IRAK-1/IRS-1 Signaling Cross Talk in Human Skeletal Muscle—Role in Insulin Resistance
Authors: CIARALDI THEODORE P. , MUDALIAR SUNDER , LI LIWU , SCALIA ROSARIO , SUN XIAO JIAN , HENRY ROBERT R. , QUON MICHAEL 
Published: June 2018

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) (1st 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 &lt; 0.05, vs. NGT). p-IRAK-1 was unaltered during HGC in 1st cohort. Acute insulin-induced reduction of IRS-1 (pS24) in SkM was also found in women with PCOS (2nd 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 3rd 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.

Disclosure
T.P. Ciaraldi: None. S. Mudaliar: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Janssen Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., National Institutes of Health. L. Li: None. R. Scalia: None. X. Sun: None. R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. M. Quon: None.