High glucose causes dysfunction of the human glomerular endothelial glycocalyx.

The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.

Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide.

AIMS/HYPOTHESIS: Hydrogen sulphide is a recently identified endogenous endothelium-dependent vasodilator. Animal models of diabetes have shown that low plasma H(2)S levels are associated with marked endothelial dysfunction and insulin resistance. However, human studies on H(2)S and vascular function in health and disease are lacking. METHODS: Plasma was obtained from male patients with type 2 diabetes (n = 11), overweight (n = 16) and lean (n = 11) volunteers. H(2)S levels were determined by zinc trap spectrophotometry. Anthropometric measurements (BMI/waist:hip ratio), lipid profile, systemic blood pressure, biochemical indices of diabetes (fasting glucose, insulin sensitivity, Hb(1Ac)) and microvascular function (minimum vascular resistance) were determined. RESULTS: Median plasma H(2)S levels (25th, 75th percentiles) in age-matched lean, overweight and type 2 diabetes individuals were 38.9 (29.7, 45.1) micromol/l, 22.0 (18.6, 26.7) micromol/l and 10.5 (4.8, 22.0) micromol/l, respectively. Median plasma H(2)S levels were significantly lower in patients with type 2 diabetes compared with lean (p = 0.001, Mann-Whitney) and overweight participants (p = 0.008). Median plasma H(2)S levels in overweight participants were significantly lower than in lean controls (p = 0.003). Waist circumference was an independent predictor of plasma H(2)S (R (2) = 0.423, standardised beta: -0.650, p < 0.001). This relationship was independent of diabetes, which only contributed a further 5% to the model (R (2) = 0.477). Waist circumference or other measures of adiposity (waist:hip ratio/BMI) remained independent predictors of plasma H(2)S after adjustment for systolic blood pressure, microvascular function, insulin sensitivity, glycaemic control and lipid profile. CONCLUSIONS/INTERPRETATION: Plasma H(2)S levels are reduced in overweight participants and patients with type 2 diabetes. Increasing adiposity is a major determinant of plasma H(2)S levels.

Capillary pressure may predict preclinical changes in the eye.

AIMS/HYPOTHESIS: Microvascular dysfunction is associated with end-organ damage. Macular oedema is an important component of diabetic retinopathy. Macular thickness can be accurately quantified by optical coherence tomography (OCT), enabling accurate assessment of the macular prior to clinically apparent abnormalities. We investigated whether macular (fovea) thickness in non-diabetic individuals is related to the microvascular variables controlling fluid filtration across a blood vessel wall, in particular capillary pressure and the microvascular filtration capacity (Kf). METHODS: We recruited 50 non-diabetic individuals (25 men, 25 women; age range: 26-78 years; BMI range: 20-46 kg/m(2)). Fovea thickness was assessed by OCT. Microvascular assessments included: finger nailfold capillary pressure; Kf; microvascular structural assessments, i.e. skin vasodilatory capacity, minimum vascular resistance (MVR) and microvascular distensibility; and endothelial function. RESULTS: At 214.6 (19.9) microm (mean [SD]), fovea thickness was within normal range. Capillary pressure, adjusted for BMI, was associated with fovea thickness (standardised beta 0.573, p = 0.006, linear regression). Fovea thickness was not associated with Kf, microvascular structural assessments or endothelial function. Capillary pressure was still associated with fovea thickness when adjusted for microvascular variables (Kf, vasodilatory capacity, MVR, microvascular distensibility or endothelial function), or for risk factors for diabetes (systemic blood pressure, insulin sensitivity, inflammation, glycaemic status and lipids) and age. CONCLUSIONS/INTERPRETATION: Capillary pressure, a key determinant of movement of fluid across a blood vessel wall, is associated with fovea thickness in non-diabetic individuals. This suggests that with regard to potential preventative or therapeutic targets, attention should be directed at the mechanisms determining retinal microvascular pressure.

Pharmacodynamic effects of orally administered dexlipotam on endothelial function in type 2-diabetic patients.

