Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-α and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) γ is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in β-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARγ-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.

Keywords:
Insulin, Insulin resistance, Insulin sensitizers, Genetic factors, Type 2 diabetes mellitus, Glucose intolerance, Glucose disposal, Obesity
1.
Yki-Järvinen H: Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet 1994;343:91–95.
2.
Garvey WT, Birnbaum MJ: Cellular insulin action and insulin resistance. Baillières Clin Endocrinol Metab 1993;7:785–873.
3.
Moller DE, Flier JS: Insulin resistance – mechanisms, syndromes, and implications. N Engl J Med 1991;325:938–948.
4.
DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214–E223.
5.
Stumvoll M, Jacob S: Multiple sites of insulin resistance: Muscle, liver and adipose tissue. Exp Clin Endocrinol Diabetes 1999;107:107–110.
6.
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 1988;37:15–21.
7.
Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck 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 1989;84:205–213.
8.
Bonadonna RC, Groop L, Kramer N, Ferrannini E, Del Prato S, DeFronzo RA: Obesity and insulin resistance in humans: A dose-response study. Metabolism 1990;39:452–459.
9.
Nurjhan N, Campbell P, Kennedy F, Miles J, Gerich J: Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 1986;35:1326–1331.
10.
Campbell PJ, Carlson MG, Hill JO, Nurjhan N: Regulation of free fatty acid metabolism by insulin in humans: Role of lipolysis and reesterification. Am J Physiol 1992;263:E1063–E1069.
11.
Campbell PJ, Carlson MG, Nurjhan N: Fat metabolism in human obesity. Am J Physiol 1994;266:E600–E605.
12.
Groop LC, Bonadonna RC, Simonson DC, Petrides AS, Shank M, DeFronzo RA: Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity. Am J Physiol 1992;263:E79–E84.
13.
Stumvoll M, Jacob S, Wahl HG, Hauer B, Löblein K, Grauer P, Becker R, Nielsen M, Renn W, Häring H: Suppression of systemic, intramuscular and subcutaneous adipose tissue lipolysis by insulin in humans. J Clin Endocrinol Metab 2000;85:3740–3745.
14.
Dinneen S, Gerich J, Rizza R: Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 1992;327:707–713.
15.
Matthaei S, Stumvoll M, Kellerer M, Häring H-U: Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev 2000;21:585–618.
16.
Laakso M: Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999;48:937–942.
17.
DeFronzo RA, Ferrannini E: Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173–194.
18.
Reaven G: Role of insulin resistance in human disease. Diabetes 1988;37:1595–1607.
19.
Tack CJ, Ong MK, Lutterman JA, Smits P: Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998;41:569–576.
20.
Laakso M, Edelman SV, Brechtel G, Baron AD: Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992;41:1076–1083.
21.
Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 1990;85:1844–1852.
22.
Heise T, Magnusson K, Heinemann L, Sawicki PT: Insulin resistance and the effect of insulin on blood pressure in essential hypertension. Hypertension 1998;32:243–248.
23.
Hsueh W, Law RE, Saad M, Dy J, Feener E, King G: Insulin resistance and macrovascular disease. Curr Opinion Endocrinol Diab 1996;3:346–354.
24.
Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Häring H-U: Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000;101:1780–1784.
25.
Taskinen M: Hyperlipidaemia in diabetes. Baillières Clin Endocrinol Metab 1990;4:743–775.
26.
Trovati M, Anfossi G: Insulin, insulin resistance and platelet function: Similarities with insulin effects on cultured vascular smooth muscle cells. Diabetologia 1998;41:609–622.
27.
Anfossi G, Mularoni EM, Burzacca S, Ponziani MC, Massucco P, Mattiello L, Cavalot F, Trovati M: Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care 1998;21:121–126.
28.
Bonadonna RC, Bonora E: Glucose and free fatty acid metabolism in human obesity. Diabetes Rev 1997;5:21–51.
29.
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 1998;102:619–624.
30.
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 1963;I:785–789.
31.
Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Furnsinn C, Moser E, Waldhäusl W: Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 1999;48:358–364.
32.
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI: Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996;97:2859–2865.
33.
Randle PJ, Priestman DA, Mistry SC, Halsall A: Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biochem 1994;55 (suppl):1–11.
34.
Foley JE: Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care 1992;15:773–784.
35.
Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997;46:3–10.
36.
Paolisso G, Howard BV: Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes. Diabetic Med 1998;15:360–366.
37.
Maggs DG, Jacob R, Rife F, Lange R, Leone P, During MJ, Tamborlane WV, Sherwin RS: Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle. J Clin Invest 1995;96:370–377.
38.
Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen C-D, Häring H-U: Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 1999;48:1113–1119.
