An update on the biology and physiology of resistin

Cellular and Molecular Life Sciences

Volumn 61, Issue 19-20, 2004, Pages 2485-2496

  Adeghate, E ^a  

^a UNITED ARAB EMIRATES UNIVERSITY   (United Arab Emirates)

Author keywords

Diabetes mellitus; Glucose metabolism; Insulin resistance; Obesity; Resistin

Indexed keywords

ADRENALIN; AMINO ACID DERIVATIVE; CYTOKINE; DEXAMETHASONE; ENDOTHELIN 1; GROWTH HORMONE; HORMONE; HUMAN GROWTH HORMONE; INSULIN; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; NEUROTRANSMITTER; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; POLYPEPTIDE; RESISTIN; RESISTIN LIKE MOLECULE ALPHA; RESISTIN LIKE MOLECULE BETA; RESISTIN LIKE MOLECULE GAMMA; ROSIGLITAZONE; SEX HORMONE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADIPOCYTE; ADRENAL GLAND; BIOLOGY; BROWN ADIPOSE TISSUE; CHEMICAL STRUCTURE; COLD; DIABETES MELLITUS; DIET RESTRICTION; DOWN REGULATION; DRUG ANTAGONISM; GASTROINTESTINAL TRACT; GENOTYPE; GLUCOSE METABOLISM; HUMAN; HYPERGLYCEMIA; HYPOPHYSIS; HYPOTHALAMUS; INSULIN RESISTANCE; LEUKOCYTE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREAS; PHYSIOLOGY; PLACENTA; PLASMA; REVIEW; SKELETAL MUSCLE; SYNOVIAL FLUID; TISSUE DISTRIBUTION; WHITE ADIPOSE TISSUE;

ADIPOSE TISSUE; AMINO ACID SEQUENCE; ANIMALS; CYTOKINES; DIABETES MELLITUS, TYPE 2; FEMALE; GLUCOSE; HORMONES, ECTOPIC; HUMANS; INSULIN; INSULIN RESISTANCE; INTERLEUKIN-6; LIPOPOLYSACCHARIDES; MALE; MODELS, BIOLOGICAL; MOLECULAR SEQUENCE DATA; RATS; RECOMBINANT PROTEINS; RESISTIN; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION;

EID: 9744274024     PISSN: 1420682X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00018-004-4083-2     Document Type: Review

References (99)