OBJECTIVE: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-alpha-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX. MATERIAL AND METHODS: DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion. RESULTS: A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA -1.51 +/- 2.98%, DEX 960 mg +1.22 +/- 3.22, p = 0.027, DEX 1,920 mg +1.47 +/- 3.78, p= 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbAlc > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure). CONCLUSION: DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.

A capillary pressure disturbance in young diabetics.

Finger nailfold capillary pressure (CP) was determined by direct microinjection technique in nine insulin-dependent male diabetic and nine matched control subjects. Mean CP, recorded under resting conditions after acclimatization in a constant temperature room at 24 degree C, was similar in all parts of the capillary loop in the two groups. Control subjects demonstrated a positive correlation between skin temperature and CP (r = + 0.74 and P < 0.01, arterial limb values; r = + 0.61 and P < 0.01, summit and venous limb values). No such relationship was found for diabetics under the initial warm conditions of study (r = - 0.15, arterial limb values; r = - 0.44, summit and venous limb values). Mean arterial limb CP, recorded during postocclusive reactive hyperemia, was significantly higher in control subjects than in diabetics (P < 0.001). The diabetic group exhibited no clinical evidence of neuropathy, and their digital vasoconstrictor capacity appeared to be intact. These findings are interpreted as evidence for an intrinsic microvascular lesion at the precapillary sphincter level in insulin-dependent diabetic patients, which may result in the failure of vasodilatation to respond to physiologic stress.

Microvascular function in human diabetes. A physiological perspective.

The late complications of diabetes represent in large part microvascular dysfunction. The development of techniques to measure microvascular function has resulted in a clearer picture of the stages of development of microangiopathy and the key pathophysiological processes involved. Considerable evidence supports the hemodynamic hypothesis of pathogenesis, which argues that early insulin-dependent diabetes is characterized by increased microvascular pressure and flow. Resultant injury to the microvascular endothelium causes adaptive microvascular sclerosis contributing to a loss of vasodilatory reserve and autoregulatory capacity with increasing disease duration. High susceptibility to microangiopathy appears to be characterized by both high capillary pressure and increased permeability, although the interrelationship between these variables needs to be better defined. In normotensive non-insulin-dependent diabetes subjects, a different pattern of microvascular functional abnormalities is apparent; it is hypothesized that these differences represent the impact of a prediabetic insulin-resistant phase on microvascular behavior and may in part explain the differential expression of vascular pathology in the two major types of diabetes. The physiological framework that has been defined reveals those pivotal processes upon which scientific attention should be centered and facilitates the generation of plausible molecular and cellular mechanisms that fit the physiological facts.

Capillary pressure in patients with NIDDM.

The hemodynamic hypothesis suggests that raised capillary pressure may play a role in the pathogenesis of diabetic microangiopathy. Although patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes NIDDM) develop a similar range of microvascular complications, differences in their expression and prevalence suggest that different pathogenic mechanisms may be operational. Capillary pressure is elevated in IDDM; the aim of this study was to assess whether capillary pressure was also elevated in NIDDM. Twenty-one patients with NIDDM (15 men) and 21 healthy control subjects matched for age, sex, and skin temperature were investigated supine with the hand at heart level. Finger nailfold capillary pressure was measured after direct cannulation at the summit of the capillary loops using glass micropipettes. The groups were matched for skin temperature (30.4 [24.2-33.8] degrees C, median [95% confidence interval], NIDDM patients vs. 30.0 [23.4-33.6] degrees C control subjects), age (62.0 [39.4-72.7] years NIDDM patients vs. 62.0 [39.4-72.0] years control subjects), and both systolic (sBP) and diastolic (dBP) blood pressures (133.0 [111.0-167.3]/78.0 [57.0-89.5] mmHg NIDDM patients vs. 133.0 [114.1-158.9]/80.0 [68.2-88.9] mmHg control subjects). Capillary pressure did not differ in the two groups (17.6 [13.1-21.2] mmHg NIDDM patients vs. 19.1 [14.1-23.6] mmHg control subjects [NS]). There was no correlation of capillary pressure with either HbA1c or glucose; however, there was a negative association between capillary pressure and diabetes duration (Rs = -0.50, P = 0.020).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight.

