Estudio del papel de los haplogrupos mitocondriales, el control glucémico y el tratamiento con metformina sobre los mecanismos moleculares subyacentes a la fisiopatología de la diabetes tipo 2

  1. Noelia Díaz Morales
Supervised by:
  1. Victor Manuel Victor González Director
  2. Milagros Rocha Barajas Director
  3. Susana Rovira Llopis Director

Defence university: Universitat de València

Year of defence: 2019

Committee:
  1. Eduardo Ruiz Pesini Chair
  2. Consuelo Borrás Blasco Secretary
  3. Pedro Escoll Guerrero Committee member

Type: Thesis

Teseo: 579793 DIALNET

Abstract

Type 2 diabetes (T2D) has become a major health problem worldwide which is related to micro- and macrovascular complications. Mitochondrial DNA (mtDNA) haplogroups might be involved in T2D and their associated complications. Thus, we aimed to determine the impact of mtDNA haplogroups on metabolic characteristics and renal function in T2D patients and healthy controls. Our results imply that the JT haplogroup (in particular the variant m.4216T>C) is associated with a worse management of glucose in T2D patients, which can contribute to a deterioration of renal function, thus predisposing the individual to the development of diabetic nephropathy. An adequate glycaemic control is essential for delaying the onset of T2D associated vascular complications, for this reason we evaluated its involvement on mitochondrial function, ROS production, and mitochondrial dynamics in leukocytes isolated from healthy volunteers and T2D patients, as well as the relationships between these parameters and leukocyte-endothelium interactions. Our data suggest that loss of glycaemic control in T2D patients is related with an imbalance of mitochondrial dynamics in their leukocytes (increased fission and decreased fusion), which compromises mitochondrial function and may lead to oxidative stress and enhanced leukocyte-endothelium interactions. Metformin is the most commonly prescribed anti-hyperglycaemic drug, and has been shown to exert beneficial effects on the vasculature. We proposed to study its effect on oxidative stress, mitochondrial and endothelial dysfunction, ER stress and autophagy, in leukocytes isolated from T2D patients that were or were not taking metformin. Our results support a beneficial impact of metformin treatment on oxidative stress (reduction in mitochondrial ROS production and increase in antioxidants), endothelial function (reduced levels of adhesion molecules), and decreased interactions of leukocytes with endothelial cells. On the other hand, the reduction in oxidative stress, together with an increase in the UPR pathways initiated by IRE1 and PERK may block the autophagic response in the leukocytes of metformin-treated patients; which contrasts with leukocytes from patients not treated with metformin, where the increased oxidative stress and the ATF6-dependent branch of UPR might increase autophagy in order to clear misfolded proteins. Overall, our findings support the involvement of the mtDNA haplogroup JT, oxidative stress, mitochondrial dynamics, endothelial dysfunction, ER stress and autophagy in the pathophysiology of T2D and suggest a role of these processes in the development of vascular complications. Moreover, they support the hypothesis that treatment of T2D patients with metformin modulates oxidative stress, UPR, and autophagy in leukocytes in order to reduce their interaction with the endothelium, which may delay the onset of the atherosclerotic process and, consequently, the development of T2D-associated vascular complications.