39.
Jacob S, Hauer B, Becker R, Artzner S, Grauer P, Löblein K, Nielsen M, Renn W, Rett K, Wahl H-G, Stumvoll M, Häring H-U: Lipolysis in muscle is rapidly regulated by low physiologic doses of insulin. Diabetologia 1999;42:1171–1174.
40.
Hube F, Hauner H: The role of TNF-alpha in human adipose tissue: Prevention of weight gain at the expense of insulin resistance? Horm Metab Res 1999;31:626–631.
41.
Hotamisligil GS, Arner P, Atkinson RL, Spiegelman BM: Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes 1997;46:451–455.
42.
Sigal RJ, Warram JH: The interaction between obesity and diabetes. Curr Opin Endocrinol Diab 1996;3:3–9.
43.
Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H: Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 1996;97:1471–1477.
44.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 2001;409:307–312.
45.
Ferrannini E, Vichi S, Beck Nielsen H, Laakso M, Paolisso G, Smith U: Insulin action and age. European Group for the Study of Insulin Resistance (EGIR). Diabetes 1996;45:947–953.
46.
Yki-Järvinen H: Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia 1995;38:1378–1388.
47.
Eriksson J, Taimela S, Koivisto VA: Exercise and the metabolic syndrome. Diabetologia 1997;40:125–135.
48.
Zierath JR, Krook A, Wallberg-Henriksson H: Insulin action and insulin resistance in human skeletal muscle. Diabetologia 2000;43:821–835.
49.
Goodyear LJ, Kahn BB: Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 1998;49:235–261.
50.
White MF: The insulin signalling system and the IRS proteins. Diabetologia 1997;40 (suppl 2):S2–S17.
51.
DeMeyts P, Christofferson CT, Tornqvist H, Seedorf K: Insulin receptors and insulin action. Curr Opinion Endocrinol Diab 1996;3:369–377.
52.
Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg Henriksson H: Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes 1998;47:1281–1286.
53.
Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL: Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 1995;95:2195–2204.
54.
Bjornholm M, Kawano Y, Lehtihet M, Zierath JR: Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 1997;46:524–527.
55.
Nolan JJ, Freidenberg 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 mellitus and obesity. J Clin Endocrinol Metab 1994;78:471–477.
56.
Maegawa H, Shigeta Y, Egawa K, Kobayashi M: Impaired autophosphorylation of insulin receptors from abdominal skeletal muscles in nonobese subjects with NIDDM. Diabetes 1991;40:815–819.
57.
Nyomba BL, Ossowski VM, Bogardus C, Mott DM: Insulin-sensitive tyrosine kinase: Relationship with in vivo insulin action in humans. Am J Physiol 1990;258:E964–E974.
58.
Arner P, Pollare T, Lithell H, Livingston JN: Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1987;30:437–440.
59.
Obermaier Kusser B, White MF, Pongratz DE, Su Z, Ermel B, Muhlbacher C, Haring H-U: 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 1989;264:9497–9504.
60.
Medici F, Hawa M, Pyke DA, Leslie RD: Concordance rate for type II diabetes mellitus in monozygotic twins: Actuarial analysis. Diabetologia 1999;42:146–150.
61.
Lehtovirta M, Kaprio J, Forsblom C, Eriksson J, Tuomilehto J, Groop L: Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins. Diabetologia 2000;43:285–293.
62.
Cocozza S, Porcellini 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 1992;41:521–526.
63.
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 1991;88:1323–1330.
64.
O’Rahilly S, Choi WH, Patel P, Turner RC, Flier JS, Moller DE: Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms. Diabetes 1991;40:777–782.
65.
Almind K, Inoue G, Pedersen O, Kahn CR: A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 1996;97:2569–2575.
66.
Hribal ML, Federici M, Porzio O, Lauro D, Borboni P, Accili D, Lauro R, Sesti G: The Gly–Arg972 amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells. J Clin Endocrinol Metab 2000;85:2004–2013.
67.
Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S, Pedersen O: Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 1993;342:828–832.
68.
Imai Y, Fusco A, Suzuki Y, Lesniak MA, D’Alfonso R, Sesti G, Bertoli A, Lauro R, Accili D, Taylor SI: Variant sequences of insulin receptor substrate-1 in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1994;79:1655–1658.
69.
Zhang Y, Wat N, Stratton IM, Warren Perry MG, Orho M, Groop L, Turner RC: UKPDS 19: Heterogeneity in NIDDM: Separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. Diabetologia 1996;39:1505–1511.
70.
Hager J, Zouali H, Velho G, Froguel P: Insulin receptor substrate (IRS-1) gene polymorphisms in French NIDDM families. Lancet 1993;342:1430.