OBJECTIVE: Low birth weight has been linked to an increased risk of type 2 diabetes and cardiovascular disease in adult life. The fetal insulin hypothesis proposed that a genetic predisposition to insulin resistance may also influence vascular development. Therefore, impaired vascular function may be an intrinsic abnormality in low-birth weight infants that antedates clinical features of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: Two groups of 3-month-old term infants were included in the study: 17 infants of lowest quartile birth weight (LQBW) and 21 infants of highest quartile birth weight (HQBW). Three aspects of skin microvascular function were examined; response to local heating, response to acetylcholine iontophoresis, and capillary density. RESULTS: Median (interquartile ranges) birth weights of the LQBW and HQBW infants were 3,140 g (2,738-3,254) and 3,920 g (3,750-4,020), respectively. Skin maximal hyperemic response to local heating was 2.14 V (1.68-2.30) in the LQBW group vs. 2.44 V (1.96-2.90) in the HQBW group (P = 0.020), and the endothelium-dependent vasodilatory response was 1.03 V (0.62-1.32) in the LQBW group vs. 0.78 V (0.45-1.32) in the HQBW group (P = 0.297). Capillary density in the LQBW and HQBW groups were 46.3 mm(-2) (40.1-53.7) and 44.1 mm(-2) (41.7-56.0), respectively (P = 0.736). CONCLUSIONS: Skin maximal hyperemic response was lower in LQBW infants, although no reduction in capillary density or defect in endothelium-dependent vasodilatation was observed. Such a lower maximal hyperemic response in early life in LQBW subjects who are at risk for type 2 diabetes and cardiovascular disease supports the hypothesis that impaired microvascular function is an early antecedent to diabetes in later life.

The peripheral microcirculation in atrial fibrillation: preservation of capillary pressure and filtration coefficient.

OBJECTIVE: The aim was to assess whether atrial fibrillation results in disturbances of capillary pressure and capillary filtration coefficient in man. METHODS: Finger nailfold capillary pressure and calf capillary filtration coefficient were measured in subjects in atrial fibrillation and in matched healthy controls in sinus rhythm. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and capillary filtration coefficient by mercury-in-Silastic strain gauge plethysmography using a technique believed not to invoke the venoarteriolar response. RESULTS: Mean capillary pressure did not differ significantly between subjects in atrial fibrillation and those in sinus rhythm [18.4(SD 5.1) mm Hg in atrial fibrillation v 18.0(2.9) mm Hg in sinus rhythm]. In a subgroup of patients restored to sinus rhythm (n = 7) by dc cardioversion there was no significant alteration in capillary pressure [15.3(4.2) mm Hg v 16.6(2.8) mm Hg]. Capillary filtration coefficient was also similar in subjects in atrial fibrillation to that in healthy controls in sinus rhythm [2.81(0.65) kfu in atrial fibrillation v 2.87(0.69) kfu in sinus rhythm]. CONCLUSIONS: These data would suggest that under resting conditions autoregulatory mechanisms are able to preserve microvascular homeostasis despite the central changes associated with atrial fibrillation.

Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy.

