J. Lambert

Endothelial dysfunction and pathogenesis of diabetic angiopathy

OBJECTIVE AND METHODS To review, from the clinical perspective, the contribution of dysfunction of the vascular endothelium to the pathogenesis of diabetic micro- and macroangiopathy. RESULTS Available data indicate that endothelial dysfunction in diabetes complicated by micro- or macroalbuminuria (renal microangiopathy) is generalised. The close linkage between microalbuminuria and endothelial dysfunction is an attractive explanation for the fact that microalbuminuria is a risk marker for atherosclerotic cardiovascular disease in diabetes. Endothelial dysfunction precedes the occurrence of even early diabetic microangiopathy. However, it is not clear whether endothelial dysfunction is a feature of the diabetic state per se or whether additional factors are required to induce endothelial dysfunction given the presence of diabetes. Convincing data from animal and in vitro models exist to indicate that endothelial dysfunction in diabetes may be related to hyperglycaemic pseudohypoxia, activation of protein kinase C, increased expression of transforming growth factor-beta and vascular endothelial growth factor, non-enzymatic glycation, oxidative stress, activation of the coagulation cascade, increased expression of tumour necrosis factor-alpha, and high levels of insulin and insulin precursor molecules. However, the importance of these proposed mechanisms have not yet been extensively assessed in diabetes in man. CONCLUSIONS Endothelial dysfunction plays a key role in the pathogenesis of diabetic angiopathy in man. The biochemical basis of endothelial dysfunction in diabetic man, however, has yet to be fully elucidated.

Endothelium-Dependent and -Independent Vasodilation of Large Arteries in Normoalbuminuric Insulin-Dependent Diabetes Mellitus

Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.

Vessel Wall Properties of Large Arteries in Uncomplicated IDDM

OBJECTIVE Patients with insulin-dependent diabetes mellitus (IDDM) are at high risk for cardiovascular disease. Arterial distensibility and compliance are vessel wall properties of large arteries. Altered large artery wall properties can be an early feature of vascular dysfunction. This study investigates vessel wall properties in 30 patients with uncomplicated IDDM and 30 matched healthy control subjects. RESEARCH DESIGN AND METHODS Vessel wall properties of the elastic common carotid (CCA) and the muscular femoral (FA) and brachial arteries (BA) were measured with a vessel wall movement detector system. Blood pressure and heart rate were recorded simultaneously with a semiautomated device. Aortic pulse wave velocity was estimated from the carotido-femoral transit time. RESULTS Blood pressure (IDDM patients: 118 ± 10/69 ± 5 mmHg), pulse pressure (IDDM patients: 49 ± 8 mmHg), and heart rate (IDDM patients: 65 ± 9 beats/min) were similar in IDDM patients and control subjects. No statistically significant changes between IDDM patients and control subjects were found for diameter, distensibility, and compliance of the elastic CCA and the muscular BA. Distensibility (IDDM patients: 16.9 ± 6.4 10-3/ kPa; control subjects: 22.4 ± 11.8 10-3/kPa) of the muscular FA was decreased in IDDM (P < 0.05). However, FA compliance (IDDM patients: 0.80 ± 0.23 mm-2/kPa; control subjects: 0.94 ± 0.41 mm2/kPa) and FA diameter (IDDM patients: 7.87 ±1.10 mm; control subjects: 7.57 ±1.11 mm) did not differ statistically between IDDM patients and control subjects. Aortic pulse wave velocity was the same in IDDM patients and control subjects (IDDM patients: 5.1 ± 0.6 m/s). No relation was found between vessel wall properties and duration of disease, actual glucose level, and HbA1c for all three arteries (CCA, BA, and FA). But the groups might have been too small to draw conclusions. CONCLUSIONS The results of the present study show that in this group of patients with uncomplicated IDDM, vessel wall properties of elastic and muscular large arteries were not obviously reduced when compared with healthy control subjects. However, distensibility of the FA was lower in IDDM patients. Early atherosclerotic changes in IDDM frequently occur at this site. A difference related to the duration of diabetes could not be excluded.

