Macro and microvascular alterations in diabetes mellitus 

1 – Diabetes as a vascular disease

Diabetes-related cardiovascular diseases are the main causes of death and disability in patients with type 2 diabetes. This is documented by the evidence that the risk of coronary artery disease is increased two to four folds in diabetes and that more than ¾ of deaths in type 2 diabetic patients have as a background a cardiovascular disease (1). Moreover, diabetics are more likely to develop congestive heart failure, ischemic and tromboembolic cerebrovascular events as well as renal failure (1), particularly when glycaemic alterations are accompanied by high blood pressure. Taking into account the pathophysiological background and the clinical outcome of diabetic vascular lesions, this paper will briefly review the macrovascular alterations, the microvascular abnormalities as well as arterial stiffness changes.

2 – Glucose metabolism, diabetes and macrocirculation 

A large number of studies have shown that as glucose tolerance worsens, the stiffness of large size arteries increases, favouring blood pressure elevation, left ventricular mass increase as well as reduction in coronary blood flow (2). In the Hoorn study (3), for example, which assessed, via the ultrasonographic technique, the status of carotid arteries in elderly people with an euglycaemic state, an impaired glucose metabolism or overt diabetes, provided evidence that carotid wall stiffness increased progressively with decreasing glucose tolerance, with the greatest alterations being observed in people with manifest diabetes mellitus. These data have been confirmed and expanded by the evidence that glycaemic values are the major determinants of carotid intima-media thickness in people with impaired fasting glucose or type 2 diabetes (4), at variance from what can be seen in euglycaemic individuals in which age and pulse pressure, i.e. the difference between systolic and diastolic values are responsible for the structural alterations of the large vessels.

These findings explain why in the United Kingdom Prospective Diabetes Study, performed in more than 4000 diabetic patients, the incidence of macrovascular complications is closely related to glycosylated haemoglobin levels (5). A further consequence of the above mentioned pathophysiological alterations is the evidence that increased thickness of the aortic artery, as assessed by aortic pulse wave velocity, is closely related to glomerular filtration rate and thus to alterations in renal function (6). Together the above mentioned data supports the concept that in diabetes, vascular dysfunction is a sensitive and accurate marker of disease progression and severity.

3 – Diabetes and microcirculation

Small artery circulation resistance is characterised by important structural changes in patients with diabetes mellitus. These include increase in the media-lume ratio, a vascular remodelling process, characterised by a displacement of the smooth muscle cells around the arteriolar wall, and a hypertrophic process of smooth muscle cells, i.e. the so called “hypertrophic remodelling process”.

Alterations in microcirculation, which may favour the development and progression of capillary rarefaction, affect not only the structural patterns of microcirculation but its functional characteristics as well. Two deserve mentioning. The first one refers to the impairment of the autoregulatory homeostatic process as well as the abnormality in the myogenic tone (1). The second one, is the endothelial dysfunction, with a reduced bioavailability of nitric oxide and thus an impaired endothelium-dependent vasodilatation (1).

A question of considerable pathophysiological and clinical relevance is whether microvascular and macrovascular alterations are early phoenomena in the clinical course of the disease. The evidence collected so far seems to support the concept that all the above mentioned vascular abnormalities are of early appearance and may represent an important pathogenetic factor for the development of the disease. This is supported by the evidence, provided by a longitudinal study (10 year observation), that the incidence of new-onset diabetes increases with increasing narrowing of the retinal arterioles (7). It is also supported by the finding that the increase in arterial stiffness (and thus the reduction in arterial distensibility) reported in diabetes may be detected in normoglycaemic normotensive offspring of type 2 diabetic patients (8). This finding reinforces the hypothesis that the genetic background may be of relevance for the development and progression of the above mentioned vascular abnormalities.

4 – Clinical and therapeutic implications

In several cardiovascular diseases both the endothelial dysfunction and the microcirculatory alterations have been reported to play an important prognostic role, the greater functional and structural abnormalities being associated with a poorer prognosis (1). The evidence is still lacking in diabetes, although some data collected in diabetic patients via the assessment of the coronary vascular responses to a sympathetic stimulus (cold pressor test) may suggest that alterations in the coronary vasomotor toner is a predictor of future events (9).