RESUMEN
Background: Obesity and the inflammation associated with it, play a key role in the development of insulin resistance through the release of inflammatory cytokines and free fatty acids and the stimulation of toll-like receptors (TLR). Interleukin-1 receptor-associated kinase (IRAK), which mediates the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, is an important molecule in TLR signaling. The NF-κB pathway can reduce insulin efficacy by increasing the expression of proinflammatory cytokines. There is no safe inhibitor for the NF-κB pathway, and for this reason, the upper mediator of this pathway was selected for investigation. Objectives: To determine the effects of an IRAK inhibitor on insulin resistance and serum biochemical factors in high-fat-fed insulin-resistant mice. Methods: Insulin resistance was developed in C57BL/6J mice by 12 weeks of a high-fat diet. Subsequently, the IRAK 1/4 inhibitor 1-(2-(4-morpholinyl)ethyl)-2-(3-nitrobenzoylamino)benzimidazole (IRAKi)/or pioglitazone, or both, were administered for a further 2 weeks. After 12 h fasting, blood and tissue samples were collected, insulin and glucose levels were assayed, and the homeostatic model assessment was used to quantify insulin resistance (HOMA-IR). Results: The IRAKi decreased blood glucose levels significantly (253 ± 14.3 mg/dL vs 390.1 ± 16.6 mg/dL) and increased insulin sensitivity compared with untreated controls. However, we did not find a synergistic effect of IRAKi with pioglitazone in increasing insulin sensitivity. Conclusion: IRAKis can increase insulin sensitivity and their efficacy is comparable to pioglitazone. However, combined administration of pioglitazone and IRAKi had no synergistic effect compared with monotherapy.
RESUMEN
Insulin resistance is a feature of most patients with type 2 diabetes mellitus. Epidemiological evidence suggest a correlation between inflammation and insulin resistant states such as obesity, but the underlying mechanisms are largely unknown. Interleukin-1 receptor-associated kinases (IRAK) play a central role in inflammatory responses by regulating the expression of various inflammatory genes in immune cells. This study was aimed to investigate the effect of IRAK inhibitor on gene transcription and serum concentration of adiponectin in insulin-resistant mice. Experimental mice were randomly divided into 6 groups: the healthy control group was fed a regular chow diet while other groups were fed with a high-fat diet for 12 weeks. After this period, the animals were treated with IRAK inhibitor, pioglitazone, both IRAK and pioglitazone, and DMSO, for two weeks. Adiponectin gene expression level was analyzed by real-time PCR. Additionally, serum adiponectin levels were measured by ELISA. Homeostasis model assessment-adiponectin (HOMA-AD) as an insulin sensitivity index was calculated. IRAK inhibitor and pioglitazone increased significantly the expression of adiponectin gene. Also, adiponectin concentration in the control group (9.67±1.1 µg/ml) increased to 25.34±2.04 µg/ml in pioglitazone treatment group. IRAK inhibitor also increased adiponectin concentration (18.24±1.53 µg/ml) but did not show a synergistic effect with pioglitazone when administered simultaneously (26.66±2.5 µg/ml). HOMA-AD was 0.33±0.04 in pioglitazone treated group, 0.6±0.13 in IRAK inhibitor group, and 0.31±0.03 in animals that received IRAKi and pioglitazone. Our findings suggest that increased adiponectin secretion from adipose tissue mediated by IRAK inhibitor may increase the insulin sensitivity in an animal model of insulin resistance.
