipoatrophic diabetes. Ann NY Acad Sci 892:289-296
242. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL 1999 Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73-76
243. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI 2000 Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275:8456-8460
244. Reue K, Xu P, Wang XP, Slavin BG 2000 Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J Lipid Res 41:1067-1076
245. Peterfy M, Phan J, Xu P, Reue K 2001 Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 27:121-124
246. Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML 2000 Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 105:271-278
247. Weber RV, Buckley MC, Fried SK, Kral JG 2000 Subcutaneous lipectomy causes a metabolic syndrome in hamsters. Am J Physiol 279:R936-R943
248. Danforth Jr E 2000 Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet 26:13
249. Bjorntorp P, Berchtold P, Tibblin G 1971 Insulin secretion in relation to adipose tissue in men. Diabetes 20:65-70
250. Schneider BS, Faust IM, Hemmes R, Hirsch J 1981 Effects of altered adipose tissue morphology on plasma insulin levels in the rat. Am J Physiol 240:E358-E362
251. Salans LB, Knittle JL, Hirsch J 1968 Role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity. J Clin Invest 47:153-165
252. Weyer C, Wolford JK, Hanson RL, Foley JE, Tataranni PA, Bogardus C, Pratley RE 2001 Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21-q23 and is associated with a common polymorphism in LMNA in Pima Indians. Mol Genet Metab 72:231-238
253. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE 2000 Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498-1506
254. Kahsyap S, Suraamornkul S, Bajaj M, Belfort R, Berria R, Mandarino L, DeFronzo R, Cusi K 2003 Effect of sustained reduction in plasma FFA concentration on insulin secretion in non-diabetic subjects with a strong family history of T2DM. Diabetes 52(Suppl 1):A336
255. McGarry JD 1992 What if Minkowski had been ageusic? An alternative angle on diabetes. Sicence 258:766-770
256. Mudaliar S, Henry RR 2001 New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers. Annu Rev Med 52:239-257
257. Fonseca VA, Valiquett TR, Huang SM, Ghazzi MN, Whitcomb RW 1998 Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group. J Clin Endocrinol Metab 83:3169-3176
258. Saltiel AR, Olefsky JM 1996 Thiazolidinediiones in the treatment of insulin resistance in type 2 diabetes. Diabetes 45:1661-1669
259. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL 1996 Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 23:1605-1611
260. Wolffenbuttel BH, Sels JP, Huijberts MS 2001 Rosiglitazone. Expert Opin Pharmacother 2:467-478
261. Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferranini E, Cusi K, Mandarino L, DeFronzo RA 2001 Improved glycemic control and enhanced insulin sensitivity in liver and muscle in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 24:710-719
262. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA 2002 Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 87:2784-2791
263. Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mandarino L, DeFronzo RA 2001 Effect of rosiglitazone on glucose and free fatty acid metabolism in type 2 diabetic patients. Diabetologia 44:2210-2219
264. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI 1998 Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867-872
265. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI 1998 Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:176-185
266. Olfesky JM 2000 Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists. J Clin Invest 106:467-427
267. Kim YB, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar S, Henry RR, Kahn BB 2002 Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p 110b protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes 51:443-448
268. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF 2002 The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797-802
269. Miyazaki Y, Matsuda M, DeFronzo RA 2002 Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes mellitus. Diabetes Care 25:517-523
270. Berkowitz K, Peters R, Kjos SL, Goico J, Marroquin A, Dunn ME, Xiang A, Azen S, Buchanan TA 1996 Effect of troglitazone on insulin sensitivity and pancreatic β-cell function in women at high risk for NIDDM. Diabetes 45:1572-1579
271. Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, Buckingham RE 2001 β-Cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 50:1021-1029
272. Higa M, Zhou YT, Ravazzola M, Baetens D, Orci L, Unger RH 1999 Troglitazone prevents mitochondrial alterations, β cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci USA 96:11513-11518
273. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T 1996 Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 19:151-156
274. Horton ES, Whitehouse F, Ghazzi MN, Venable TC, Troglitazone Study Group, Whitecomb RW 1998 Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. Diabetes Care 21:1462-1469
