Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.

Oxidative Stress and Diabetic Vascular Complications

This Is the second of two articles describing a symposium on the relationship between inflammation and insulin resistance that was held in Niagra Falls, NY, 20–21 September 2002.

Antonio Ceriello (Udine, Italy) discussed the role of glucose intake and postprandial hyperglycemia in the development of diabetes complications, as well as the relationship of hyperglycemia to oxidative stress. The DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) study showed high 2-h postload glucose to be associated with increased mortality independent of fasting glucose (1), and the Pacific and Indian Ocean Study showed isolated 2-h hyperglycemia to double the risk of mortality (2). The Funagata Diabetes Study showed that impaired glucose tolerance (IGT) but not impaired fasting glucose was a risk factor for cardiovascular disease (CVD) (3). There is evidence that lowering postprandial glucose improves outcome. Post hoc analysis of the STOP-type 2 diabetes study showed that myocardial infarction and hypertension decrease with use of the prandial glucose-lowering agent acarbose (4). In the Kumamoto study, postprandial hyperglycemia strongly predicted retinopathy and nephropathy (5).

Endothelial dysfunction (ED) is a potential mediator of the effect of prandial glycemia, with altered vasodilation and procoagulant abnormalities. ED can be induced by hyperglycemia following a 75-g oral glucose load in persons with normal or IGT or with diabetes, with reduction of flow-mediated brachial artery dilation proportional to the degree of hyperglycemia (6). In a study of 225 persons with hypertension followed for 32 months, forearm ED was a marker of future CVD events (7), with a 4.5-year follow-up of 281 persons showing both ED and measures of oxidative stress to predict CVD events (8). Acute hyperglycemia may suppress vasodilation, which may involve oxidant stress, as it is reversed with antioxidant or l-arginine treatment (9).

Glucose increases endothelial cell free radical production leading …

https://care.diabetesjournals.org/content/diacare/26/6/1922.full.pdf

Inflammation and Insulin Resistance

The glycemic index was proposed in 1981 as an alternative system for classifying carbohydrate-containing food. Since then, several hundred scientific articles and numerous popular diet books have been published on the topic. However, the clinical significance of the glycemic index remains the subject of debate. The purpose of this review is to examine the physiological effects of the glycemic index and the relevance of these effects in preventing and treating obesity, diabetes, and cardiovascular disease.

https://jamanetwork.com/journals/jama/articlepdf/194907/JSC10297.pdf

The Glycemic Index: Physiological Mechanisms Relating to Obesity, Diabetes, and Cardiovascular Disease

Type 2 diabetes is a worldwide increasing disease resulting from the interaction between a subject's genetic makeup and lifestyle. In genetically predisposed subjects, the combination of excess caloric intake and reduced physical activity induces a state of insulin resistance. When beta cells are no longer able to compensate for insulin resistance by adequately increasing insulin production, impaired glucose tolerance appears, characterized by excessive postprandial hyperglycemia. Impaired glucose tolerance may evolve into overt diabetes. These 3 conditions, ie, insulin resistance, impaired glucose tolerance, and overt diabetes, are associated with an increased risk of cardiovascular disease. Because all these conditions are also accompanied by the presence of an oxidative stress, this article proposes oxidative stress as the pathogenic mechanism linking insulin resistance with dysfunction of both beta cells and endothelium, eventually leading to overt diabetes and cardiovascular disease. This hypothesis, moreover, may also contribute to explaining why treating cardiovascular risk with drugs, such as calcium channel blockers, ACE inhibitors, AT-1 receptor antagonists, and statins, all compounds showing intracellular preventive antioxidant activity, results in the onset of new cases of diabetes possibly being reduced.

Is Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis Revisited

Increasing evidence suggests that the postprandial state is a contributing factor to the development of atherosclerosis. In diabetes, the postprandial phase is characterized by a rapid and large increase in blood glucose levels, and the possibility that the postprandial "hyperglycemic spikes" may be relevant to the onset of cardiovascular complications has recently received much attention. Epidemiological studies and preliminary intervention studies have shown that postprandial hyperglycemia is a direct and independent risk factor for cardiovascular disease (CVD). Most of the cardiovascular risk factors are modified in the postprandial phase in diabetic subjects and directly affected by an acute increase of glycemia. The mechanisms through which acute hyperglycemia exerts its effects may be identified in the production of free radicals. This alarmingly suggestive body of evidence for a harmful effect of postprandial hyperglycemia on diabetes complications has been sufficient to influence guidelines from key professional scientific societies. Correcting the postprandial hyperglycemia may form part of the strategy for the prevention and management of CVDs in diabetes.

https://diabetes.diabetesjournals.org/content/diabetes/54/1/1.full.pdf

Postprandial Hyperglycemia and Diabetes Complications Is It Time to Treat

The present study aimed at evaluating whether acute elevations of plasma glucose concentrations could influence systemic hemodynamic parameters and baroreflex activity in humans. Plasma glucose con...

Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non-diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 micromol l(-1) ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet-rich plasma with insulin at two physiological concentrations (120 and 480 pmol l(-1)). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p < 0.01) and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p < 0.01), as well as lower values of blood filterability (p < 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non-diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s(-1)) (p < 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s(-1)) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The effects of insulin were not dose-related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications.

Effect of insulin on blood rheology in non-diabetic subjects and in patients with Type 2 diabetes mellitus.

https://doi.org/10.1016/j.aquaculture.2022.738127

C. La Marca

Papers

Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects

Effect of insulin on blood rheology in non-diabetic subjects and in patients with Type 2 diabetes mellitus.

The stakeholder's perception of socio-economic impacts generated by COVID-19 pandemic within the Italian aquaculture systems