Antonio Ceriello

contents

Abstract 123

Introduction 124

Possible Role of Hyperglycemic Spikes in Cardiovascular Diseases 124

Fasting Hyperglycemia and Cardiovascular Disease 124

Post-Prandial Hyperglycemia and Cardiovascular Disease:

Epidemiological Evidence 125

Post-Prandial Hyperglycemia and Cardiovascular Disease:

Intervention Studies 126

Mechanisms Involved 127

Post-Prandial Hyperglycemia and Oxidative and Nitrosative Stress 128

Conclusions 131

References 132

abstract

Increasing evidence suggests that the post-prandial state is a contributing factor to the development of atherosclerosis. In diabetes, the post-prandial phase is characterized by a rapid and large increase in blood glucose levels. The possibility that the post-prandial "hyperglycemic spikes" may be relevant to the onset of cardiovascular complications recently received much attention. Epidemiological studies and preliminary intervention studies have shown that post-prandial hyperglycemia is a direct and independent risk factor for cardiovascular disease. Most of the cardiovascular risk factors are modified in the post-prandial 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 post-prandial hyperglycemia on diabetic complications has been sufficient to influence guidelines from key professional scientific societies. Correcting post-prandial hyperglycemia may form part of a strategy for the prevention and management of cardiovascular diseases in diabetes.

introduction

Diabetes mellitus is characterized by a high incidence of cardiovascular disease1 and poor control of hyperglycemia appears to play a significant role in the development of cardiovascular disease in diabetes.2 Increasing evidence indicates that the post-prandial state is an important contributing factor to the development of atherosclerosis.3 In diabetes, the post-prandial phase is characterized by a rapid and large increase in blood glucose levels. The possibility that these post-prandial "hyperglycemic spikes" may be relevant to the pathophysiology of late diabetic complications is recently receiving much attention.

In this chapter, epidemiological data and preliminary results of intervention studies indicating that post-prandial hyperglycemia represents an increased risk for cardiovascular disease are surveyed. The proposed mechanisms involved in this effect are summarized.

possible role of hyperglycemic spikes in cardiovascular diseases

Fasting Hyperglycemia and Cardiovascular Disease

Over the last 10 years, many studies showed an independent relationship between cardiovascular diseases and glycemic control in patients with type 2 diabetes.2 These studies involved thousands of subjects, often newly diagnosed, who were followed up for periods ranging from 3.5 to 11 years and were evaluated on the basis of various cardiovascular end-points.2 It is necessary to underline that the majority of these studies used a single baseline fasting glycemic value or a single value of glycated hemoglobin A1c (HbA1c) to predict cardiovascular events occurring many years later.

For instance, the observational version of the United Kingdom Prospective Diabetes Study (UKPDS) showed that the mean HbA1c value was a good predictor of ischemic heart disease.4 In particular, multivariate analysis showed that for each 1% increment in HbA1c there was an approximate 10% increase in the risk of coronary heart disease.4 This evidence is not substantially different compared with the results of the interventional version of the UKPDS. In this trial, even though the result was not significant (p <0.052), intensive treatment leading to an approximate 1% reduction in HbA1c levels led to a 16% reduction in the occurrence of myocardial infarction.5

Interestingly, the UKPDS noted significant impacts on cardiovascular events in the metformin-treated group.6 However, it is reasonable that metformin, while improving insulin resistance, may have significantly improved the "cluster" of cardiovascular risk factors associated with insulin resistance.

The relationship existing between macroangiopathy and fasting plasma glucose or HbAlc is weaker than that observed with microangiopathy.2 This was found in cross-sectional or longitudinal studies. These data support the hypothesis that fasting plasma glucose or HbAlc alone is unable to describe thoroughly the glycemic disorders occurring in diabetes and its impact on cardiovascular disease. In addition to fasting glycemia and HbAlc, emphasis has recently been given to the relationship between post-prandial hyperglycemia and cardiovascular diseases.

Post-Prandial Hyperglycemia and Cardiovascular Disease: Epidemiological Evidence

The oral glucose tolerance test (OGTT) has been used mostly in epidemiological studies that attempt to evaluate the risk of cardiovascular disease. The main advantage of the OGTT is its simplicity: a single plasma glucose measurement 2 hours after a glucose load determines whether glucose tolerance is normal, impaired, or indicates overt diabetes.

The caveats of the OGTT are numerous because 75 or 100 g glucose is almost never ingested during a meal and, more importantly, many events associated with ingesting a pure glucose solution do not incorporate the numerous metabolic events associated with eating a mixed meal. Moreover, the relationship between glycemia and meal content is contingent upon the contents of the meal.7 However, it has recently been demonstrated that the level of glycemia reached 2 hours after an OGTT was closely related to the level of glycemia after a standardized meal (mixed meal in the form of wafers containing oat fractionation products, soy protein, and canola oil sweetened with honey: 345 kcal, 10.7 g fat, 12.1 g protein, 8.9 g simple sugars, 41.1 g starch, and 3.8 g dietary fiber), suggesting that the OGTT may represent a valid tool to reveal altered carbohydrate metabolism during a meal.8 Interestingly, the correlation is more consistent for the values of glycemia in the impaired glucose tolerance range.8

From an epidemiological point of view, the Hoorn Study,9 the Honolulu Heart Study,10 the Chicago Heart Study,11 and the more recent DECODE Study12 have clearly shown that glucose serum levels 2 hours after oral challenge with glucose are powerful predictors of cardiovascular risk. This evidence is confirmed also by two important meta-analyses: the first by Coutinho et al. examined studies of 95,783 subjects.13 The second, covering more than 20,000 subjects, pooled the data of the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.14

The possible role of post-prandial hyperglycemia as an independent risk factor has also been supported by the Diabetes Intervention Study showing how in type 2 diabetics post-prandial hyperglycemia predicts infarction15 and by another study associating post-prandial hyperglycemia levels with medio-intimal carotid thickening.16

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