275. Mori Y, Murakawa Y, Okada K, Horikoshi H, Yokoyama J, Yajima N, Ikeda Y 1999 Effects of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 22:908-912
276. Fonseca V, Foyt HL, Shen K, Whitcomb R 2000 Long-term effects of troglitazone: open-label extension studies in type 2 diabetic patients. Diabetes Care 23:354-359
277. Patel J, Anderson RJ, Rappaport EB 1999 Rosiglitazone monotherapy improve glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obesity Metab 1:165-172
278. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI 2001 The Rosiglitazone Clinical Trials Study Group. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 86:280-288
279. Chilcott J, Tappenden P, Jones ML, Wight JP 2001 A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Clin Ther 23:1792-1823
280. Sims EA, Donforth Jr E, Horton ES, Bray GA, Glennon JA, Salans LB 1973 Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 29:457-496
281. Henry RR, Wallace P, Olefsky JM 1986 Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus. Diabetes 35:990-998
282. Chilcott J, Tappenden P, Jones ML, Wight JP 2001 A systematic review of the effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Clin Ther 23:1792-1823
283. Willson TM, Brown PJ, Stembach DD, Henke BR 2000 The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527-550
284. Berger J, Moller DE 2002 The mechanisms of action of PPARs. Annu Rev Med 53:409-435
285. Kahn CR, Chen L, Cohen SE 2000 Unraveling the mechanism of action of thiazolidinediones. J Clin Invest 106:1305-1307
286. Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM 1996 The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39:665-668
287. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS 1997 Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss and regulation by insulin and glucocorticoids. J Clin Invest 99:2416-2422
288. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Iavilie M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J 1997 The organization promoter analysis, and expression of the human PPARγ gene. J Biol Chem 272:18779-18789
289. Mukherjee R, Jow L, Croston GE, Paterniti Jr JR 1997 Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 272:8071-8076
290. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Stembach DD, Lehmann JM, Wisley GB, Willson TM, Kliewer SA, Milburn MV 1999 Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3:397-403
291. Nagy L, Tontonoz P, Alvarez JGA, Chen H, Evans RM 1998 Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 93:229-240
292. Ren D, Collingwood TN, Rebar EJ, Wolffe AP, Camp HS 2002 PPARγ knockdown by engineered transcription factors: exogenous PPARγ2 but not PPARγ1 reactivates adipogenesis. Genes Dev 16:27-32
293. Tontonoz P, Hu E, Spiegelman BM 1994 Stimulation of adipogenesis in fibroblasts by P, PARγ2, a lipid-activated transcription factor. Cell 79:1147-1156
294. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM 1999 PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4:611-617
295. Hallakou S, Doare F, Foufelle F, Kergost M, Guerre-Mlllo, Berthault MF, Dugail I, Mortin J, Auwerx J, Farre P 1997 Pioglitazone induces in vivo adipocyte differentiation in obese Zucker fa/fa rats. Diabetes 46:1393-1399
296. Morrison RF, Farmer SF 2000 Hormonal signaling and transcriptional control of adipocyte differentiation. J Nutr 130:31165-31215
297. Rosen Ed, Walkey CJ, Puigserver P, Spiegelman BM 2000 Transcriptional regulation of adipogenesis. Genes Dev 14:1293-1307
298. Fajas L, Fruchart JC, Auwerx J 1998 Transcriptional control of adipogenesis. Curr Opin Cell Biol 10:165-173
299. Spiegelman BM, Flier JS 1996 Adipogenesis and obesity: rounding out the big picture. Cell 87:377-389
300. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM 2002 C/EBPα induces adipogenesis through PPARγ: a unified pathway. Genes Dev 16:22-26
301. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ, Spiegelman BM 1999 Cross-regulation of C/EBP α and PPAR γ controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 3:151-158
302. El-Jack AK, Hamm JK, Pilch PF, Farmer SR 1999 Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARγ and C/EBPα. J Biol Chem 274:7946-7951
303. Tontonoz P, Hu E, Grraves RA, Budavari AI, Spiegelman BM 1994 mmP-PARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224-1234
304. Tontonoz P, Hu E, Devine J, Beale EG, Spiegelman BM 1995 PPAR-γ2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 15:351-357
305. Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J 1995 Induction of the acylcoenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem 270:19269-19276
306. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J 1996 PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via PPRE in thelipoprotein lipase gene. EMBO J 15:5336-5348
307. Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J 1997 Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARα and PPARγ activators. J Biol Chem 272:25210-25217
