Raquel Seiça

Endothelial dysfunction — A major mediator of diabetic vascular disease

The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications.

Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes

It has been argued that in late-onset Alzheimers disease a disturbance in the control of neuronal glucose metabolism consequent to impaired insulin signalling strongly resembles the pathophysiology of type 2 diabetes in non-neural tissue. The fact that mitochondria are the major generators and direct targets of reactive oxygen species led several investigators to foster the idea that oxidative stress and damage in mitochondria are contributory factors to several disorders including Alzheimers disease and diabetes. Since brain possesses high energetic requirements, any decline in brain mitochondria electron chain could have a severe impact on brain function and particularly on the etiology of neurodegenerative diseases. This review is primarily focused in the discussion of brain mitochondrial dysfunction as a link between diabetes and Alzheimers disease.

Methylglyoxal promotes oxidative stress and endothelial dysfunction.

Modern diets can cause modern diseases. Research has linked a metabolite of sugar, methylglyoxal (MG), to the development of diabetic complications, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether MG could directly influence endothelial function, oxidative stress and inflammation in Wistar and Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes. Wistar and GK rats treated with MG in the drinking water for 3 months were compared with the respective control rats. The effects of MG were investigated on NO-dependent vasorelaxation in isolated rat aortic arteries from the different groups. Insulin resistance, NO bioavailability, glycation, a pro-inflammatory biomarker monocyte chemoattractant protein-1 (MCP-1) and vascular oxidative stress were also evaluated. Methylglyoxal treated Wistar rats significantly reduced the efficacy of NO-dependent vasorelaxation (p<0.001). This impairment was accompanied by a three fold increase in the oxidative stress marker nitrotyrosine. Advanced glycation endproducts (AGEs) formation was significantly increased as well as MCP-1 and the expression of the receptor for AGEs (RAGE). NO bioavailability was significantly attenuated and accompanied by an increase in superoxide anion immunofluorescence. Methylglyoxal treated GK rats significantly aggravated endothelial dysfunction, oxidative stress, AGEs accumulation and diminished NO bioavailability when compared with control GK rats. These results indicate that methylglyoxal induced endothelial dysfunction in normal Wistar rats and aggravated the endothelial dysfunction present in GK rats. The mechanism is at least in part by increasing oxidative stress and/or AGEs formation with a concomitant increment of inflammation and a decrement in NO bioavailability. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of atherosclerosis and development of macrovascular diabetic complication.

Diabetes and mitochondrial oxidative stress: A study using heart mitochondria from the diabetic Goto-Kakizaki rat

Increasing evidence shows that the overproduction of reactive oxygen species, induced by diabetic hyperglycemia, contributes to the development of several cardiopathologies. The susceptibility of diabetic hearts to oxidative stress, induced in vitro by ADP-Fe2+ in mitochondria, was studied in 12-month-old Goto-Kakizaki rats, a model of non-insulin dependent diabetes mellitus, and normal (non-diabetic) Wistar rats. In terms of lipid peroxidation the oxidative damage was evaluated on heart mitochondria by measuring both the O2 consumption and the concentrations of thiobarbituric acid reactive substances. Diabetic rats display a more intense formation of thiobarbituric acid reactive substances and a higher O2 consumption than non-diabetic rats. The oxidative damage, assessed by electron microscopy, was followed by an extensive effect on the volume of diabetic heart mitochondria, as compared with control heart mitochondria. An increase in the susceptibility of diabetic heart mitochondria to oxidative stress can be explained by reduced levels of endogenous antioxidants, so we proceeded in determinating α-tocopherol, GSH and coenzyme Q content. Although no difference of α-tocopherol levels was found in diabetic rats as compared with control rat mitochondria, a significant reduction in GSH (21.5% reduction in diabetic rats) and coenzyme Q levels of diabetic rats was observed. The data suggest that a significant decrease of coenzyme Q9, a potent antioxidant involved in the elimination of mitochondria-generated reactive oxygen species, may be responsible for an increased susceptibility of diabetic heart mitochondria to oxidative damage.

Metformin restores endothelial function in aorta of diabetic rats

The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus.

