Elsevier

Archives of Medical Research

Volume 36, Issue 3, May–June 2005, Pages 241-249
Archives of Medical Research

Review article
Metabolic and Vascular Abnormalities in Subjects at Risk for Type 2 Diabetes: The Early Start of a Dangerous Situation

https://doi.org/10.1016/j.arcmed.2005.03.013Get rights and content

Various groups at risk for type 2 diabetes have been identified, including individuals with family history of type 2 diabetes, obesity, prior gestational diabetes, polycystic ovary syndrome, metabolic syndrome, hypertension, dyslipidemia and particularly those with pre-diabetes (impaired glucose tolerance and/or impaired fasting glucose). To various degrees, all these groups have also been identified with significant vascular abnormalities that range from endothelial dysfunction and low-grade or sub-clinical inflammation to evident atherosclerosis. The mechanisms involved in establishing a link between the risk of type 2 diabetes and vascular dysfunction are multiple and complex. The presence in the circulation of various cytokines, hormones and substrates associated with increased visceral fat and insulin resistance, the frequent appearance of associated cardiovascular risk factors and/or the possibility of some genetically determined intrinsic vascular abnormalities are all explanatory mechanisms that are being evaluated in clinical research. Whereas the possibility of appreciating a significant reduction in cardiovascular outcomes in long-term prospective clinical trials in all these groups at risk for type 2 diabetes is still lacking, understanding these mechanisms and recognizing how various interventions may improve vascular health is a worthwhile area of research that may translate into important clinical strategies to reduce the burden of type 2 diabetes and cardiovascular disease.

Introduction

Type 2 diabetes represents a major worldwide health problem due to its increasing prevalence and complications (1). It is now more frequently identified in children and adolescents. Coronary heart disease (CHD) is the main cause of death in people with diabetes. CHD, usually secondary to atherosclerosis, gradually develops over many years and may precede the development of type 2 diabetes 2, 3. Several factors increase the risk of CHD in people with diabetes. Chronic hyperglycemia may directly participate in the development of CHD (4); however, significant damage to the vasculature results from the common presence of well-known cardiovascular risk factors such as hypertension, dyslipidemia, altered fibrinolysis and obesity, all components of the insulin resistance or metabolic syndrome (5).

Because cardiovascular disease may precede the development of type 2 diabetes, it has been considered that these two conditions have common antecedents. Insulin resistance, endothelial dysfunction and sub-clinical inflammation have often been reported in various groups at risk for type 2 diabetes, some of whom are also at risk for cardiovascular disease (6). Individuals with insulin resistance have a higher risk of developing vascular disease after controlling for the most common traditional cardiovascular risk factors. For instance, hyperinsulinemia, a surrogate marker for the presence of insulin resistance, was found to be an independent risk factor for cardiovascular disease in non-diabetic individuals in the Quebec Cardiovascular Study (7). In addition, The Insulin Resistance and Atherosclerosis Study (IRAS) found an independent correlation of insulin resistance assessed through intravenous glucose tolerance testing and the intimal medial thickness of the carotid artery, a marker of the degree of atherosclerosis (8).

Endothelial dysfunction and vascular sub-clinical inflammation are considered key elements in the development of vascular complications in people with diabetes, including atherosclerosis, and have also been found to be associated with insulin resistance 2, 9, 10. Interesting information is becoming available about how metabolic and vascular abnormalities are clearly evident in specific groups at risk for type 2 diabetes, opening the possibility for interventions that may reduce the progression not only to type 2 diabetes but also to cardiovascular disease. The purpose of this review is to present and discuss this information as we advance in our understanding of these pathophysiologic processes.

Section snippets

Risk for Type 2 Diabetes

The main groups considered at increased risk for type 2 diabetes are first-degree relatives of patients with type 2 diabetes, women with history of gestational diabetes, overweight and obese individuals (mostly those with central or abdominal obesity), some persons with hypertension, those with insulin resistance-associated dyslipidemia (high triglycerides, low HDL-cholesterol and increased LDL- cholesterol small dense particles), people with impaired fasting glucose and/or impaired glucose

The Endothelium in Health and Disease

The endothelium used to be considered a mechanical barrier between the blood and the tissues. It is now well recognized that the endothelium is a lot more than that. It plays a vital role in vascular homeostasis, regulating vascular tone, vascular smooth muscle cell proliferation, transendothelial leukocyte migration, as well as thrombosis and thrombolysis. In response to various mechanical and chemical stimuli, endothelial cells synthesize and release a large number of vasoactive substances,

Endothelial Dysfunction and Cardiovascular Risk

Endothelial dysfunction and sub-clinical inflammation are key elements in the atherosclerotic process 10, 13, 14, 15, 16. Several measures of endothelial dysfunction and inflammation have been shown to precede the development of cardiovascular disease, such as impaired vascular reactivity in the coronary circulation or the brachial artery, elevated levels of adhesion molecules, PAI-1 and, more recently, increased hs-CRP levels 17, 18, 19, 20, 21, 22.

Whereas no current clinical recommendation

Endothelial Dysfunction and Diabetes Risk

The association between endothelial dysfunction, sub-clinical inflammation and diabetes risk is not as strong as with cardiovascular risk but is rapidly emerging as a fascinating topic in the literature. For instance, several studies have shown an association between some markers of inflammation, including C-reactive protein and interleukin 6 and increased diabetes risk 23, 24. Some markers of coagulation/fibrinolysis such as PAI-1 levels have also been associated with increased type 2 diabetes

Family History of Type 2 Diabetes

Several metabolic and vascular abnormalities have been reported in normoglycemic individuals with family history of type 2 diabetes (Table 2). Vascular dysfunction has been identified in this group through the assessment of vascular reactivity in the brachial artery and in the skin microcirculation, through the measurement of plasma levels of various markers of endothelial activation (adhesion molecules) of vasoconstriction such as endothelin-1, of coagulation/fibrinolysis such as PAI-1 and of

The Underlying Mechanisms

What are the mechanisms that explain the presence of all these significant vascular abnormalities in people at risk for type 2 diabetes? Is it the underlying presence of insulin resistance, increased abdominal fat and/or is it a specific genetically determined vascular derangement that operates in these individuals? The mechanisms are not clear; however, it is possible that a combination of all these possibilities plays a role in creating all these deleterious changes in vascular function (

Conclusions

Important metabolic abnormalities, particularly insulin resistance, alone or in combination with abdominal obesity, are present in many groups at risk for type 2 diabetes. Significant vascular abnormalities that include impaired vascular reactivity, increased levels of some markers of endothelial activation, coagulation/fibrinolysis, and/or inflammation are commonly encountered in these groups as well. Evidence for atherosclerosis through the assessment of intima-media thickness of the common

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