Arterial compliance and distensibility are modulated by body composition in both men and women but by insulin sensitivity only in women

Summary Large artery stiffening could contribute to the development of cardiovascular disease. The aim of this study was to investigate associations between arterial stiffness and diameter with insulin sensitivity and body composition in healthy men and women. In healthy, young (< 41 years old), non-obese (BMI < 27 kg/m2) men (n = 17) and women (n = 17), we measured the arterial diameter, the distension, the distensibility coefficient and the compliance coefficient of the elastic common carotid and muscular femoral arteries with a non-invasive ultrasonographic method. We also assessed glucose uptake (by a euglycaemic hyperinsulinaemic clamp technique), total body fat and lean body mass (by bioelectrical impedance analysis) and abdominal subcutaneous and visceral fat area (by magnetic resonance imaging). In women, but not in men, the distension and distensibility and compliance coefficients of the femoral artery were negatively associated with insulin concentrations (β = –0.62, p = 0.008; β = –0.65, p = 0.005 and β = –0.59, p = 0.01), and positively with glucose uptake (β = 0.59, p = 0.02; β = 0.68, p = 0.005 and β = 0.54, p = 0.04). Associations with glucose uptake were independent of the mean arterial pressure and body composition. In men and women, arterial compliance was positively associated with fat mass variables, which were mediated by a strong association between the femoral artery diameter and lean body mass (β = 0.80, p < 0.001) and between the common carotid artery diameter and visceral fat area (β = 0.56, p = 0.001). We found an independent association between insulin resistance and arterial stiffness, which was more pronounced in women than in men. [Diabetologia (1999) 42: 214–221]

Carotid Artery Stiffness is Increased in Microalbuminuric IDDM Patients

OBJECTIVE In IDDM, the development of microalbuminuria, which is associated with an elevation in blood pressure within the normal range, is a risk factor for future cardiovascular disease. Vascular stiffness might be one of the factors involved because it increases systolic blood pressure and the workload of the heart. RESEARCH DESIGN AND METHODS We investigated carotid artery stiffness with a noninvasive ultrasound method in 24 microalbuminuric and 53 normoalbuminuric IDDM patients and in 54 healthy control subjects. RESULTS The distensibility coefficient, a measure of intrinsic vascular wall elasticity, was decreased in microalbuminuric IDDM (21.6 × 10−3/kPa) as compared with normoalbuminuric IDDM (24.8 × 10−3/kPa) and control subjects (25.9 × 10−3/kPa; P = 0.02). This result was based on a higher blood pressure in microalbuminuric patients. After correction for the difference in blood pressure, the distensibility coefficients were similar in the three groups. In the two diabetic patient groups taken together, age, blood pressure, female sex, diabetes duration, and cigarette smoking were determinants of a decreased distensibility. CONCLUSIONS Blood pressure is a major determinant of increased arterial stiffness in microalbuminuric IDDM patients. Increased arterial stiffness may contribute to the accelerated progression of complications if concomitant hypertension exists.

ACE-inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients.

The usefulness of treatment with an angiotensin‐converting enzyme‐inhibitor (ACE‐inhibitor) in normotensive patients with type 1 diabetes is controversial. We investigated whether ACE‐inhibition improves endothelial function in such patients and compared the responses to those in healthy subjects.

