Glucolipotoxicity-induced Oxidative Stress is Related to Mitochondrial Dysfunction and Apoptosis of Pancreatic β-cell

Abstract

: Glucolipotoxicity-induced oxidative stress and mitochondrial dysfunction of pancreatic β-cells are one of the mechanisms that have been related to the low insulin secretion and cell death during diabetes development. In early or non-chronic stages, the pancreatic β-cells respond to hyperglycemia or hyperlipidemia, stimulating insulin secretion. However, the chronic effect of both leads to the establishment of glucolipotoxicity which induces constant overstimulation of pancreatic β-cells, a condition that leads to cell death by apoptosis. The mechanism described, at this moment, is the accelerated mitochondrial dysfunction triggered by the high production of reactive oxygen species (ROS) due to excess nutrients. At first, mitochondria respond to over-nutrition accelerating oxygen consumption and consequently increasing the ATP synthesis. A permanent increase of ATP/ADP ratio leads to a constant inhibition of K+ ATP-channel and therefore a continuous insulin secretion accompanied by an increase in ROS. Finally, ROS accumulation compromises mitochondrial function due to the uncontrolled oxidation of proteins, lipids, and DNA generating functional alterations such as a drop of membrane potential, deregulation of mitochondrial dynamics, low rate of ATP synthesis and consequently the cell death. This review aims to describe the effect of glucolipotoxicity-induced oxidative stress and its relationship with mitochondrial dysfunction in β-cell during type 2 diabetes development.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

“…Our data support this framework because GLT decreased the GSH concentration and redox potential; however, TMAO showed no effect on this oxidative mechanism ( Figure 4 A,C).The beneficial TMAO phenotype we observed on β-cell function corresponds with increased IRE1α and decreased P-PERK protein levels during GLT-induced ER stress. β-cell function begins with insulin production via translation and folding at the ER, followed by maturation into secretory granules [ 41 , 45 , 46 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ]. Therefore, ER stress and accumulation of unfolded proteins at the ER plays a major role in T2D β-cell damage [ 115 , 132 , 133 , 134 ].…”

Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity

“…So far, the mechanisms of lipotoxicity in pancreatic beta-cells have been extensively studiedmainly in rodent insulin-secreting beta-cell lines and islets due to a scarce supply of human islets. Numerous groups have demonstrated that toxic effects of FFAs in beta-cells involve an induction of oxidative stress, activation of ER stress and mitochondrial dysfunction [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The generation of the human EndoC-βH1 beta-cell line [ 57 ] has enabled studies on the specific effects of various FFAs in human beta-cells [ 13 , 14 , 56 , 60 , 61 ].…”

“…Elevated plasma free fatty acid (FFA) levels have been detected at the prediabetes state and in T2DM patients, and it is believed that chronic exposure of pancreatic insulin-secreting beta-cells to FFAs induce beta-cell dysfunction and death [ 3 , 4 , 5 , 6 ]. FFAs induce a multimodal stress response, including oxidative stress, endoplasmic reticulum (ER) stress and mitochondrial dysfunction, leading to dysfunction and death of beta-cells [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The two most abundant dietary FFAs in plasma are saturated palmitic acid (PA) and monounsaturated oleic acid (OA)—of which, OA exerts toxic effects in human pancreatic beta-cells [ 13 , 14 ], in contrast to rodent beta-cells in which it protects from PA-mediated cell death [ 15 ].…”

The role of counterinsular hormones in the regulation of glucose homeostasis and the pathogenesis of type 2 diabetes mellitus in COPD

“…Гиперсекреция гормона роста приводит к усилению процессов глюконеогенеза и липолиза, сопровождающихся снижением проницаемости клеточных мембран для глюкозы, усилением секреции инсулина с постепенным истощением инсулярного аппарата. При этом имеют место симптомы гиперфункции гипофиза (акромегалия, гигантизм), сухость слизистых оболочек и кожи, жажда, полиурия [13] [14]. Инсулинорезистентность (ИР), развивающаяся в результате вышеуказанных факторов и являющаяся ведущим патогенетическим механизмом нарушений углеводного обмена при ХОБЛ, и неадекватная секреция инсулина могут усиливать друг друга.…”