Deletion of interleukin 1 receptor-associated kinase 1 (Irak1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.

Abstract

Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) 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 IRAK-1. 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 (versus 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.

• Authors: Xiao-Jian Sun, Soohyun Park Kim, Dongming Zhang, Helen Sun, Qi Cao, Xin Lu, Zhekang Ying, Liwu Li, Robert R Henry, Theodore P Ciaraldi, Simeon I Taylor, Michael J Quon
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 29 Pg. 12339-12350 (07 21 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28572512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Biomarkers
• Hypoglycemic Agents
• Insulin
• Interleukin-1 Receptor-Associated Kinases
• Irak1 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Biomarkers (blood, metabolism)
• Crosses, Genetic
• Diet, Fat-Restricted
• Diet, High-Fat (adverse effects)
• Endothelium, Vascular (drug effects, enzymology, metabolism, physiopathology)
• Glucose Clamp Technique
• Glucose Intolerance (etiology, metabolism, physiopathology, prevention & control)
• Hemizygote
• Hypoglycemic Agents (pharmacology)
• Insulin (pharmacology)
• Insulin Resistance
• Interleukin-1 Receptor-Associated Kinases (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Skeletal (drug effects, enzymology, metabolism)
• Obesity (etiology, physiopathology)
• Organ Specificity
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Subcutaneous Fat, Abdominal (drug effects, enzymology, metabolism)