EFEITOS DA ESPERMIDINA SOBRE CAMUNDONGOS COM DIABETES MELLITUS TIPO 2: O Papel Do Estresse Do Retículo Endoplasmático

Abstract

Polyamine spermidine (SPD) is used by the population as an anti-aging supplement and, experimentally, improves energy metabolism in some animal models of obesity. However, its effect on experimental models of sucrose-induced Type 2 diabetes mellitus (T2DM) and its mechanisms has not yet been evaluated. Additionally, its oral pharmacology is poorly studied. Thus, this study has two objectives: 1 - to investigate, in silico, the pharmacokinetic and pharmacodynamic parameters of SPD; 2 - to analyze the effects of SPD in mice with T2DM induced by a high-sucrose diet (HSD). The in-silico assays were performed using the software SWISSADME, PROTOX-II, SWISSTargetPrediction, and Pass to evaluate, respectively, the physicochemical, pharmacokinetic, pharmacodynamic, and toxicological properties of SPD. In the in vivo study, post-weaning female mice were divided into three groups: control group (CTR; n=7) fed with standard diet and DRS (n=7) and DRS/ESP (n=7) groups that received 30% sucrose solution for 20 weeks. From the 12th week onwards, the DRS/ESP group received 20 mg/kg of oral SPD, while the other groups received water. Treatment lasted 8 weeks, with monitoring of weight, food intake, blood glucose and glucose tolerance test (GTT). Subsequently, the animals were euthanized, blood samples were collected for biochemical and insulin resistance analyses. Liver samples were collected for evaluation of hepatic lipids, histology and protein expression of endoplasmic reticulum (ER) markers. Samples of brown (BAT) and white adipose tissue were collected for morphometry. Moreover, samples of perigonadal adipose tissue (PAT) were using lipolysis assays. All data were represented as mean ± s.e.m and differences were demonstrated by ANOVA (p<0.05. SPD demonstrated to have a good oral bioavailability, with a bioavailability score equal to 0.55 and satisfactory results according to the Lipinski, Veber and Egan parameters. Regarding pharmacokinetic behavior, SPD showed high absorption by the gastrointestinal tract, does not penetrate the blood-brain barrier, not being a substrate for glycoprotein P, and not inhibiting any of the main cytochrome P450 enzymes. About toxicokinetic settings, the lethal dose of SPD was 820 mg/kg, and it was inactive for hepatotoxicity, carcinogenicity, immunotoxicity and mutagenicity parameters. Regarding the experimental approach, continuous exposure to sucrose increased the body mass of animals when compared to CTR, which is explained by the increase in energy consumption. This greater energy intake increased retroperitoneal, mesenteric, and perigonadal fat deposits. DRS and DRS/ESP animals also showed an increase in glycaemia, serum triglycerides (TG) and hepatic total fat and TG. The lipolytic activity of the PAT of animals exposed to sucrose was impaired under all conditions: basal, with adrenergic stimulation and with insulin inhibition. ESP increased the BAT and improved serum TG, glucose homeostasis by TTG and insulin resistance by TyG index. In the histological analysis, ESP reduced sucroseinduced steatohepatitis. This effect must be due to the restoration of protein expressions of hepatic GRP78, PDI and ATF4, key proteins in the maintenance of ER homeostasis. Therefore, ESP was able to improve the glycolipid metabolism of mice with T2DM that can be explained by restoration of hepatic ER homeostasis. In addition, it has pharmacokinetic and toxicological characteristics that make it a potential drug for the treatment of this disorder by oral route.