71.
Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K, Haraldsdottir J, Borch-Johnson K, Pedersen O: Insulin resistance: Interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 1995;346:397–402.
72.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl M-C, Nemesh J, Lane CD, Schaffner SF, Bolk A, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPAR gamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
73.
Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn W, Haring HU: Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 1999;107:318–322.
74.
Stumvoll M, Fritsche A, Volk A, Stefan N, Madaus A, Maerker E, Teigeler A, Koch M, Machicao F, Häring H: The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans. Diabetes 2001;50:882–885.
75.
Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G: The Gly972→Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 1999;104:357–364.
76.
Federici M, Hribal ML, Ranalli M, Marselli L, Porzio O, Lauro D, Borboni P, Lauro R, Marchetti P, Melino G, Sesti G: The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. FASEB J 2001;15:22–24.
77.
Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner Weir S, White MF: Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998;391:900–904.
78.
Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR: A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998;2:559–569.
79.
Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR: Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999;96:329–339.
80.
Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, et al: A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 1996;13:161–166.
81.
Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000;26:163–175.
82.
Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen G-Q, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C: A calapin-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 2000;106:R69–R73.
83.
Permutt AM, Bernal-Mizrachi E, Inoue H: Calpain 10: The first positional cloning of a gene for type 2 diabetes. J Clin Invest 2000;106:819–821.
84.
Auwerx J: PPAR-gamma, the ultimate thrifty gene. Diabetologia 1999;42:1033–1049.
85.
Spiegelman BM: PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor. Diabetes 1998;47:507–514.
86.
Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR: Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes 1998;47:1806–1808.
87.
Valve R, Sivenius K, Miettinen R, Pihlajamaki J, Rissanen A, Deeb SS, Auwerx J, Uusitupa M, Laakso M: Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated with severe overweight among obese women. J Clin Endocrinol Metab 1999;84:3708–3712.
88.
Stumvoll M, Wahl HG, Löblein K, Becker R, Machicao F, Jacob S, Häring H: Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity. Diabetes 2001;50:876–881.
89.
Jacob S, Stumvoll M, Becker R, Koch M, Nielsen M, Löblein K, Maerker E, Volk A, Renn W, Balletshofer B, Machicao F, Rett K, Häring HU: The PPARgamma2 polymorphism Pro12Ala is associated with better insulin sensitivity in the offspring of type 2 diabetic patients. Horm Metab Res 2000;32:413–416.
90.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J: A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998;20:284–287.
91.
Miles PD, Barak Y, He W, Evans RM, Olefsky JM: Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000;105:287–292.
92.
Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T, et al: PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999;4:597–609.
93.
Stumvoll M, Wahl HG, Löblein K, Becker R, Volk A, Renn W, Jacob S, Häring H: A novel use of the hyperinsulinemic-euglycemic clamp technique to estimate insulin sensitivity of systemic lipolysis. Horm Metab Res 2001;33:89–95.
94.
Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K, Horikoshi H: Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. J Med Chem 1989;32:421–428.
95.
Fujiwara T, Okuno A, Yoshioka S, Horikoshi H: Suppression of hepatic gluconeogenesis in long-term troglitazone-treated diabetic KK and C57BL/KsJ-db/db mice. Metabolism 1995;44:486–490.
96.
Fujiwara T, Wada M, Fukuda K, Fukami M, Yoshioka S, Yoshioka T, Horikoshi H: Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 1991;40:1213–1218.
97.
Fujita T, Sugiyama Y, Taketomi S, Sohda T, Kawamatsu Y, Iwatsuka H, Suzuoki Z: Reduction of insulin resistance in obese and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, ciglitazone), a new antidiabetic agent. Diabetes 1983;32:804–810.
98.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–1193.
99.
Teboul L, Gaillard D, Staccini L, Inadera H, Amri EZ, Grimaldi PA: Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. J Biol Chem 1995;270:28183–28187.
100.
Tontonoz P, Hu E, Spiegelman BM: Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147–1156.
101.
Tafuri SR: Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 1996;137:4706–4712.
102.
Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA: Troglitazone action is independent of adipose tissue. J Clin Invest 1997;100:2900–2908.
103.
Schoonjans K, Martin G, Staels B, Auwerx J: Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997;8:159–166.
104.
Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM: Altered gene expression for tumor necrosis factor-α and its receptor during drug and dietary modulation of insulin resistance. Endocrinology 1994;134:264–270.
105.
De Vos P, Lefebvre AM, Miller SG, Guerre Millo M, Wong K, Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J: Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest 1996;98:1004–1009.
106.
Kallen CB, Lazar MA: Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1996;93:5793–5796.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.