1. Anonymous (1996) International Diabetes Federation Press Release. Int. J. Diabetes 4: 97
2. Amos A. F., McCarty D. J. and Zimmet P. (1997) The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet. Med. 14 Suppl 5: S1-85
3. King H., Aubert R. E. and Herman W. H. (1998) Global burden of diabetes, 1995-2025. Prevalence, numerical estimates and projections. Diabetes Care 21: 1414-1431
4. Zimmet P. (2000) Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? J. Intern. Med. 247: 301-310
5. Roivainen M., Knip M., Hyoty H., Kulmala P., Hiltunen M., Vahasalo P. et al. (1998) Several different enterovirus serotypes can be associated with prediabetic autoimmune episodes and onset of overt IDDM. Childhood Diabetes in Finland (DiMe) Study Group. J. Med. Virol. 56: 74-78
6. Syllaba J. (1994) New findings in type I diabetes. (Article in Czech) Cas Lek Cesk 133: 37-40
7. Steppan C. M., Bailey S. T., Bhat S., Brown E. J., Banerjee R. R., Wright C. M. et al. (2001) The hormone resistin links obesity to diabetes. Nature 409: 307-312
8. Lin J., Choi Y. H., Hartzell D. L., Li, C., Della-Fera M. A. and Baile C. A. (2003) CNS melanocortin and leptin effects on stearoyl-CoA desaturase-1 and resistin expression. Biochem. Biophys. Res. Commun. 311: 324-328
9. Strausberg R. L., Feingold E. A., Grouse L. H., Derge J. G., Klausner R. D., Collins F. S. et al. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc. Natl. Acad. Sci. USA 99: 16899-16903
10. Dai M. and Yang Z. (2004) Cloning and Expression of Porcine Resistin, NCBI, National Library of Medicine, Bethesda, USA
11. Patel L., Buckels A. C., Kinghorn I. J., Murdock P. R., Holbrook J. D., Plumpton C. et al. (2003) Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem. Biophys. Res. Commun. 300: 472-476
12. Rajala M. W., Lin Y. Ranalletta M., Yang X. M., Qian H., Gingerich R. et al. (2002) Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol. Endocrinol. 16: 1920-1930
13. Banerjee R. R. and Lazar M. A. (2001) Dimerization of resistin and resistin-like molecules in determined by a single cysteine. J. Biol. Chem. 276: 25970-25973
14. Chen J., Wang L., Boeg Y. S., Xia B. and Wang J. (2002) Differential dimerization and association among resistin family proteins with implications for functional specificity. J. Endocrinol. 175: 499-504
15. Hartman H. B., Hu X., Tyler K. X., Dalal C. K. and Lazar M. A. (2002) Mechanisms regulating adipocyte expression of resistin. J. Biol. Chem. 277: 19754-19761
16. Juan C. C., Kan L. S., Huang C. C., Chen S. S., Ho L. T. and Au L. C. Production and characterization of bioactive recombinant resistin in Escherichia coli. J. Biotechnol. 103: 113-117
17. Aruna B., Ghosh S., Singh A. K., Mande S. C., Srinivas V., Chauhan R. et al. (2003) Human recombinant resistin protein displays a tendency to aggregate by forming intermolecular disulfide linkages. Biochemistry 42: 10554-10559.
18. Del Arco A., Peralta S., Carrascosa J. M., Ros M., Andres A. and Arribas C. (2003) Alternative splicing generates a novel non-secretable resistin isoform in Wistar rats. FEBS Lett. 555: 243-249
19. Steppan C. M., Brown E. J., Wright C. M., Bhat S., Banerjee R. R., Dai C. Y. et al. (2001) A family of tissue-specific resistin-like molecules. Proc. Natl. Acad. Sci. USA 98: 502-506
20. Steppan C. M. and Lazar M. A. (2002) Resistin and obesity-associated insulin resistance. Trends Endocrinol. Metab. 13: 18-23
21. Holcomb I. N., Kabakoff R. C., Chan B., Baker T. W., Gurney A., Henzel W. et al. (2000) FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19: 4046-4055
22. Blagoev B., Kratchmarova I., Nielsen M. M., Fernandez M. M., Voldby J., Andersen J. S. et al. (2002) Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J. Biol. Chem. 277: 42011-42016
23. Liu T., Dhanasekaran S. M., Jin H., Hu B., Tomlins S. A., Chinnaiyan A. M. et al. (2004) FIZZ1 stimulation of myofibroblast differentiation. Am. J. Pathol. 164: 1315-1326
24. Bing C., Gomez-Ambrosi J., Zabalegui N., Williams G. and Trayhurn P. (2002) Resistin and RELM-alpha gene expression in white adipose tissue of lactating mice. Biochem. Biophys. Res. Commun. 296: 458-462
