title: Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes.
abstract: TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.
authors.affiliation: Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Sao Paulo 13083-970, Brazil.
authors.forename: Eliana P
authors.initials: EP
authors.lastname: Araújo
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: De Souza
authors.forename: Mirian
authors.initials: M
authors.lastname: Ueno
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.forename: Manoel B
authors.initials: MB
authors.lastname: Bertolo
authors.forename: José B
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Mário J
authors.initials: MJ
authors.lastname: Saad
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004041:Dietary Fats; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D000069285:Infliximab; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D048031:JNK Mitogen-Activated Protein Kinases