Elsevier

Vascular Pharmacology

Volume 54, Issues 3–6, March–June 2011, Pages 68-74
Vascular Pharmacology

Review
Cellular and molecular mechanisms of vascular injury in diabetes — Part I: Pathways of vascular disease in diabetes

https://doi.org/10.1016/j.vph.2011.03.005Get rights and content

Abstract

Diabetes-induced micro- and macrovascular complications are the major causes of morbidity and mortality in diabetic patients. While hyperglycemia is a key factor for the pathogenesis of diabetic microvascular complications, it is only one of the multiple factors capable of increasing the risk of macrovascular complications.

Hyperglycemia induces vascular damage probably through a single common pathway – increased intracellular oxidative stress – linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways. In addition, in conditions of insulin resistance, i.e., preceding the onset of type 2 diabetes, the phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway is selectively inhibited, while the mitogen activated protein (MAP)-kinase pathway remains largely unaffected, thus allowing compensatory hyperinsulinemia to elicit pro-atherogenic events in vascular smooth muscle and endothelial cells, including increased cell proliferation, and the expression of plasminogen activator inhibitor-1, as well as of proinflammatory cytokines and endothelial adhesion molecules.

Introduction

According to the International Diabetes Federation Atlas in 2009, the estimated worldwide prevalence of diabetes for 2010 has risen to 285 million, representing 6.6% of the world's adult population (Unwin et al., 2010). Diabetes-induced vascular complications are the major causes of morbidity and mortality in such a huge cohort of patients. Efforts in understanding the mechanisms underlying the development of vascular disease in diabetes therefore hold the promise of a major health impact, limiting the huge burden of this disease.

A thorough understanding of vascular complications in diabetes requires the distinction of two different types of disease, one affecting small resistance arteries, arterioles and capillaries (microvascular disease), and the other affecting large conductance vessels (macrovascular disease). Atherosclerosis occurs earlier in patients with diabetes, frequently with greater severity and more diffuse distribution, in the form of coronary artery disease, cerebrovascular disease and peripheral arterial disease (Beckman et al., 2002). Microvascular disease also however contributes importantly to morbidity and mortality: diabetic retinopathy is a leading cause of blindness, and diabetic nephropathy is currently the major cause of chronic renal failure (Merimee, 1990, Zatz and Brenner, 1986). Characteristically, microvascular disease is almost never found before the onset of diabetes (both type 1 and type 2), while macrovascular disease frequently precedes, sometimes by years, the onset of overt type 2 diabetes, within the context of the “metabolic syndrome” (Basta et al., 2002, Haffner et al., 1990).

Two large studies, The Diabetes Control and Complications Trial Research Group (DCCT) and the UK Prospective Diabetes Study (UKPDS), clearly showed that intensive treatment of hyperglycemia can reduce the progression of microvascular complications, including retinopathy, nephropathy and neuropathy (Ahern et al., 1993, UK Prospective Diabetes Study (UKPDS) Group, 1998a). Attempts at reducing consequences of macrovascular disease in diabetes have been much more frustrating. Only recently, the long-term follow-up studies of DCCT and UKPDS have shown that patients who received intensive blood glucose control had also, in the long-term, a decreased incidence of macrovascular complications (Cleary et al., 2006, Nathan et al., 2003, Nathan et al., 2005, Ruiz et al., 2010). The magnitude of such beneficial changes has been in any case relatively minor. These clinical observations suggest that hyperglycemia is a major factor for the pathogenesis of diabetic microvascular disease, but only one of the many other factors increasing the risk of atherosclerosis in large conductance arteries (Nathan et al., 2003).

In addition, the growing list of newly identified CHD-risk loci and single nucleotide polymorphisms (SNPs) provided by genome-wide association studies (GWASs) (Hayes et al., 2007) (for which recent examples are triglyceride-related genotypes (Sarwar et al., 2010, Thompson et al., 2010) and genetic variants at chromosome 9p21 associated with enhanced cardiovascular risk in type 2 diabetes through interaction with poor glucose control (McPherson et al., 2007, Zhou et al., 2008)), provides compelling evidence for the key role of genetic susceptibility in the pathogenesis of vascular disease in diabetes.

Section snippets

Glucose toxicity and cardiovascular disease

Haist and Best, in 1940, first observed that high glucose exerts multiple pathological effects on pancreatic β-cells (Haist and Best, 1940). Subsequently, the term “glucose toxicity” or “glucotoxicity” was coined to describe the adverse effects of chronic exposure of pancreatic β-cells to high concentrations of glucose (DeFronzo, 1988). At present, it is well established that high glucose exerts multiple pathological effects on many other cells and tissues, including those of the cardiovascular

Insulin resistance, hyperinsulinemia and cardiovascular disease

Insulin resistance has been defined as a state of a cell, tissue or body system in which greater-than-normal amounts of insulin are required to elicit a quantitatively normal response (Yalow and Berson, 1970). In between one and two thirds of people characterized by the metabolic syndrome (a cluster or cardiovascular risk factors such as obesity, hypertriglyceridemia, low concentrations of high-density lipoprotein cholesterol, hypertension, microalbuminuria, dysglycemia and compensatory

Conclusions

Oxidative stress appears to be the main final common pathway for four major mechanisms of glucose toxicity in the pathogenesis of vascular disease in diabetes, namely the polyol pathway, AGEs formation, PKC-DAG and the hexosamine pathways, leading to both microvascular complications (of which they are a largely prevailing pathogenetic mechanisms) and macrovascular complications. Glucose-related hyperosmolarity appears to be an important component of glucotoxicity, through activation of the

Acknowledgements

This work was supported by the Italian Ministry of Research and Scientific Research through funding to the Center of Excellence on Aging at the University of Chieti (to RDC), and a grant of the Istituto Italiano Ricerche Cardiovascolari (to RDC and RM).

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