OBJECTIVES: Previous studies of peripheral microvascular function in human heart failure have concentrated on changes in flow, and there is little information concerning the impact of heart failure on the principal determinants of transcapillary fluid exchange. This study investigated whether alterations in capillary pressure and microvascular fluid permeability can be detected in subjects with idiopathic dilated cardiomyopathy. METHODS: Finger nailfold capillary pressure and calf capillary filtration coefficient (CFC) were measured in parallel studies of two overlapping groups of 12 non-oedematous subjects with idiopathic dilated cardiomyopathy and mild to moderate heart failure and in age- and sex-matched healthy controls. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and CFC by mercury-in-silastic strain gauge plethysmography using a modification of the technique which avoids assumptions concerning isovolumetric venous pressure. RESULTS: Following correction for differences in skin temperature, capillary pressure was lower in the subjects with heart failure (P = 0.02). Both CFC and isovolumetric venous pressure were greater in the subjects with heart failure than in controls (3.4 +/- 0.9 vs. 2.6 +/- 0.7 ml.min-1.mmHg-1.100 ml-1, P = 0.03; 27.1 +/- 8.4 vs. 17.2 +/- 7.2 mmHg, P = 0.01). CONCLUSIONS: These data suggest that factors other than changes in arterial inflow and venous outflow pressures are likely to play an important role in the disruption of microvascular homeostasis which occurs in heart failure. Changes in capillary hydraulic conductance may contribute to the pathogenesis of oedema.

Oedema in patients with Addison's disease on replacement therapy: glucocorticoid excess and mineralocorticoid deficiency?

Steroid hormones influence mechanisms related to oedema formation, including postural vasoconstriction and vascular tone. We studied fifteen patients (7 male, 8 female) with primary adrenal failure on clinically optimal replacement therapy. Five patients, all female, had clinically detectable oedema. Patients with oedema had evidence of mineralocorticoid deficiency, with increased supine and erect plasma renin activity and greater postural fall in blood pressure. Mean morning plasma cortisol levels were significantly higher in the group with oedema, suggesting they were receiving insufficient mineralocorticoid and a possible relative excess of glucocorticoid. There were no significant differences between patients with and without oedema in lower-limb cutaneous blood flow or in postural vasoconstrictor responses measured by laser Doppler flowmetry. The mechanism of oedema formation is unclear, but appears not to be modulated by haemodynamic mechanisms with expansion of intravascular volume or, in contrast to the known effects of sex hormones, by impairment of postural vasoconstriction. Theoretically, excess glucocorticoid replacement may result in oedema formation, by direct action on vascular tone, by altering capillary permeability, or by influencing other factors such as atrial natriuretic peptide. Measurement of plasma renin activity in conjunction with plasma cortisol profiles may be useful in adjusting replacement therapy in patients with Addison's disease and oedema.

Disturbance of peripheral microvascular fluid permeability by the onset of atrioventricular asynchrony in patients with programmable pacemakers.

BACKGROUND: In vitro and in vivo evidence suggests that atrial natriuretic peptide can enhance fluid flux from intravascular to extravascular compartments. The relevance of this to human pathophysiology remains unclear. OBJECTIVES: To determine whether a central haemodynamic change associated with increased plasma concentrations of atrial natriuretic peptide produces detectable change in the capillary filtration coefficient in a peripheral microvascular bed. PATIENTS: 12 patients with programmable dual chamber permanent pacemakers. METHODS: Calf capillary filtration coefficient (using a modified plethysmographic technique) and plasma atrial natriuretic peptide concentrations were measured during atrioventricular synchronous and ventricular pacing. RESULTS: Atrioventricular asynchrony was associated with higher mean (SD) concentrations of atrial natriuretic peptide (231.9 (123.1) v 53.5 (38.8) pg/ml) and an increased mean (SD) calf capillary filtration coefficient (4.2 (1.1) v 3.6 (1.1) ml/min.mm Hg.100 ml x 10(-3)), but there was no correlation between the magnitude of the change in these variables in individual patients. CONCLUSIONS: The peripheral capillary filtration coefficient may change in response to altered central haemodynamics. Atrial natriuretic peptide remains one potential candidate mechanism, but other factors are also likely to be involved.

Peripheral microvascular disease in diabetes.