Sex Steroids, Insulin, and Arterial Stiffness in Women and Men

Arterial stiffness may be influenced by sex steroids and insulin; the association with fasting insulin level may be stronger in women than in men. Therefore, we analyzed the effects of sex steroid administration on (1) arterial stiffness and (2) the relationship between fasting insulin level and arterial stiffness. Twelve male-to-female transsexuals were treated with ethinyl estradiol and cyproterone acetate, and 18 female-to-male transsexuals were treated with testosterone esters, with assessments made at baseline and after 4 and 12 months. Changes in distensibility and compliance coefficients (DC and CC, respectively) of the common carotid artery, femoral artery (FA), and brachial artery (BA) were analyzed in relation to changes in fasting plasma levels of glucose, insulin, HDL-cholesterol, and triglycerides. After 4 months of estrogens and antiandrogens in men, significant reductions in the CC and DC of the FA (P=0.006 and P=0.04, respectively) and BA (P=0.04 and P=0.04, respectively) were observed. In women, testosterone, on average, did not affect DC or CC, but the changes in fasting insulin level were strongly negatively associated with changes in the CC and DC, especially in the FA and BA. These associations were significantly less strong in genetic men and were independent of age, mean arterial pressure, and glucose and lipid levels. This experimental study shows (1) that short-term administration of estrogens and antiandrogens increases FA and BA stiffness in men and (2) that the fasting insulin level is a stronger determinant of arterial stiffness in women than in men.

Familial hyperhomocysteinaemia and endothelium-dependent vasodilatation and arterial distensibility of large arteries

OBJECTIVES Mild hyperhomocysteinaemia, fasting as well as after a methionine load, occurs in families and is associated with premature atherosclerosis. We hypothesised that endothelial dysfunction plays a role in the relation between hyperhomocysteinaemia and clinical vascular disease. METHODS In this study flow-mediated, endothelium-dependent vasodilatation of the brachial artery and, as a marker of biophysical changes of the vessel wall such as increased smooth muscle cell tone or collagen formation, arterial distensibility of the common carotid artery were investigated in 123 healthy first-degree relatives of patients with mild hyperhomocysteinaemia and coronary, cerebral or peripheral artery disease. RESULTS In multiple linear regression analyses, the increase in the homocysteine concentration after a standard methionine load was a significant determinant of an impaired flow-mediated vasodilatation of the brachial artery (measured on a separate day). The only other predictors were the baseline vessel diameter and age. Fasting homocysteine level was not associated with flow-mediated vasodilatation in the brachial artery. There was no relationship between homocysteine levels and nitroglycerine-induced, endothelium-independent vasodilatation of the brachial artery. Arterial distensibility of the carotid artery was also not related to homocysteine levels. CONCLUSIONS In healthy first-degree relatives of patients with mild hyperhomocysteinaemia, the increase in homocysteine level after a methionine load is an independent predictor of endothelial dysfunction. The results also suggest that fasting and post-methionine homocysteine levels may reflect distinct disturbances in methionine metabolism, which may be linked to vascular dysfunction through distinct mechanisms.

Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women.

Abstract.  Duschek EJJ, Stehouwer CDA, de Valk‐de Roo GW, Schalkwijk CG, Lambert J, Netelenbos C (VU University Medical Center, Amsterdam; Sophia Hospital, Zwolle; The Netherlands). Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women. J Intern Med 2003; 254: 85–94.

The acute effect of hyperglycaemia on vessel wall properties

Arterial distensibility is a marker of functional and structural vessel wall properties. A decreased distensibility is an important risk factor for cardiovascular disease. In insulin-dependent diabetes mellitus of short duration, arterial stiffness has been reported to be increased, decreased or the same as in healthy control subjects. The influence of acute hyperglycaemia on arterial stiffness is unclear and might be one of the factors responsible for the divergent results which have been observed. We investigated arterial distensibility locally in the carotid artery during hyper- and normoglycaemia using a glucose clamp technique. Eleven healthy normotensive men underwent both a hyperglycaemic and a euglycaemic clamp on separate days. Before and after 2 h of clamping, arterial diameter (D) and change in arterial diameter during the heart cycle (dD) were measured with a non-invasive vessel wall movement detector system. Blood pressure (BP), pulse pressure (dP) and heart rate (HR) were recorded with a semi-automated device. Distensibility coefficients (DC), reflecting the intrinsic vascular wall elasticity, and compliance coefficients (CC), reflecting the buffering capacity of the vessel, were calculated from D, dD and dP. (DC = 2*dD/ D*dP, CC = pi*dD*D/2*dP). There were no significant differences between the hyperglycaemic and the euglycaemic clamp for D, DC and CC. These results suggest that an acute systemic hyperglycaemia is not responsible for changes in diameter, distensibility and compliance of the carotid artery.