A. Ceriello

Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress.

Aims/hypothesis. Oxidative stress plays an important role in diabetic vascular complications. It has been shown that an imbalance in the ratio of nitric oxide: superoxide anion, because of a prevalence of superoxide anion, leads to an alteration in vascular reactivity. In this condition peroxynitrite production, resulting from the reaction between nitric oxide and superoxide, could increase. Peroxynitrite is responsible for nitration of tyrosine residues in proteins. Therefore, the presence of nitrotyrosine in plasma proteins is considered indirect evidence of peroxynitrite production. The aim of this study was to demonstrate the presence of nitrotyrosine in the plasma of patients with Type II (non-insulin-dependent) diabetes mellitus and to correlate its concentrations with the plasma concentrations of glucose and antioxidant defenses. Methods. A total of 40 Type II diabetic patients and 35 healthy subjects were enrolled, and glycaemia, plasma nitrotyrosine, total antioxidant parameter and glycated haemoglobin were measured. Nitrotyrosine was detected by ELISA with a detection limit of 10 nmol/l. Results. Nitrotyrosine was found in the plasma of all diabetic patients (means ± SD = 0.251 ± 0.141 μmol/l), whereas it was not detectable in the plasma of healthy control subjects. Nitrotyrosine plasma values were correlated with plasma glucose concentrations (r = 0.38, p < 0.02) but not with total antioxidant parameter or glycated haemoglobin. Total antioxidant parameter was reduced in diabetic patients (p < 0.01). Conclusions. The presence of nitrotyrosine in the plasma of diabetic patients indicates that peroxynitrite is generated in diabetes, suggesting a possible involvement of peroxynitrite in the development of diabetic complications. [Diabetologia (2001) 44: 834–838]

Coagulation activation in diabetes mellitus : the role of hyperglycaemia and therapeutic prospects

SummaryNumerous studies have shown that coagulation abnormalities occur in the course of diabetes mellitus, resulting in a state of thrombophilia. These observations are supported by epidemiological studies which demonstrate that thromboembolic events are more likely to occur in diabetic patients. The coagulation abnormalities observed in diabetic patients seem to be caused by the hyperglycaemia, which also constitutes the distinguishing feature of this disease. These data are also supported by in vitro studies which demonstrate how glucose can directly determine alterations in the coagulation system. The abnormalities observed involve all stages of coagulation, affecting both thrombus formation and its inhibition, fibrinolysis, platelet and endothelial function. The final result is an imbalance between thrombus formation and dissolution, favouring the former. Hyperglycaemia probably determines the onset of these abnormalities through three mechanisms which are, respectively, non-enzymatic glycation, the development of increased oxidative stress and a decrease in the levels of heparan sulphate. The first seems to affect the functionality of key molecules of coagulation in a negative sense. Oxidative stress constitutes an important pro-thrombotic stimulus, while the decrease in heparan sulphate determines a reduction in antithrombotic defenses. Good metabolic control could play a key role in controlling the coagulation irregularities in diabetes. However, considering the difficulties in achieving such an objective, it is possible that the use of drugs may represent a valid alternative. In fact, several drugs exist which are of potential interest. It is, however, necessary to perform long-term studies which demonstrate unequivocably that by controlling the coagulation abnormalities in diabetic patients, prolongation of life is possible.

The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications.

It is both common and wise practice to adjust the treatment of diabetic patients to obtain plasma glucose concentrations as close as possible to the normal range, correcting both postprandial hyperglycaemic spikes and the less increased, but persistently high, plasma glucose concentration between meals. The Diabetes Control and Complications Trials (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have provided evidence that intensive treatment can prevent complications associated with diabetes mellitus. In both studies, effectiveness of hyperglycaemic treatment was assessed by means of the glycated haemoglobin level. This is an integrated measure of both postprandial and fasting hyperglycaemia. The absolute and relative importance of the two conditions, however, could differ depending upon the organ or system suffering from diabetic complications and other more or less known individual factors. This paper aims to emphasize the effects of acute hyperglycaemia, in particular, postprandial hyperglycaemia, on the development of diabetic complications. The role of oxidative stress as a mediator of acute hyperglycaemia is further discussed. More investigation in this area is required so that treatment can be eventually individualised. Perhaps, in some patients, efforts could be concentrated on the control of hyperglycaemic spikes and/or specific organ or system susceptibility to either acute or chronic hyperglycaemia.

Post-meal coagulation activation in diabetes mellitus: the effect of acarbose

SummaryIt has been previously demonstrated that hyperglycaemia activates haemostasis; diabetes mellitus is considered a thrombosis-prone state. Acarbose, by inhibiting dietary carbohydrate absorption, reduces post-meal hyperglycaemia. In this study we evaluated the effect of post-meal hyperglycaemia on two markers of coagulation activation: prothrombin fragments 1 + 2 and D-dimer. Seventeen non-insulin-dependent diabetic patients maintained on diet therapy alone were randomly assigned to receive — with a cross-over study design — acarbose (100 mg orally) or placebo before a standard meal. Blood samples for measurement of plasma glucose, insulin, prothrombin fragments 1 + 2 and D-dimer were drawn at 0, 60, 120 and 240 min. After both placebo and acarbose, hyperglycaemia and hyperinsulinaemia which followed a standard meal were accompanied by a significant increase of plasma concentration of prothrombin fragments 1 + 2 and D-dimer in comparison to their baseline values. Acarbose administration significantly reduced the rise of glucose, insulin, prothrombin fragments 1 + 2 and D-dimer from 0 to 240 min in comparison to placebo. We conclude that post-meal hyperglycaemia, at the level reached by many diabetic patients on diet therapy alone, induces a coagulation activation. Acarbose, by decreasing post-meal hyperglycaemia, may be useful in reducing meal-induced activation of haemostasis in diabetic patients.

