No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients.
Paquot, Nicolas; Castillo, M. J.; Lefebvre, Pierreet al.
2000 • In Journal of Clinical Endocrinology and Metabolism, 85 (3), p. 1316-9
[en] Inhibition of tumor necrosis factor (TNF)-alpha results in a marked increase in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean +/- SD age, 41 +/- 4 yr; body mass index, 36.1 +/- 4.7 kg/m2; waist to hip ratio, 0.99 +/- 0.11) were studied (three patients with normal glucose tolerance and four patients with impaired glucose tolerance or mild diabetes; all were hyperinsulinemic). Each patient underwent two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h after injection of placebo and 48 h after a single i.v. injection of 50 mg Ro 45-2081. In both tests, steady-state plasma glucose and insulin levels were similar. Insulin-mediated glucose disposal (2.23 +/- 0.74 vs. 2.38 +/- 0.99 mg/kg(-1) x min(-1)) and glucose metabolic clearance rate (2.28 +/- 0.85 vs. 2.48 +/- 1.03 mL/kg(-1) x min(-1)) were similar after placebo and after the drug. Indirect calorimetry showed no difference in substrate oxidation rates between the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single i.v. administration of a recombinant TNF receptor: Fc fusion protein.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Paquot, Nicolas ; Centre Hospitalier Universitaire de Liège - CHU > Diabétologie,nutrition, maladies métaboliques
Castillo, M. J.
Lefebvre, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Diabétologie,nutrition, maladies métaboliques
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
Language :
English
Title :
No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients.
Publication date :
2000
Journal title :
Journal of Clinical Endocrinology and Metabolism
ISSN :
0021-972X
eISSN :
1945-7197
Publisher :
Endocrine Society, Chevy Chase, United States - Maryland
O'Doherty R., Stein D., Foley J. (1997) Insulin resistance. Diabetologia 40.
Kahn C.R. (1995) Causes of insulin resistance. Nature 373:384-385.
Hotamisligil G.S., Shargill N.S., Spiegelman B.M. (1993) Adipose expression of tumor necrosis factor-α. Direct role in obesity-linked insulin resistance. Science 259:87-91.
Hotamisligil G.H., Spiegelman B.M. (1994) Tumor necrosis factor α. A key component of the obesity-diabetes link. Diabetes 43:1271-1278.
Hotamisligil G.H., Arner P., Caro J.F., Atkinson R.L., Spiegelman B.M. (1995) Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 95:2409-2415.
Saghizadeh M., Ong J.M., Garvey W.T., Henry R.R., Kern P.A. (1996) The expression of TNF-α by human muscle. Relationship to insulin resistance. J Clin Invest 97:1111-1116.
Dandona P., Weinstock R., Thusu (1998) Tumor necrosis factor-α in sera of obese patients: Fall with weight loss. J Clin Endocrinol Metab 83:2907-2910.
Katsuki A., Sumida Y., Murashima S. (1998) Serum levels of tumor necrosis factor-α are increased in obese patients with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 83:859-862.
Zinman B., Hanley A.J., Harris S.B., Kwan J., Fantus I.G. (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.
Lang C.H., Dobrescu C., Bagby G.J. (1992) Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130:43-52.
Van der Poll T., Romijn J.A., Endert E., Borm J.J., Büller H.R., Sauerwein H.P. (1991) Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 261:457-465.
Loetscher H.R., Gentz R., Zulauf (1991) Recombinant 55kDa TNF receptor. Stoichiometry of binding to TNF α and TNF β and inhibition of TNF activity. J Biol Chem 266:18324-18329.
Ofei F., Hurel S., Newkirk J., Sopwith M., Taylor R. (1996) Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881-885.
Scheen A.J., Paquot N., Castillo M.J., Lefèbvre P.J. (1994) How to measure insulin action in vivo. Diabetes Metab Rev 10:151-188.
Hales C.N., Randle P.J. (1963) Immunoassay of insulin with insulin antibody precipitate. Biochem J 88:137-146.
Heding L.G. (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11:541-548.
Kroder G., Bossenmaier B., Kellerer (1996) Tumor necrosis factor-α and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 97:1471-1477.
Moreland L.W., Margolies G., Heck L.W. Jr. (1996) Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: Toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 23:1849-1855.
