Leukotriene Involvement in the Insulin Receptor Pathway and Macrophage Profiles in Muscles from Type 1 Diabetic Mice

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.

The pathogenetic role of pro- and anti- inflammatory cytokines in developing of diabetic myopathy in children

“…All revealed violations occurred on the background of increased level of IL-6 and decreased IL-13 level in the blood serum, which implied the chronic inflammatory process in patients with diabetes. It is known that chronic increasing of IL-6 amount causes damages to the skeletal muscles as a result of intercellular signals transferring and leads to loss of myofibrillar protein and muscle atrophy [8,31]. Moreover, IL-6 reduces the transferring of insulin signals to skeletal muscles, which causes the reduced amount of glucose transported inside [15].…”

“…Guimarães, et al (2019) experimental investigation. He revealed that the higher expression of IL-6 had correlations with lower expression of receptors to insulin in muscles of mice with diabetes WT [8].…”

Endangered Lymphocytes: The Effects of Alloxan and Streptozotocin on Immune Cells in Type 1 Induced Diabetes

“…Diabetes mellitus is a chronic disorder characterized by persistent levels of hyperglycemia caused by an insufficient production of insulin by the β cells of the pancreas due to a destruction of these cells in type 1 diabetes (T1D) or by ineffective insulin action in type 2 diabetes (T2D) [ 1 – 3 ]. Rodents have been extensively used as diabetes experimental models [ 4 ]—chemically induced diabetes is mainly useful for studying T1D.…”

Caracterização fenotípica e funcional de linfócitos T em camundongos diabéticos induzidos por aloxana e estreptozotocina

“…Diferentes materiais foram introduzidos nas gaiolas para enriquecer o ambiente dos animais (algodão, iglu, tubos de papelão, etc).Foram incluídos no estudo animais adultos jovens e machos que apresentaram perda de peso, acompanhada de glicemia superior a 300 mg/dL (16,6 mM), após administração de ALX e STZ, conforme delineamento descrito a seguir. Não foram incluídos os animais com glicemia inferior a 300 mg/dL após o uso dos agentes diabetogênicos(AYALA et al, 2019;GUIMARÃES et al, 2019). Para a indução de DM1 com STZ, os animais foram deixados em jejum de 5 horas, antes de receberem injeção intraperitoneal (i.p) de STZ (65 mg/kg; 300µL) dissolvida em tampão citrato de sódio a 0,05 M gelado (pH 4,0-4,5) por 5 dias consecutivos (Figura 6)(GUIMARÃES et al, 2019).…”

“…Não foram incluídos os animais com glicemia inferior a 300 mg/dL após o uso dos agentes diabetogênicos(AYALA et al, 2019;GUIMARÃES et al, 2019). Para a indução de DM1 com STZ, os animais foram deixados em jejum de 5 horas, antes de receberem injeção intraperitoneal (i.p) de STZ (65 mg/kg; 300µL) dissolvida em tampão citrato de sódio a 0,05 M gelado (pH 4,0-4,5) por 5 dias consecutivos (Figura 6)(GUIMARÃES et al, 2019).…”