Effects of α‐lipoic acid on endothelial function in aged diabetic and high‐fat fed rats

This study was conducted to investigate the effects of α‐lipoic acid (α‐LA) on endothelial function in diabetic and high‐fat fed animal models and elucidate the potential mechanism underlying the benefits of α‐LA.

Methylglyoxal, obesity, and diabetes

Methylglyoxal (MG) is a highly reactive compound derived mainly from glucose and fructose metabolism. This metabolite has been implicated in diabetic complications as it is a strong AGE precursor. Furthermore, recent studies suggested a role for MG in insulin resistance and beta-cell dysfunction. Although several drugs have been developed in the recent years to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the mechanisms of MG formation, detoxification, and action. Furthermore, we review the current knowledge about its implication on the pathophysiology and complications of obesity and diabetes.

Insulin protects against amyloid β-peptide toxicity in brain mitochondria of diabetic rats

This study compared the status of brain mitochondria isolated from 12-week streptozotocin (STZ)-diabetic rats versus STZ-diabetic animals treated with insulin during a period of 4 weeks. Brain mitochondria isolated from 12-week citrate (vehicle)-treated rats were used as control. For that purpose, several mitochondrial parameters were evaluated: respiratory indexes (respiratory control ratio (RCR) and ADP/O ratio), transmembrane potential (DeltaPsim), repolarization lag phase, repolarization level, ATP, glutathione and coenzyme Q (CoQ) contents, production of H2O2, ATPase activity, and the capacity of mitochondria to accumulate Ca2+. Furthermore, the effect of Abeta1-40 was also analyzed. We observed that STZ-induced diabetes promoted a significant decrease in mitochondrial CoQ9, ATPase activity, and a lower capacity of mitochondria to accumulate Ca2+ when compared with control and insulin-treated diabetic rats. The presence of 4 microM Abeta1-40 induced a significant decrease in RCR in the three groups of rats. However, this peptide induced a significant increase in the repolarization lag phase and a significant decrease in the repolarization level in control and diabetic animals without insulin treatment. Furthermore, this peptide exacerbated significantly the production of H2O2 in STZ-diabetic rats, this effect being avoided by insulin treatment. Our data show that although diabetes induces some alterations in brain mitochondrial activity, those alterations do not interfere significantly with mitochondria functional efficiency. Similarly, insulin does not affect basal mitochondria function. However, in the presence of amyloid beta-peptide, insulin seems to prevent the decline in mitochondrial oxidative phosphorylation efficiency and avoids an increase in oxidative stress, improving or preserving the function of neurons under adverse conditions, such as Alzheimers disease.

Brain and liver mitochondria isolated from diabeticGoto-Kakizaki rats show different susceptibility to induced oxidative stress

Increased oxidative stress and changes in antioxidant capacity observed in both clinical and experimental diabetes mellitus have been implicated in the etiology of chronic diabetic complications. Many authors have shown that hyperglycemia leads to an increase in lipid peroxidation in diabetic patients and animals reflecting a rise in reactive oxygen species production. The aim of the study was to compare the susceptibility of mitochondria from brain and liver of Goto‐Kakizaki (12‐month‐old diabetic) rats (GK rats), a model of non‐insulin dependent diabetes mellitus, to oxidative stress and antioxidant defenses.

CoQ10 therapy attenuates amyloid β-peptide toxicity in brain mitochondria isolated from aged diabetic rats

Using brain mitochondria isolated from 20-month-old diabetic Goto-Kakizaki rats, we evaluated the efficacy of CoQ10 treatment against mitochondrial dysfunction induced by Abeta1-40. For that purpose, several mitochondrial parameters were evaluated: respiratory indexes (RCR and ADP/O ratio), transmembrane potential (DeltaPsim), repolarization lag phase, repolarization and ATP levels and the capacity of mitochondria to produce hydrogen peroxide. We observed that 4 microM Abeta1-40 induced a significant decrease in the RCR and ATP content and a significant increase in hydrogen peroxide production. CoQ10 treatment attenuated the decrease in oxidative phosphorylation efficiency and avoided the increase in hydrogen peroxide production induced by the neurotoxic peptide. These results indicate that CoQ10 treatment counteracts brain mitochondrial alterations induced by Abeta1-40 suggesting that CoQ10 therapy can help to avoid a drastic energy deficiency that characterizes diabetes and Alzheimers disease pathophysiology.