Abstract
Background and Aims Since hyperglycemia promotes inflammation by different pathways and inflammation participates in the development of chronic diabetes complications, we investigated the association between the leukotriene (LT) pathway and microvascular diabetes complications. Methods and Results Quantitative polymerase chain reaction was employed to quantify the expression of ALOX5 (encodes 5-lipoxygenase), LTB4R (encodes one of the LTB4 receptors), and MYD88 in peripheral blood mononuclear cells from 164 type 1 diabetes (T1D) individuals presenting or not diabetes kidney disease, retinopathy, peripheral neuropathy, and cardiovascular autonomic neuropathy (CAN); 26 nondiabetic subjects were included as controls. LTB4 plasmatic concentrations were also evaluated. The expression of LTB4R was significantly higher in T1D individuals than in controls. T1D individuals with microvascular complications presented lower MYD88 mRNA expression when compared to those without microvascular complications. Higher LTB4 concentrations were found in individuals with CAN versus without CAN. The observation of two distinct subgroups of T1D individuals in the correlation analyses motivated us to evaluate the characteristics of each one of these groups separately. The group presenting higher expression of ALOX5 and of LTB4R also presented higher values of HbA1C, of fructosamine, and of plasmatic LTB4. Conclusion In the diabetes setting, the LT pathway is not only activated by hyperglycemia but is also modulated by the status of the autonomic nervous system.
Highlights
Increasing evidence has accumulated pointing out inflammation as an important player in the development of chronic diabetes complications [1,2,3]
Comparing type 1 diabetes (T1D) and nondiabetic controls, no differences were observed in the mRNA expressions of ALOX5 and MYD88 and in the plasma concentrations of LTB4 after adjustment for sex, age, and use of statins, ARB, and ACEI (Figures 1(a), 1(b), and 1(d), respectively)
When participants were sorted according to the presence or absence of each one of the chronic microvascular complications, higher LTB4 concentrations were found in participants with cardiovascular autonomic neuropathy (CAN) versus without CAN (P = 0:005; Figure 2(e)) after adjustment for those confounding factors and for diabetic retinopathy (DR), diabetes kidney disease (DKD), and peripheral neuropathy
Summary
Increasing evidence has accumulated pointing out inflammation as an important player in the development of chronic diabetes complications [1,2,3]. Hyperglycemia accelerates the generation of advanced glycation end products (AGEs) that, by binding to RAGE (advanced glycation end productspecific receptor), activate NFkB in several cell types [5] This proinflammatory signaling pathway is counteracted by an anti-inflammatory pathway mediated by AGE-R1, a receptor that promotes AGE endocytosis and that acts in synergy with sirtuin-1, exerting anti-inflammatory and antioxidant actions [6]. Quantitative polymerase chain reaction was employed to quantify the expression of ALOX5 (encodes 5-lipoxygenase), LTB4R (encodes one of the LTB4 receptors), and MYD88 in peripheral blood mononuclear cells from 164 type 1 diabetes (T1D) individuals presenting or not diabetes kidney disease, retinopathy, peripheral neuropathy, and cardiovascular autonomic neuropathy (CAN); 26 nondiabetic subjects were included as controls. The LT pathway is activated by hyperglycemia but is modulated by the status of the autonomic nervous system
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