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.

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…In addition, infliximab, one of these commercial anti-TNF biological agents, was tested in obese diabetic mice, and it improved insulin signal transduction in muscle, liver, and hypothalamus. In doing so, it completely restored the activity of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation (Araú jo et al, 2007). In the same vein, others have reported that insulin signaling in endothelial progenitor cells, measured by the phosphorylated to total Akt ratio, was reduced by 56% on exposure to TNF (Desouza et al, 2011).…”

Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity

“…The main molecular events determining this phenotype are the systemic and local production of cytokines (Howard et al, 2004;De Souza et al, 2005) and the activation of inflammatory pathways in cells of restricted areas of the hypothalamus involved in the control of feeding and thermogenesis (Howard et al, 2004;De Souza et al, 2005;Prada et al, 2005;Araú jo et al, 2007). Although it is generally accepted that consumption of fat-rich diets is among the most important environmental factors leading to obesity, little is known about the mechanisms linking dietary fats to the activation of inflammatory response and impairment of anorexigenic/thermogenic signaling in the hypothalamus.…”

Chronic TNF-α Neutralization Does Not Improve Insulin Resistance or Endothelial Function in “Healthy” Men with Metabolic Syndrome

“…There are a number of reports showing that endogenous (that is, in mice lacking TNF-α or TNF receptor) (22,23) or exogenous (TNF-α neutralization) interference with TNF-α signaling ameliorates insulin resistance during development of obesity (7,24), whereas other reports using similar strategies have failed to show an effect of TNF-α neutralization on insulin sensitivity (25,26). The reason for this discrepancy is unclear, but it may reflect dietary differences or differences in genetic backgrounds of the mice studied.…”

“…Although studies in patients with chronic inflammatory conditions such as rheumatoid arthritis clearly show that quenching TNF-α activity improves insulin sensitivity, (7,8) a putative role of TNF-α in the development of insulin resistance in human obesity is unclear. There is no evidence for TNF-α release from human subcutaneous (27) and visceral adipose tissue (28) in vivo; thus challenging an endocrine link between adipose tissue and whole body insulin resistance.…”

“…TNF-α has thus been proposed to be causatively involved in the evolution of insulin resistance and type 2 diabetes, and its complications (6). This hypothesis is supported by animal studies showing that interference with TNF-α signaling protects against devolvement of the metabolic syndrome during development of obesity (7), and by human studies showing that TNF-α neutralization improves insulin sensitivity in patients with chronic inflammatory disease (8,9).…”