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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.

SUBMITTER: Sun XJ

PROVIDER: S-EPMC5519380 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Sun Xiao-Jian XJ Kim Soohyun Park SP Zhang Dongming D Sun Helen H Cao Qi Q Lu Xin X Ying Zhekang Z Li Liwu L Henry Robert R RR Ciaraldi Theodore P TP Taylor Simeon I SI Quon Michael J MJ

The Journal of biological chemistry 20170601 29

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 <i>Irak1</i> null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body wei ...[more]

PMID: 28572512

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Project description:OBJECTIVE:Cytokines are elevated in various insulin-resistant states, including type 2 diabetes and obesity, although the contribution of interleukin-6 (IL-6) in the induction of these diseases is controversial. RESEARCH DESIGN AND METHODS:We analyzed the impact of IL-6 on insulin action in murine primary myocytes, skeletal muscle cell lines, and mice (wild type and protein-tyrosine phosphatase 1B [PTP1B] deficient). RESULTS:IL-6 per se increased glucose uptake by activating serine/threonine protein kinase 11 (LKB1)/AMP-activated protein kinase/protein kinase B substrate of 160 kDa (AS160) pathway. A dual effect on insulin action was observed when myotubes and mice were exposed to this cytokine: additive with short-term insulin (increased glucose uptake and systemic insulin sensitivity) but chronic exposure produced insulin resistance (impaired GLUT4 translocation to plasma membrane and defects in insulin signaling at the insulin receptor substrate 1 [IRS-1] level). Three mechanisms seem to operate in IL-6-induced insulin resistance: activation of c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), accumulation of suppressor of cytokine signaling 3 (socs3) mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired phosphorylation of IRS-1 (Ser307), restored insulin signaling, and normalized insulin-induced glucose uptake in myotubes. When using a pharmacological approach, liver X receptor agonists overcome IL-6-induced insulin resistance by producing downregulation of socs3 and ptp1b gene expression. Finally, the lack of PTP1B confers protection against IL-6-induced insulin resistance in skeletal muscle in vitro and in vivo, in agreement with the protection against the IL-6 hyperglycemic effect observed on glucose and insulin tolerance tests in adult male mice. CONCLUSIONS:These findings indicate the important role of IL-6 in the pathogenesis of insulin resistance and further implicate PTP1B as a potential therapeutic target in the treatment of type 2 diabetes.

Project description:Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.

Dataset Information

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

Publications

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

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