308. Sfeir Z, Ibrahimi A, Amri E, Grimaldi P, Abumrad N 1997 Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. Prostaglandins Leukotrienes Essent Fatty Acids 57:17-21
309. Ribon V, Johnson JH, Camp HS, Saltiel AR 1998 Thiazolidinediones and insulin resistance: peroxisome proliferator-activated receptor γ activation stimulates expression of the CAP gene. Proc Natl Acad Sci USA 95:14751-14756
310. Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, Digby JE, Sewter CP, Lazer MA, Chatterjee VKK, O'Rahilly S 1997 Activators of peroxisome proliferators-activated receptor γ have depot-specific effects on human preadipocyte differentiation. J Clin Invest 100:3149-3153
311. Okuno A, Tmemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fijiwara T, Horikoshi H, Yazaki Y, Kadowaki T 1998 Troglitazone increase the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101:1354-1361
312. de Souza CJ, Eckhardt M, Gagen K, Dong M, Chen W, Laurent D, Burkey BF 2001 Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50:1863-1871
313. Gurnell M, Wentworth JM, Agostini M, Adams M, Collingwood TN, Provenzano C, Browne PO, Rajanayagam O, Burris TP, Schwabe JW, Lazar MA, Chatterjee VK 2000 A dominant-negative peroxisome proliferator-activated receptor γ (PPARγ) mutant is a constitutive repressor and inhibits PPARγ-mediated adipogenesis. J Biol Chem 275:5754-5759
314. Boden G, Cheung P, Mozzoli M, Fried SK 2003 Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. Metabolism 52:753-759
315. Ciaraldi TP, Kong APS, Chu NV, Kim DD, Baxi S, Loviscach M, Plodkowski R, Reitz R, Caulfield M, Mudaliar S, Henry RR 2002 Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects. Diabetes 51:30-36
316. Kelley IE, Walsh K, Han TS, Lean MEJ 1999 Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 22:288-293
317. Kawai T, Takei I, Oguma Y, Ohashi N, Tokui M, Oguchi S, Katsukawa F, Hirose H, Shimada A, Watanabe K, Saruta T 1999 Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 48: 1102-1107
318. Barzilai N, She L, Liu BQ, Vuguin P, Cohen P, Wang J, Rossetti L 1999 Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 48:94-98
319. Rebuffe-Scrive M, Andersson B, Olbe L, Bjomtorp P 1989 Metabolism of adipose tissue in intraabdominal depots of nonobese men and women. Metabolism 38:453-458
320. Smith SR, Lovejoy JC, Greenway F, Ryan D, deJone L, de la Bretonne J, Volafova J, Bray GA 2001 Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity. Metabolism 50:425-435
321. Frayn KN, Smara JS, Summers LK 1997 Visceral fat in relation to health: is it a major culprit or simply an innocent bystander? Int J Obes Relat Metab Disord 21:1191-1192
322. Engfeldt P, Arner P 1988 Lipolysis in human adipocytes, effects of cell size, age, and of regional differences. Horm Metab Res 19(Suppl):26-29
323. Colberg SR, Simoneau JA, Thaete FL, Kelley DE 1995 Skeletal muscle utilization of free fatty acids in women with visceral obesity. J Clin Invest 95:1846-1853
324. Miyazaki Y, He H, Mandarino LJ, DeFronzo RA 2003 Rosiglitazone improves downstream insulin-receptor signaling in type 2 diabetic patients. Diabetes 52:1943-1950
325. Song H, Shojima N, Sakoda H, Ogihara T, Fujishoro M, Katagiri H, Anai M, Onishi Y, Ono H, Inukai K, Fukushima Y, Kikuchi M, Shimano H, Yamada N, Oka Y, Asano T 2002 Resistin is regulated by C/EBPs, PPARs, and signal-transducing molecules. Biochem Biophy Res Commun 299:291-298
326. Fonseca VA, Reynolds T, Hemphill D 1998 Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 12:181-186
327. Yu JG, Javorschi S, Hevener AI, Norman RA, Sinha M, Olefsky JM 2002 The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968-2974
328. Sreenan S, Sturis J, Pugh W, Burant CF, Polonsky KS 1996 Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol 271:E742-E747
329. Smith SA, Lister CA, Toseland CD, Buckingham RE 2000 Rosiglitazone prevent the onset of hyperglycemia and proteinuria in the Zucker diabetic fatty rat. Diabetes Obesity Metab 2:363-372
330. Finegood DT, McArthur D, Kojwang M, Thomas J, Topp BG, Leonard T, Buckingham RE 2001 β-Cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes 50:1021-1029
331. Lupi R, Del Guerra S, Marselli L, Bugliani M, Boggi U, Mosca F, Marachetti P, Del Prato S 2002 PPARγ ligand-specificity in the modulation of insulin release from isolated human islets in response to fatty acid incubation. Diabetologia 45(Suppl 2):A161
332. Marselli L, Bambini MC, Lupi R, Del Guerra S, Boggi U, Mosca F, Del Prato S, Marchetti P 2002 Rosiglitazone partially prevents free fatty acid-induced cytotoxicity of human pancreatic islet cells. Diabetologia 45(Suppl 2):A161
333. Buchanan TA, Xiang AH, Peters RK 2002 Preservation of pancreatic β cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 51:2796-2803
334. Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS 1997 Treatment with the oral antidiabetic agent troglitazone improves β cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 100:530-537