Original Article
Relation of Skin Capillary Pressure in Patients with Insulin-Dependent Diabetes Mellitus to Complications and Metabolic Control
N Engl J Med 1992; 327:760-764September 10, 1992
- Abstract
- Abstract
Background
Microvascular disease is a major problem in patients with diabetes mellitus. It has been suggested that diabetic microangiopathy may result from an increase in capillary blood flow and capillary hypertension, but direct evidence of capillary hypertension in such patients is lacking.
Methods
We measured capillary pressure at the summit of the capillary loop by direct microcannulation of skin nail-fold capillaries and a dynamic method of pressure measurement in 29 patients with insulin-dependent (Type I) diabetes and 29 normal subjects matched for age and sex. Among the diabetic patients, 7 had had diabetes for less than one year, 12 had incipient nephropathy (albumin excretion, 20 to 200 μ per minute), and 10 had overt nephropathy (albumin excretion, >200 μg per minute). In addition, seven patients with no evidence of nephropathy were studied before and after three months of improved glycemic control.
Results
The median capillary pressure in the diabetic patients was 20.4 mm Hg (range, 13.6 to 25.3), as compared with 16.7 mm Hg (range, 12.8 to 22.8; P<0.001) in the normal subjects. The values were higher in each subgroup of diabetic patients than in the corresponding group of normal subjects, but the values did not differ among the three subgroups of diabetic patients. In the seven patients who were studied before and after three months of improved glycemic control, the median capillary pressure fell from 20.0 mm Hg (range, 18.5 to 21.7) to 17.8 mm Hg (range, 14.1 to 20.3; P = 0.02).
Conclusions
Nail-fold capillary hypertension may develop early in the course of diabetes, before the emergence of microvascular disease, and may be influenced by changes in metabolic control. (N Engl J Med 1992; 327:760–4.)
Media in This Article
Figure 1
Schematic Representation of the Site and Shape of Nail-Fold Capillaries in the Finger and the Site of Capillary Cannulation (Not to Scale).Figure 2
Nail-Fold Capillary Pressures in Patients with Type I Diabetes and Normal Subjects Matched for Age and Sex.Article Activity
- Article
STUDIES of blood flow in tissues and organs in patients with diabetes mellitus have revealed a typical pattern of change.1 , 2 There is an early increase in flow that is partly attenuated by improved glycemic control. With increasing duration of disease, blood flow becomes impaired and autoregulation is lost. The remarkable conformity of this pattern of changes in diverse microcirculatory beds, such as skin,3 , 4 subcutaneous tissue,4 , 5 eye,6 , 7 and kidney,8 , 9 suggests that a basic microvascular control mechanism is disordered, either directly or indirectly, by the metabolic disturbance of diabetes.
Several groups of investigators have proposed a hemodynamic hypothesis to link these changes in blood flow in tissues and organs to the genesis of clinical diabetic microangiopathy.2 , 10 , 11 It is argued that the increased flow results from precapillary vasodilatation. The capillary hypertension that inevitably accompanies such precapillary vasodilatation acts as a stimulus for the development of capillary sclerosis, the histologic hallmark of diabetic microangiopathy.12 Direct evidence to support the central tenet of this hypothesis, capillary hypertension, comes from studies of experimental diabetes. High capillary pressure has been demonstrated in the glomeruli of rats with streptozocin-induced diabetes, and the high pressure appears to promote sclerotic changes in the capillaries.13 However, the role of glomerular sclerosis in the pathogenesis of diabetic nephropathy is disputed.14 , 15
The aim of this study was to examine whether capillary pressure, measured in nail-fold capillaries in the finger, is elevated in patients with insulin-dependent (Type I) diabetes.
Methods
Study Subjects
We studied 29 patients considered to have insulin-dependent diabetes on the basis of clinical criteria (age less than 40 years at the onset of the disease, the presence of ketonuria, and a requirement for insulin within one month after diagnosis) and 29 normal subjects matched for age and sex. Three groups of patients were recruited from the hospital diabetic clinic: a group that had had diabetes for less than one year (the "short-duration group"), a group with incipient nephropathy, and a group with overt nephropathy (Table 1Table 1
Characteristics of the Diabetic Patients and the Normal Subjects.*). The patients were screened for nephropathy by determining the ratio of the concentration of albumin (in milligrams per liter) to that of creatinine (in millimoles per liter) in an early-morning urine sample. A value ≤2.5 was defined as a normal rate of albumin excretion.16 If the value exceeded 2.5, the rate was measured by an immunoturbidimetric method17 in three timed overnight urine collections. Incipient nephropathy was defined as a mean rate of albumin excretion of 20 to 200 μg per minute, and overt nephropathy as a mean rate of more than 200 μg per minute.18 Other forms of renal disease were excluded on the basis of clinical findings, biochemical studies, microbiologic analysis of urine, and ultrasonography of the kidneys and urinary tracts. All the patients had normal serum creatinine concentrations (0.5 to 1.4 mg per deciliter [45 to 120 mmol per liter]). None of the patients were excessively obese. In the two subgroups of patients with renal disease, 15 patients had proliferative retinopathy, 1 had preproliferative retinopathy, and 5 had background retinopathy; 10 patients had evidence of mild-to-moderate sensory neuropathy. There was no evidence of microvascular complications in the group that had had diabetes for less than one year.The effect of improved glycemic control for three months was studied in 7 patients, 1 of whom was among the 29 patients described above. Three were female and four were male. They ranged in age from 16 to 43 years, and they had had diabetes for periods ranging from 1 to 17 years. None had incipient or overt nephropathy. Improvement in glycemic control was achieved by alterations in diet, insulin dosage, and lifestyle, supported by regular home monitoring of blood glucose levels and medical review.