25. He W., Wang M. L., Jiang H. Q., Steppan C. M., Shin M. E., Thurnheer M. C. et al. (2003) Bacterial colonization leads to the colonie secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 125: 1388-1397
26. Chumakov A. M., Kubota T., Walter S. and Koeffler H. P. (2004) Identification of murine and human XCP1 genes as C/EBP-ε-dependent members of FIZZ/Resistin gene family. Oncogene 23: 3414-3425
27. Gerstmayer B., Kusters D., Gebel S., Muller T., Van Miert E., Hofmann K. et al. (2003) Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics 81: 588-595
28. Nogueiras R., Gallego R., Gualillo O., Caminos J. E., Garcia-Caballero T., Casanueva F. F. et al. (2003) Resistin is expressed in different rat tissues and is regulated in a tissue- and gender-specific manner. FEBS Lett. 548: 21-27
29. Morash B. A., Willkinson D., Ur E. and Wilkinson M. (2002) Resistin expression and regulation in mouse pituitary. FEBS Lett. 526: 26-30
30. Papa P. C., Seraphim P. M. and Machado U. F. (1997) Loss of weight restores GLUT 4 content in insulin-sensitive tissues of monosodium glutamate-treated obese mice. Int. J. Obes. Relat. Metab. Disord. 21: 1065-1070
31. Kim K. H., Lee K., Moon Y. S. and Sul H. S. (2001) A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol. Chem. 276: 11252-11256
32. McTernan C. L., McTernan P. G., Harte A.L., Levick P. L., Barnett A. H. and Kumar S. (2002) Resistin, central obesity and type 2 diabetes. Lancet 359: 46-47
33. McTernan P. G., McTernan C. L., Chetty R., Jenner K., Fisher F. M., Lauer M. N. et al. (2002) Increased resistin gene and protein expression in human abdominal adipose tissue. J. Clin. Endocrinol. Metab. 87: 2407
34. Janke J., Engeli S., Gorzelniak K., Luft F. C. and Sharma A. M. (2002) Resistin gene expression in human adipocytes is not related to insulin resistance. Obes. Res. 10: 1-5
35. Viengchareun S., Zennaro M. C., Pascual-Le Tallec L. and Lombes M. (2002) Brown adipocytes are novel sites of expression and regulation of adiponectin and resistin. FEBS Lett. 532: 345-350
36. Lu S. C., Shieh W. Y., Chen C. Y., Hsu S. C. and Chen H. L. (2002) Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett. 530: 158-162
37. Yang R. Z., Huang Q., Xu A., McLenithan J. C., Eison J. A., Shuldiner A. R. et al. (2003) Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem. Biophys. Res. Commun. 310: 927-935
38. Csaba G., Kovacs P. and Pallinger E. (2003) Gender differences in the histamine and serotonin content of blood, peritoneal and thymic cells: a comparison with mast cells. Cell Biol. Int. 27: 387-389
39. Milan G., Granzotto M., Scarda A., Calcagno A., Pagano C., Federspil G. et al. (2002) Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes Res. 10: 1095-1103
40. Song H., Shojima N., Sakoda H., Ogihara T., Fujishiro M., Katagiri H. et al. (2002) Resistin is regulated by C/EBPs, PPARs and signal-transducing molecules. Biochem. Biophys. Res. Commun. 299: 291-298
41. Yura S., Sagawa N., Itoh H., Kakui K., Nuamah M. A., Korita D. et al. (2003) Resistin is expressed in the human placenta. J. Clin. Endocrinol. Metab. 88: 1394-1397
42. Minn A. H., Patterson N. B., Pack S., Hoffmann S. C., Gavrilova O., Vinson C. et al. (2003) Resistin is expressed in pancreatic islets. Biochem. Biophys. Res. Commun. 310: 641-645
43. Schaffler A., Ehling A., Neumann E., Herfarth H., Tarner I., Scholmerich J. et al. (2003) Adipocytokines in synovial fluid. JAMA 290: 1709-1710
44. Stejskal D., Proskova J., Adamovska S., Jurakova R. and Bartek J. (2002) Preliminary experience with resistin assessment in common population. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 146: 47-49
45. Azuma K., Katsukawa F., Oguchi S., Murata M., Yamazaki H., Shimada A. et al. (2003) Correlation between serum resistin level and adiposity in obese individuals. Obes Res. 11: 997-1001
46. Delhanty P. J., Mesotten D., McDougall F. and Baxter R. C. (2002) Growth hormone rapidly induces resistin gene expression in white adipose tissue of spontaneous dwarf (SDR) rats. Endocrinology 143: 2445-2448
47. Holdaway I. M., Rajasoorya R. C. and Gamble G. D. (2004) Factors influencing mortality in acromegaly. J. Clin. Endocrinol. Metab. 89: 667-674
