Análise do perfil metabolômico de pacientes com diabetes tipo 2 considerando genótipos do RS266729 do gene da adiponectina e a presença de complicações

Abstract

Diabetic retinopathy (DR) is a microvascular complication that affects approximately 30% of patients with type 2 diabetes mellitus (T2DM). Studies exploring risk factors for diabetes and its complications are relevant, as they contribute to the development of early recognition mechanisms for patients at risk. Among the genes investigated in relation to T2DM risk, the ADIPOQ gene stands out. It encodes adiponectin, an adipokine that plays a key role in carbohydrate metabolism regulation, reducing peripheral insulin resistance in diabetes. The rs266729 polymorphism in the ADIPOQ gene has been associated with T2DM; however, there are still gaps in the literature regarding its association with DR. Metabolomics, a large-scale analysis of metabolites, is a promising tool for revealing metabolic changes and underlying mechanisms involved in the pathogenesis of diabetic complications. The aim of this study was to analyze and compare the metabolomic profile of samples from healthy individuals and from patients with T2DM without DR, patients with DR in two stages of severity—non-proliferative (NPDR) and proliferative (PDR)—as well as from patients who had undergone limb amputation. In addition, the metabolomic profile of T2DM patients carrying different genotypes of the rs266729 polymorphism was evaluated. The study included a sample of 127 individuals, divided into groups according to disease progression for the analysis of the ADIPOQ gene polymorphism. For the metabolomic analysis, participants were grouped as follows: Control (CONT), Amputees (AMP), T2DM without DR (DM2), Non-proliferative DR (NPDR), and Proliferative DR (PDR). Sociodemographic data, physical activity (IPAQ), anthropometric and clinical data, and venous blood were collected for biochemical profile assessment (glucose, glycated hemoglobin, total cholesterol, HDL-c, LDL-c, and triglycerides). Genotyping of the ADIPOQ polymorphism was performed using the restriction fragment length polymorphism (RFLP) technique, and metabolomic profiling was carried out using Nuclear Magnetic Resonance (NMR) spectroscopy. Regarding metabolites in the DR stages, it was observed in the studied sample that valine, isobutyrate, and the arginine and proline pathways were discriminatory for the NPDR group. Ketone body synthesis and degradation metabolism, associated with the metabolite acetoacetate, as well as the biosynthesis of phenylalanine, tyrosine, and tryptophan, were discriminatory for the PDR group. Histidine metabolism was present and discriminatory in the AMP group. Insulin therapy was more frequent among carriers of the rs266729 G allele (CG+GG group).Glutamate was found to be discriminatory for the CG+GG group, potentially indicating a poor disease prognosis, while glutamine and citrulline were discriminatory for the CC group, possibly indicating a more favorable prognosis. The urea cycle also differentiated the CG+GG group from the CC group. The findings of this study contributed to advances in the metabolomic analysis of T2DM and its complications, highlighting histidine as a marker for the AMP group and the glutamate/glutamine ratio as potentially relevant to explain the association of the rs266729 allele with T2DM.