Proteínas e peptídeos bioativos de vegetais e seus mecanismos envolvidos no controle glicêmico

Abstract

Type 2 diabetes mellitus (T2DM) is a disease characterized by a chronic state of hyperglycemia, which can trigger changes in the body's functional and structural properties. Thus, the objective was to analyze the mechanism of action and the effect of bioactive proteins of plant origin in controlling blood glucose in the context of T2DM, seeking new therapeutic targets for this disease. This thesis was divided into three chapters. In the first and second, there are the protocol and the systematic review (SR), respectively, aiming to answer the question: how the isolated (pool) and purified proteins and peptides extracted from vegetables act to reduce blood glucose in experimental models of T2DM? The protocol was registered in the International Prospective Registry of Systematic Reviews (PROSPERO) under CRD42019110956. For SR, experimental studies were selected with bioactive proteins and peptides of plant origin that affect the glycemic control of animals with experimentally induced T2DM. The articles were selected according to the PICOS strategy (population, interventions, control and outcome) in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, EMBASE and Virtual Health Library. The initial search retrieved 916 articles. After reading the title, abstract and keywords, 24 articles were eligible for a full reading. After this process, five articles were included in the SR. The study's assessment of evidence and risk of bias was performed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) protocol. As a result of the SR, all pathways stimulated by the five molecules of vegetable protein origin mediated secondary stimuli in the insulin signaling cascade up to glucose uptake. In the third chapter, a preclinical study with the trypsin inhibitor isolated from tamarind seed (TTI) and in silico analysis with the TTIp model number 56 and conformation number 287 (TTIp 56/287) was presented. In the preclinical study, the effect of TTI on the hyperglycemic state in Wistar rats with T2DM induced by a high glycemic index and high glycemic load (HGLI) diet for 17 weeks was evaluated. From the diagnosis of T2DM, the animals (n = 15) were divided into three groups (n = 5): 1. T2DM without treatment; 2. T2DM treated with a standard diet (nutritionally adequate); and 3. T2DM treated with TTI (25 mg/kg), administered by oral gavage (1 ml) for 10 days. After this period, fasting insulin and glycemia were analyzed, in addition to the Homeostasis model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) models. At the end of the analysis, the group of animals that received the treatment with the TTI had lower fasting glucose concentration (p = 0.0031) and the HOMA-IR index (p = 0.0432), in addition to being higher HOMA-β index (p = 0.0052) when compared to the animals of the other groups evaluated. In the study by molecular dynamics simulation, the interaction between the TTIp 56/287 and the insulin receptor (IR) (PDB ID 4OGA) was observed. The TTIp 56/287-IR (-1591.54 kJ mol-1 ± 234.90), showed lower potential energy of interaction (EPI) compared to the Insulin-IR (Ins-IR) (-894.98 kJ mol-1 ± 32.16), with distinct amino acid residues involved in this interaction. Thus, TTI acted as a hypoglycemic agent in a preclinical study, and its connection to RI can trigger this action. This thesis shows that plant proteins, such as TTI, have antidiabetic potential as an adjuvant in glycemic control by acting in metabolic pathways common to RI.