In recent years a variety of techniques have been developed for studying peripheral microvascular function in man, which have provided important information regarding the functional breakdown of the microcirculation in diabetes mellitus. In insulin dependent diabetes a sequence of physiological changes have been described which support the so-called haemodynamic hypothesis: control-dependent increases in capillary pressure result in microvascular sclerosis leading to limitation of hyperaemia and loss of autoregulation. Furthermore, capillary pressure appears to be especially raised in patients with incipient nephropathy who are at particular risk of microangiopathy. The limitation of maximum hyperaemia is duration related, may be observed in early childhood, and is correlated with the degree of basement membrane thickening. In contrast in normotensive non-insulin dependent patients a different array of functional disturbances are described: Capillary pressure and capillary filtration coefficient are normal whereas maximum hyperaemia is profoundly depressed even at diagnosis. This differential pattern of abnormalities arguably reflects the impact of a prediabetic insulin resistant phase on the subsequent expression of microangiopathy. An understanding of the physiological breakdown of the microcirculation in diabetes permits the generation of plausible candidate cellular and molecular mechanisms, knowledge of which will accelerate the development of protective therapy.

Microvascular functional abnormalities in diabetes: the role of the endothelium.

The development of techniques for measuring microvascular pressure, flow and permeability in man has allowed the construct of a pathophysiological framework for the development of diabetic microangiopathy. In insulin dependent disease the abnormalities observed conform to the haemodynamic hypothesis with early elevation of capillary pressure playing a primary role. In non insulin dependent diabetes differences are apparent, supporting the concept that changes in microvascular vasodilatory mechanisms may antedate the emergence of diabetes. Given the crucial role played by the endothelium in the regulation of local microvascular haemodynamics it is not surprising that disturbance of this tissue has been implicated in the pathogenetic process, an assertion supported by mounting experimental evidence suggesting that the nitric oxide pathway is crucially involved.

Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes.

The expression of large and small vessel disease in type 2 diabetes differs from that observed in type 1, with a higher prevalence of atherosclerosis and hypertension, maculopathy rather than proliferative retinopathy, and nephropathy of a more complex nature. Such differences are mirrored by differences in vascular pathophysiology with an early impairment of microvascular vasodilatory reserve being a prominent feature. The defect appears to be endothelium dependent and in conjunction with evidence of endothelium activation suggests that the endothelium plays a crucial role in the pathogenesis of vascular disease in type 2 diabetes and may even be an intrinsic feature or common antecedent of the insulin resistance syndrome. Several cellular mechanisms may be proposed linking insulin resistance and endothelial dysfunction including (i) abnormalities of common signal transduction mechanisms, (ii) alterations in cell membrane fluidity altering the expression and/or presentation of a wide range of receptors, or (iii) changes in oxidative stress. It is intuitively unlikely that the alteration of a single signal transduction mechanism could be a common cause, particularly as aspects of endothelial dysfunction implicate different mechanisms. Accordingly, changes in oxidative stress, either stemming from glucose-mediated increased free-radical generation and/or reduction of antioxidant capacity, are strong contender mechanisms. Not only may increased oxidative stress result in the quenching of nitric oxide, neutralizing its many protective functions, but it may also damage DNA, protein structure, and membrane properties. Elucidating the links between oxidative stress, endothelial function, and insulin resistance has important implications for the prevention of diabetic angiopathy and perhaps for the prevention of diabetes itself.

Capillary filtration coefficient in type II (non-insulin-dependent) diabetes.

Changes in microvascular permeability may be important in the pathogenesis of diabetic microangiopathy. In order to assess microvascular fluid permeability, the capillary filtration coefficient was determined in the forearm of 24 normotensive type II diabetic patients with minimal evidence of microangiopathy and satisfactory glycemic control, and 24 age- and sex-matched control subjects, using a sensitive strain gauge plethysmographic system. The median capillary filtration coefficient was not significantly different in the type II diabetic patients and control subjects [5.3 (3.2 - 9.1) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1 versus 5.4 (3.5 - 8.0) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1, p = 0.98)]. There were no correlations between capillary filtration coefficient and age, blood pressure, body mass index, duration of diabetes, glycemic control, or the presence of microvascular complications. These findings contrast with type I diabetes, where capillary filtration coefficient is elevated at an early stage in the disease, and lend support to the theory that there are differences in early microvascular functional abnormalities between type I and type II diabetes.

