IRAK-1/IRS-1 Signaling Cross Talk in Human Skeletal Muscle—Role in Insulin Resistance

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is downstream from IL-1 receptors and TLRs. We identified IRS-1 (pSer²⁴) as the first physiological substrate for IRAK-1. Decreased binding of IRS-1 (pS²⁴) to PI 3-kinase impairs insulin action. IRAK-1 k/o mice have improved metabolic insulin action. Currently unknown is the relevance of IRAK-1/IRS-1 interactions to human pathophysiology. To investigate this topic, we examined human skeletal muscle (SkM) from NGT (n=10), IGT (n=6), and T2D (n=12) (1^st cohort). Fasting protein expression of IRAK-1 and phospho-IRAK-1 (p-IRAK-1, activity proxy) and IRS-1 (pS²⁴) did not differ significantly across groups. Insulin infusion during hyperinsulinemic glucose clamp (HGC), caused acute reductions in IRS-1 (pS²⁴) in NGT that was diminished in IGT, and absent in T2D (p < 0.05, vs. NGT). p-IRAK-1 was unaltered during HGC in 1^st cohort. Acute insulin-induced reduction of IRS-1 (pS²⁴) in SkM was also found in women with PCOS (2^nd cohort, n=12). Insulin sensitivity improved after pioglitazone treatment (pio, 6 mo). This was associated with reduction in IRS-1 (pS²⁴) (both fasting and HGC (acute insulin stimulation); (vs. pio pre-treatment). In a 3^rd cohort, nondiabetic (n=13) and T2D subjects (n=13), associations between IRAK-1 phosphorylation in the fasting state and measures of insulin sensitivity were noted: HOMA-IR (r=0.57, p=0.01; consistent with HGC data from PCOS pre- and post-pio, and trend in 1st cohort). In sum: 1) p-IRAK-1 in SkM (activity surrogate), predicts insulin resistance (IR) in human subjects. 2) Ability of acute insulin stimulation to reduce IRS-1 (pS²⁴) is absent in T2D and improved after pio intervention in PCOS. 3) Changes in IRAK-1 phosphorylation of IRS-1 (S²⁴) represents cross-talk between immune signaling and insulin signaling that may cause IR in human SkM. Our findings suggest that IRS-1 (pS²⁴) and p-IRAK-1 are biomarkers of IR that may be molecular targets for therapy of IR in human metabolic diseases.