48. Shojima N., Sakoda H., Ogihara T., Fujishiro M., Katagiri H., Anai M. et al. (2002) Humoral regulation of resistin expression in 3T3-E1 and mouse adipose cells. Diabetes 51: 1737-1744
49. Cai E. and Kang Y. J (2001) Oxidative stress and cardiomyopathy: a brief review. Cardiovasc. Toxicol. 1: 181-193
50. Fiordaliso F., Leri A., Cesselli D., Limana F., Safai B., Nadal-Ginard B. et al. (2001) Hyperglycaemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50: 2363-2357
51. Cai L., Li W., Wang G., Guo L., Jiang Y. and Kang Y. J. (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51: 1938-1948
52. Adeghate E. (2004) Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol. Cell Biochem. 261: 187-291
53. Fukui Y. and Motojima K. (2002) Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator- activated receptor alpha. Diabetes Obes. Metab. 4: 342-345
54. Nogueiras R., Gualillo O., Caminos J. E., Casanueva F. F. and Dieguez C. (2003) Regulation of resistin by gonadal, thyroid hormone and nutritional status. Obes. Res. 11: 408-414
55. Ling C., Kindblom J., Wennbo H. and Billig H. (2001) Increased resistin expression in the adipose tissue of male prolactin transgenic mice and in male mice with elevated androgen levels. FEBS Lett. 507: 147-150
56. Wallerius S., Rosmond R., Ejung T., Holm G. and Bjorntorp P. (2003) Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report. J. Endocrinol. Invest. 26: 616-619
57. Nicod N., Giusti V., Besse C. and Tappy L. (2003) Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers. Obes. Res. 11: 625-631
58. Yuzuriha H., Inui A., Goto K., Asakawa A., Fujimiya M. and Kasuga M. (2003) Intracerebroventricular administration of NPY stimulates resistin gene expression in mice. Int. J. Mol. Med. 11: 675-676
59. Schwartz M. W. and Morton G. J. (2002) Obesity: keeping hunger at bay. Nature 418: 595-597
60. Oliver P., Pico C., Serra F. and Palou A. (2003) Resistin expression in different adipose tissue depots during rat development. Mol. Cell Biochem. 252: 397-400
61. Wilson P. W., and Kannel W. B. (2002) Obesity, diabetes and risk of cardiovascular disease in the elderly. Am. J. Geriatr. Cardiol. 11: 119-23
62. Kawashima J., Tsuruzoe K., Motoshima H., Shirakami A., Sakai K., Hirashima Y. et al. (2003) Insulin down-regulates resistin mRNA through the synthesis of protein(s) that could accelerate the degradation of resistin mRNA in 3T3-E1 adipocytes. Diabetologia 261: 187-291
63. Banerjee R. R., Rangwala S. M., Shapiro J. S., Rich A. S., Rhoades B., Qi Y. et al. (2004) Regulation of fasted blood glucose by resistin. Science 303: 1195-1198
64. Silha J. V., Krsek M., Skrha J. V., Sucharda P., Nyomba B. L. and Murphy L. J. (2003) Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur. J. Endocrinol. 149: 331-335
65. Iglesias P., Alvarez Fidalgo P., Codoceo R. and Diez J. J. (2003) Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function. Clin. Endocrinol. 59: 621-629
66. Hoogwerf B. J. and Nuttall F. Q. (1984) Long-term weight regulation in treated hyperthyroid and hypothyroid subjects. Am. J. Med. 76: 963-970
67. Zhong Q., Lin C. Y. Clarke K. J., Kemppainen R. J., Schwartz D. D. and Judd R. L. (2002) Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 296: 383-387
68. Highsmith R. F. (ed.) (1998) Endothelin: Molecular Biology, Physiology and Pathology, Humana Press, Totowa, NJ
69. Verma S., Li S. H., Wang C. H., Fedak P. W., Li R. K., Weisel R. D. et al. (2003) Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 108: 736-740
70. Fasshauer M., Klein J., Neumann S., Eszlinger M. and Paschke R. (2001) Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes. FEBS Lett. 500: 60-63
71. Reaven G. M., Lithell H. and Landsberg E. (1996) Hypertension and associated metabolic abnormalities - the role of insulin resistance and the sympathoadrenal system. N. Engl. J. Med. 334: 374-381
72. Walczak R. and Tontonoz P. (2002) PPARadigms and PPARa-doxes. Expanding roles for PPARγ in the control of lipid metabolism. J. Lipid Res. 43: 177-186
73. Arner P. (2003) The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends Endocrinol. Metab. 14: 137-145
74. Kaser S., Kaser A., Sandhofer A., Ebenbichler C. F., Tilg H. and Patsch J. R. (2003) Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem. Biophys. Res. Commun. 309: 286-290
