Abstract
Type 1 diabetes (T1D) is a metabolic disease associated with systemic low-grade inflammation and macrophage reprogramming. There is evidence that this inflammation depends on the increased systemic levels of leukotriene (LT) B4 found in T1D mice, which shifts macrophages towards the proinflammatory (M1) phenotype. Although T1D can be corrected by insulin administration, over time T1D patients can develop insulin resistance that hinders glycemic control. Here, we sought to investigate the role of leukotrienes (LTs) in a metabolically active tissue such as muscle, focusing on the insulin signaling pathway and muscle-associated macrophage profiles. Type 1 diabetes was induced in the 129/SvE mouse strain by streptozotocin (STZ) in mice deficient in the enzyme responsible for LT synthesis (5LO−/−) and the LT-sufficient wild type (WT). The response to insulin was evaluated by the insulin tolerance test (ITT), insulin concentration by ELISA, and Akt phosphorylation by western blotting. The gene expression levels of the insulin receptor and macrophage markers Stat1, MCP-1, Ym1, Arg1, and IL-6 were evaluated by qPCR, and that of IL-10 by ELISA. We observed that after administration of a single dose of insulin to diabetic mice, the reduction in glycemia was more pronounced in 5LO−/− than in WT mice. When muscle homogenates were analyzed, diabetic 5LO−/− mice showed a higher expression of the insulin receptor gene and higher Akt phosphorylation. Moreover, in muscle homogenates from diabetic 5LO−/− mice, the expression of anti-inflammatory macrophage markers Ym1, Arg1, and IL-10 was increased, and the relative expression of the proinflammatory cytokine IL-6 was reduced compared with WT diabetic mice. These results suggest that LTs have an impact on the insulin receptor signaling pathway and modulate the inflammatory profile of muscle-resident macrophages from T1D mice.
Highlights
The incidence of metabolic disorders is increasing dramatically and is widely considered a serious threat to public health
Considering studies involving LTs in inflammation and how they may be involved in the development of metabolic syndromes, in the present study we investigated the participation of LTs in the insulin receptor pathway, an important checkpoint pathway related with insulin resistance, and the macrophage profile, an important cell in inflammatory processes
Body weight loss is one of the symptoms of Type 1 diabetes (T1D), and in our study both wild type (WT) and 5LO-/- diabetic mice showed significant body weight loss compared with healthy mice (Figure 1(c))
Summary
The incidence of metabolic disorders is increasing dramatically and is widely considered a serious threat to public health In diseases such as diabetes, obesity, atherosclerosis, and gout, metabolic imbalance is associated with the establishment of low-grade systemic inflammation, which in turn is a determining factor in the pathophysiology of these diseases. This happens as a consequence of the accumulation of certain metabolic products, such as glucose, fatty acids, uric acid, and cholesterol, which activate receptors of innate immunity in leukocytes and induce the chronic production of proinflammatory cytokines and lipid mediators [1,2,3]. It is believed that in both T1D and T2D, insulin resistance is due to a systemic low-grade inflammation; the mechanisms involved may be distinct and still need to be elucidated
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