Deletion of interleukin 1 receptor associated kinase 1 (IRAK1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle

  1. Michael J. Quon2
  1. 1 University of Maryland School of Medicine; Baltimore Veterans Affairs Medical Center, United States;
  2. 2 University of Maryland School of Medicine, United States;
  3. 3 The Second Affiliated Hospital of Zhengzhou University, China;
  4. 4 Virginia Tech, United States;
  5. 5 University of California, San Diego School of Medicine, United States;
  6. 6 Veterans Affairs San Diego Healthcare System, United States
  1. ↵* Corresponding author; email: xsun{at}medicine.umaryland.edu

  1. Author contributions: XJS designed, performed and analyzed the experiments and coordinated the study and wrote the paper, SPK performed the animal care, IPGTT and ITT, ELISA measurement and immunoblotting analysis, DZ and HS participated in the immunoblotting of animal tissues, QC and XL performed and analyzed the experiments shown in Figure S3, ZY contributed to the discussion, LL contributed to the Irak1 k/o mice, RRH and TPC contributed to the interpretation of data and writing of the manuscript. ST contributed to the discussion of the project and writing the manuscript. MJQ conceived and coordinated the study, analyzed all data, wrote, and edited the manuscript.

Abstract

Chronic inflammation may contribute to insulin resistance (IR) via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor associated kinase 1 (IRAK1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male Irak1 null (k/o) mice to investigate the metabolic role of IRAK1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice (vs. WT) had substantially improved glucose tolerance [assessed by the intraperitoneal glucose tolerance test (IPGTT)]. As assessed with the hyperinsulinemic-euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the Irak1 k/o mice on chow diet, but the Irak1 deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in Irak1 k/o mice in vivo. Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from Irak1 k/o mice ex vivo. In conclusion, Irak1 deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice.

  • Received January 31, 2017.
  • Accepted June 1, 2017.

This Article

  1. First Published on June 1, 2017 doi: 10.1074/jbc.M117.779108 jbc.M117.779108.
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