The post‐prandial state in Type 2 diabetes and endothelial dysfunction: effects of insulin aspart

Objectiveu2003 Recently, much attention has been focused on the possibility that the post‐prandial state may be a cardiovascular risk factor in diabetes. The aim of the present study was to evaluate whether the post‐prandial state is associated with endothelial dysfunction in patients with diabetes and to explore the effect on this aspect of managing post‐prandial hyperglycaemia by insulin aspart.

Glycemic index, glycemic load and glycemic response: An International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC)

BACKGROUND AND AIMSnThe positive and negative health effects of dietary carbohydrates are of interest to both researchers and consumers.nnnMETHODSnInternational experts on carbohydrate research held a scientific summit in Stresa, Italy, in June 2013 to discuss controversies surrounding the utility of the glycemic index (GI), glycemic load (GL) and glycemic response (GR).nnnRESULTSnThe outcome was a scientific consensus statement which recognized the importance of postprandial glycemia in overall health, and the GI as a valid and reproducible method of classifying carbohydrate foods for this purpose. There was consensus that diets low in GI and GL were relevant to the prevention and management of diabetes and coronary heart disease, and probably obesity. Moderate to weak associations were observed for selected cancers. The group affirmed that diets low in GI and GL should always be considered in the context of diets otherwise understood as healthy, complementing additional ways of characterizing carbohydrate foods, such as fiber and whole grain content. Diets of low GI and GL were considered particularly important in individuals with insulin resistance.nnnCONCLUSIONSnGiven the high prevalence of diabetes and pre-diabetes worldwide and the consistency of the scientific evidence reviewed, the expert panel confirmed an urgent need to communicate information on GI and GL to the general public and health professionals, through channels such as national dietary guidelines, food composition tables and food labels.

Optimal dietary approaches for prevention of type 2 diabetes: a life-course perspective

In recent years, several alternative dietary approaches, including high-protein and low-glycaemic-load diets, have produced faster rates of weight loss than traditional low-fat, high-carbohydrate diets. These diets share an under-recognised unifying mechanism: the reduction of postprandial glycaemia and insulinaemia. Similarly, some food patterns and specific foods (potatoes, white bread, soft drinks) characterised by hyperglycaemia are associated with higher risk of adiposity and type 2 diabetes. Profound compensatory hyperinsulinaemia, exacerbated by overweight, occurs during critical periods of physiological insulin resistance such as pregnancy and puberty. The dramatic rise in gestational diabetes and type 2 diabetes in the young may therefore be traced to food patterns that exaggerate postprandial glycaemia and insulinaemia. The dietary strategy with the strongest evidence of being able to prevent type 2 diabetes is not the accepted low-fat, high-carbohydrate diet, but alternative dietary approaches that reduce postprandial glycaemia and insulinaemia without adversely affecting other risk factors.

The preventive anti-oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance.

Backgroundu2003 Hyperglycaemia‐derived oxygen free radicals may be mediators of diabetic complications.

Effects of S21403 (mitiglinide) on postprandial generation of oxidative stress and inflammation in type 2 diabetic patients

Aim/hypothesisEvidence suggests that postprandial hyperglycaemia may be a cardiovascular risk factor in diabetes. Oxidative stress and inflammation are involved in the pathogenesis of diabetic complications and previous studies have shown increased oxidative stress and inflammation in the postprandial phase in diabetic patients. The aim of the present study was to evaluate whether controlling postprandial hyperglycaemia with S21403 (mitiglinide) is accompanied by a reduced generation of oxidative stress and inflammation.Subjects and methodsForty type 2 diabetic patients participated in the study. Two different breakfast-tests were performed in each patient, with placebo or S21403. Plasma nitrotyrosine, plasma malondialdehyde (MDA), oxidised LDL (oxLDL), plasma total radical-trapping antioxidant parameter (TRAP), IL-6, IL-18, TNF-α, plasma glucose and insulin were measured.ResultsAfter the administration of S21403, 40xa0mg, a rapid stimulation of insulin secretion was observed, accompanied by a reduction of postprandial hyperglycaemia. With S21403, a significant decrease of either nitrotyrosine, MDA and oxLDL levels, and a preservation of plasma TRAP compared with placebo was found. Significant decreases of IL-6, IL-18 and TNF-α were also observed with S21403 compared with placebo.Conclusions/interpretationThis study shows that controlling postprandial hyperglycaemia with S21403 significantly improves the cluster of oxidative stress and inflammation markers that are increased in the postprandial state in diabetic patients.

Screening for peripheral arterial disease by means of the ankle‐brachial index in newly diagnosed Type 2 diabetic patients

Aimu2003 To evaluate the prevalence of peripheral arterial disease (PAD) with the ankle‐brachial index (ABI) in newly diagnosed Type 2 diabetic subjects.