Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

Abstract

Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

“…Lowering LDL cholesterol (LDL-C) with statins is the best strategy documented to date for decreasing CVD risk in T1DM, but substantial residual risk remains. The increased risk is often attributed to hyperglycemia, fluctuating glucose levels, or glucosemediated metabolic memory (8,9). However, several lines of evidence suggest that glucose does not directly account for the increased CVD risk in patients with diabetes, or at least is not the only risk factor (7,10,11).…”

The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin: Implications for Clinical Practice

“…The endothelium plays a crucial role in developing diabetic complications: long-term hyperglycemia-induced oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation lead to a reduction in vascular endothelial function [ 8 , 9 ], perpetuating cellular environment changes (metabolic memory) [ 8 , 10 ] and micro- or macrovascular events. From a clinical perspective, this theory supports the importance of early treatment to prevent diabetic complications [ 10 , 11 ].…”

Mesa 1: Diabetes mellitus tipo 1 y enfermedad cardiovascular

“…La aterosclerosis comienza con la activación y lesión endotelial que lleva al depósito lipídico de LDL modificadas en la íntima y su posterior oxidación para iniciar la formación de la estría grasa y progresar en el desarrollo de la placa aterosclerótica 29 especial la formación de productos de glicación avanzada (en inglés, advanced glycation end products, AGEs) y el aumento en la expresión de sus receptores asociados a ligandos activadores (RAGEs, sus siglas en inglés) 30 . La unión a RAGEs induce la producción de especies reactivas de oxígeno (ROS, sus siglas en inglés) que activan vías proinflamatorias (NFκB), estimulan la proliferación de células musculares lisas y modifican proteínas vasculares.…”

“…La unión a RAGEs induce la producción de especies reactivas de oxígeno (ROS, sus siglas en inglés) que activan vías proinflamatorias (NFκB), estimulan la proliferación de células musculares lisas y modifican proteínas vasculares. Además, la hiperglucemia y el aumento de ácidos grasos libres generan menor actividad de óxido nítrico endotelial (eNOS) con disminución de óxido nítrico (ON), mayor producción de sustancias vasoactivas como la endotelina-1, la expresión de moléculas de proliferación y adhesión celular (ICAM-1, VCAM-1) 30,31 .…”