Influence of the glycemic control and nephropathy stage on the reverse cholesterol transport in Diabetes mellitus: role of metabolic memory induced by advanced glycated albumin

Abstract

Advanced glycation end products are prevalent in hyperglycemia but also in detoxification failure of glycation intermediate compounds that intensify the carbonyl stress in diabetic kidney disease. Advanced glycated albumin (AGE-alb) independently associates with cardiovascular risk in diabetes mellitus (DM) and in chronic kidney disease. In macrophages, AGE-alb increases oxidative stress and endoplasmic reticulum stress and primes these cells to inflammation elicited by calgranulins and lipopolysacharides. These events are related to a diminished cholesterol efflux by apo A-I and HDL, due to the reduction, respectively, in ABCA-1 and ABCG-1 receptors that damages cholesterol trafficking from arterial wall to the liver. We recently demonstrated that AGE-albumin isolated from poorly controlled type 1 and type 2 diabetes mellitus patients' serum reduces cellular cholesterol removal favoring intracelular lipid accumulation by inducing ABCA-1 degradation. In a similar manner, AGE-albumin drawn from uremic rats disturbs macrophage reverse cholesterol transport (RCT). AGE and oxidative stress are the basis for the metabolic memory which underlies the elevated risk for long term DM complications even after regularization of the glycemic control. Our hypothesis is that the deleterious effects of AGE-alb on the RCT can persist, even after the removal of glycoxidative insult and that the adequate glycemic control of DM patients - reflected by the reduction of albumin glycation - can prevent this event. Considering the great generation of AGE in chronic kidney disease it is possible that the gradual modification of albumin by glycation, according to the stages of diabetic nephropathy, may lead to distinct and increasing biological effects, enhancing cardiovascular risk. Finally, we will test the hypothesis that microvascular complications in type 1 DM (retinopathy, nepropathy and neuropathy) are related to the loss of HDL antioxidant and vasodilation properties. These findings will contribute to elucidate how AGE-alb affects the lipid flux in macrophages and atherogenesis taken into account the legacy effect or metabolic memory and the role of glycemic control in the modulation of cardiovascular risk in DM. (AU)