75. Fasshauer M., Klein J., Neumann S., Eszlinger M. and Paschke R. (2001) Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 288: 1027-1031
76. Yannakoulia M., Yiannakouris N., Bluher S., Matalas A. E., Klimis-Zacas D. and Mantzoros C. S. (2003) Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin and resistin concentrations in healthy humans. J. Clin. Endocrinol. Metab. 88: 1730-1736
77. Puerta M., Abelenda M., Rocha M. and Trayhurn P. (2002) Effect of acute cold exposure on the expression of the adiponectin, resistin and leptin genes in rat white and brown adipose tissues. Horm. Metab. Res. 34: 629-634
78. Spiegelman B. M. (1998) PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47: 507-514
79. Rajala M. W., Obici S., Scherer P. E and Rossetti E. (2003) Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J. Clin. Invest. 111: 225-230
80. Vernon R. G., Denis R. G. P. and Sorensen A. (2001) Signals of obesity. Domestic Animal Endocrinol. 21: 197-214
81. Sethi J. K. and Hotamisligil G. S. (1999) The role of TNF alpha in adipocyte metabolism. Semin. Cell Dev. Biol. 10: 19-29
82. Hube F. and Hauner H. (1999) The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance? Horm. Metab. Res. 31: 626-631
83. Moon B., Kwan J. J., Duddy N., Sweeney G. and Begum N. (2003) Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am. J. Physiol. Endocrinol. Metab. 285: E106-115
84. Levy J. R., Davenport B., Clore J. N. and Stevens W. (2002) Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats. Am. J. Physiol. Endocrinol. Metab. 283: E626-633
85. Mooradian A. D. (2001) Obesity: a rational target for managing diabetes mellitus. Growth Horm. IGF Res. 11 Suppl. A: S79-S83
86. Degawa-Yamauchi M., Bovenkerk J. E., Juliar B. E., Watson W., Kerr K., Jones R. et al. (2003) Serum resistin (FIZZ3) protein is increased in obese humans. J. Clin. Endocrinol. Metab. 88: 5452-5455
87. Way J. M., Gorgun C. Z., Tong Q., Uysal K. T., Brown K. K., Harrington W. W. et al. (2001) Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem. 276: 25651-25653
88. Le Lay S., Boucher J., Rey A., Castan-Laurell I., Krief S., Ferre P. et al. (2001) Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem. Biophys. Res. Commun. 289: 564-567
89. Nagaev I. and Smith U. (2001) Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem. Biophys. Res. Commun. 285: 561-564
90. Moore G. B., Chapman H., Holder J. C., Lister C. A., Piercy V., Smith S. A. et al. (2001) Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice. Biochem. Biophys. Res. Commun. 286: 735-741
91. Flier J. S. (1995) The adipocyte: storage depot or node on the energy information superhighway? Cell 80: 15-18
92. Cepica S., Rohrer G. A., Masopust M., Kubickova S., Musilova P. and Rubes J. (2002) Partial cloning, cytogenetic and linkage mapping of the porcine resistin (RSTN) gene. Anim. Genet. 33: 381-383
93. Engert J. C., Vohl M. C., Williams S. M., Lepage P., Loredo-Osti J. C., Faith J. et al. (2002) 5′ flanking variants of resistin are associated with obesity. Diabetes 51: 1629-634
94. Sentinelli F., Romeo S., Area M., Filippi E., Leonetti F., Banchieri M. et al. (2002) Human resistin gene, obesity and type 2 diabetes: mutation analysis and population study. Diabetes 51: 860-862
95. Osawa H., Onuma H., Murakami A., Ochi M., Nishimiya T., Kato K. et al. (2002) Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes. Diabetes 51: 863-866
96. Ma X., Warram J. H., Trischitta V. and Doria A. (2002) Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians. J. Clin. Endocrinol. Metab. 87: 4407-4410
97. Tan M. S., Chang S. Y., Chang D. M., Tsai J. C. and Lee Y. J. (2003) Association of resistin gene 3′-untranslated region +62G→A polymorphism with type 2 diabetes and hypertension in a Chinese population. J. Clin. Endocrinol. Metab. 88: 1258-1263
98. Furuhashi M., Ura N., Higashiura K., Murakami H. and Shimamoto K. (2003) Circulating resistin levels in essential hypertension. Clin. Endocrinol. 59: 507-510
99. Lee J. H., Chan J. L., Yiamiakouris N., Kontogianni M., Estrada E., Seip R. et al. (2003) Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant and diabetic subjects. J. Clin. Endocrinol. Metab. 88: 4848-4856