Quality of life in type II diabetes: evaluation and applications.

Issues of quality of life (QOL) have often been considered for patients with insulin-dependent diabetes mellitus (IDDM, type I diabetes). Daily blood glucose monitoring and need for self-injections pose an obvious threat to the attainment of QOL, as does concern about long term complications. In contrast, non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) may be considered less severe, and has attracted less research interest. In fact, type II patients may also be aware of their heightened vulnerability to physical complications, as well as being affected by the need for heightened vigilance and attention to diet and exercise regimens. Issues associated with the theory and development of QOL measures are discussed largely in relation to type I diabetes and cancer. Generic measures have advantages in allowing comparisons to be made across different disease groups, and are, therefore, often favoured by health economists. In contrast, disease-specific scales are more sensitive to changes in treatment regimens, and may therefore be the instruments of choice in evaluating new treatments. In general, there has been less attention paid to how the meaning of QOL changes throughout the lifespan, and our review of the literature therefore emphasises a developmental perspective when considering the processes through which diabetes may affect an individual's QOL. Measures which, at the least, take into account changes in meaning of QOL throughout the lifespan need to be developed.

Direct and indirect costs of cardiovascular and cerebrovascular complications of type II diabetes.

Macroangiopathy (atherosclerosis) is a common chronic complication in non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) with a significant attendant mortality and morbidity. While there are inherent difficulties in estimating the economic burden of large vessel disease in type II diabetes, this has been attempted in several studies by use of insurance claims, hospital inpatient statistics, and extrapolation from standard mortality data. This evidence suggests that the macrovascular complications of type II diabetes (ischaemic heart disease, peripheral vascular disease, and cerebrovascular disease) account for approximately one-third of all healthcare expenditures and one-quarter of disability related to type II diabetes in developed countries. The large and growing economic burden of these complications of diabetes in developing countries is unknown.

Capillary blood pressure.

Human capillary blood pressure may be measured directly in nailfold capillaries of the fingers and toes. By applying servonulling pressure measuring techniques rapid fluctuations in capillary pressure may be recorded, opening the way to a greater understanding of capillary pressure control in health and disease. The estimation of mean pressure which may be accomplished manometrically is of value in determining the mechanism of oedema, identifying the site of raised peripheral resistance in disease states, evaluating the effects of vasoactive drugs on peripheral resistance, and investigating haemodynamic abnormalities associated with microangiopathies. Capillary pulse waveform analysis, made possible by servonulling techniques and computer analysis has already revealed important changes in hypertension.

Limb capillary filtration coefficient in human subjects: the importance of the site of measurement.

Capillary filtration coefficient is a critical determinant of fluid flux across the microvascular wall. Changes in capillary filtration coefficient have been described in a number of disease processes. Measurement is typically made by venous occlusion plethysmography using either the upper or lower limb, but a variety of measurement protocols have been used and the importance of the site of measurement remains unclear. In this study, forearm and calf capillary filtration coefficient were measured in healthy volunteers, either simultaneously (group A; n = 11) or sequentially in random order (group B; n = 11) using venous occlusion plethysmography, with the subject supine and the limb at heart level. In both studies capillary filtration coefficient was significantly higher when measured at the forearm than at the calf (group A: 6.1 +/- 1.0 versus 3.7 +/- 1.1 x 10(-3) ml min(-1) mmHg(-1) 100 ml(-1) (mean +/- SD), p < 0.01; group B: 5.1 +/- 1.2 versus 3.2 +/- 1.1 x 10(-3) ml min(-1) mmHg(-1) 100 ml(-1), p < 0.01). Isovolumetric venous pressure (the maximum pressure at which there is neither net filtration nor absorption at the microvascular wall) was similar in upper and lower limbs in both groups of subjects. We conclude that limb capillary filtration coefficient is dependent on the site of measurement. Caution is required when comparing data recorded at different sites even if corrected for the volume of soft tissue under study.