Benefícios do tratamento com insulina no diabete Mellitus tipo 1 em roedores - associação com a via de quinureninas

Abstract

Diabetes mellitus is a chronic multifactorial endocrine and metabolic disease associated with risks in the development of cardiovascular diseases such as vasculopathy and acute myocardial infarction. The role of the quinurenin metabolic pathways in diabetes mellitus is not yet well understood, so the investigation of the mechanisms associated with the disease and its vascular repercussions, objects of this study, might elucidate new pharmacological targets for its treatment. This study aimed to establish a relationship between the benefits of insulin treatment in type 1 diabetic animals and the quinurenin pathway. For the experiments, Wistar rats were divided into three experimental groups: Control (Healthy), Diabetic (DM) and Diabetes treated with insulin (DM + INS). DM rats received insulin treatment for 14 days (10 IU / kg, 2x / day, IP). Insulin treatment of DM rats was found to increase the activity of indoleamine 2,3 dioxigenase (IDO1) compared to DM and control rats. These findings were concomitant with the observation of a significant vasodilator response in the DM + INS group in relation to DM rats, both in the aorta and periaortic vasa vasorum, whose luminal volume was reduced in DM rats. Atrophy of the middle layer of vasa vasorum was observed in DM rats, which was reversed by treating DM rats with insulin. The thickness of the aortic middle layer was similar between groups. Additionally, the stereological evaluation demonstrated a reduction in perivascular adipose tissue volume in DM rats, which was reversed with insulin treatment. We also observed an increase in urinary protein and creatinine excretion with a respective reduction in their plasma levels in DM rats, which may be caused by a physiological upregulation of the urinary flow, an initial characteristic of diabetic nephropathy. Taken together, the data reveal that 14 days after induction of type 1 diabetes in Wistar rats were able to inhibit the metabolic route of quinurenins and compromise vascular function, but were not sufficient to generate severe renal injury. Until the end of this study, we have not identified in the literature studies that correlates insulin treatment, the metabolic route of quinurenins and their association on vascular effects in type 1 diabetes. Although these initial results do not allow the definitive establishment of a causal relationship, we were abble to observe that the standard treatment for DM1 with insulin was able to reverse structural changes on PVAT and middle layer of the periaortic vasa vasorum, correct protein excretion, and promote restoration of vascular tone concurrently with increased IDO1 activity and, therefore, with higher KYN production, suggesting a possible regulatory role of this pathway products on vascular and renal changes associated with type 1 diabetes. Further investigation of the pathway in this setting may elucidate new therapeutic targets for the treatment of these diseases, specialy its vascular and renal complications.