The study protocol was approved by the local ethics committee, and all the patients gave informed verbal consent.
Measurements of Capillary Pressure
The subjects were asked not to smoke on the day of the study and to avoid any caffeine-containing beverages for two hours before the measurements. All the subjects ate a light lunch, and the patients ate their usual afternoon snack. Patients taking multiple doses of insulin administered their normal lunchtime insulin dose. The measurements were conducted under standardized conditions in the afternoon in a room with a controlled temperature (mean [±SD], 22.0 ±0.4°C). The subjects lay supine, with their left hands supported on a padded table at the level of the midaxillary line for 45 minutes before blood pressure was measured and capillary cannulation was attempted. The fingers of the left hand, the nondominant hand in the majority of subjects, were used, because they are the least traumatized and thus facilitate capillary cannulation. It would have been technically difficult to transpose the equipment to allow measurement of the nondominant hand in each subject.
Brachial-artery pressure was measured five times at one-minute intervals (Dinamap, Critikon, Tampa, Fla.) with the subject supine and relaxed. The mean arterial blood pressure was calculated from the average of these five readings as the mean diastolic blood pressure plus one third of the mean pulse pressure. The skin temperature was measured throughout the study with a thermocouple (Comark Electronic, Littlehampton, Sussex, United Kingdom) placed on the skin adjacent to the nail fold. Capillary blood glucose was measured (BM test 144, Reflolux II Meter, Boehringer Mannheim, Mannheim, Germany) at the beginning and end of each study, and hemoglobin A1 was measured by column chromatography (Bio-Rad, Richmond, Calif.) from a venous-blood sample collected at the end of the study (normal range, 5.4 to 7.8 percent).
The method of capillary-pressure measurement is described in detail elsewhere.19 Nail-fold capillaries were visualized by television microscopy (final magnification, ×160) and cannulated with glass micropipettes filled with 2M sodium chloride (tip diameter, 7 to 10 (im) with the aid of a Leitz micromanipulator (Leitz, Rockleigh, N.J.). The servonull method used to measure pressure (IPM, San Diego, Calif.) depends on monitoring the electrical impedance at the pipette tip. When the capillary is cannulated, the capillary pressure drives plasma (of high relative impedance) into the pipette. The pressure required to restore (i.e., to servonull) the change in electrical impedance of the pipette tip was recorded after digitization directly onto a hard disk for subsequent analysis.20 The persons performing the measurements were sometimes aware that the study subject was either diabetic or normal, but the actual pressure measurements were not known until later.
The pressure measurements were performed in the nail-fold capillaries at the summit of the capillary loop (Fig. 1Figure 1
Schematic Representation of the Site and Shape of Nail-Fold Capillaries in the Finger and the Site of Capillary Cannulation (Not to Scale).). In each subject 3 to 12 capillaries in one or two fingers were cannulated. A cannulation was accepted as satisfactory only if there was no appreciable change in the flow of red cells in the capillaries as viewed on the videomicroscope monitor throughout each cannulation (even slight changes in flow may be accompanied by changes in pressure).The results of the 3 to 12 measurements were averaged for each patient. The variability in pressure from capillary to capillary across the nail fold was small. The coefficient of variation when five to nine adjacent capillaries were cannulated in each of four subjects was 5.4 percent. The variation between subjects was also small; in four subjects, each studied on four occasions over a six-month period, the coefficient of variation was 5.7 percent.
Statistical Analysis
The Wilcoxon rank-sum and signed-rank tests were used to compare the results in the diabetic patients and the individually matched normal subjects. The results with both tests were similar; those of the Wilcoxon rank-sum tests are presented here. A Kruskal—Wallis analysis of variance was used to compare the results in the three subgroups of diabetic patients. Spearman rank-correlation coefficients (Rs) were calculated where appropriate. The results are reported as median values and ranges.
Results
The median capillary pressure measured at the summit of the finger nail-fold capillary loop in the diabetic patients was 20.4 mm Hg (range, 13.6 to 25.3), as compared with 16.7 mm Hg (range, 12.8 to 22.8) in the matched normal subjects (P<0.001) (Table 2Table 2
Capillary Pressure, Mean Blood Pressure, and Biochemical Values in the Diabetic Patients and the Normal Subjects.* and Fig. 2Figure 2Nail-Fold Capillary Pressures in Patients with Type I Diabetes and Normal Subjects Matched for Age and Sex.). The capillary pressure was higher in the normal men (18.9 mm Hg [range, 12.8 to 22.8]) than in the normal women (14.2 mm Hg [range, 13.0 to 18.3]; P = 0.002), but the values in the men and women with diabetes were similar (men, 20.4 mm Hg [range, 16.5 to 23.8]; women, 20.6 mm Hg [range, 13.6 to 25.3]). When each sex was considered separately, capillary pressure was higher in the diabetic patients than in the normal subjects (diabetic men, 20.4 mm Hg [range, 16.5 to 23.8]; normal men, 18.9 mm Hg [range, 12.8 to 22.8]; P<0.03; diabetic women, 20.6 mm Hg [range, 13.6 to 25.3]; normal women, 14.2 mm Hg [range, 13.0 to 18.3]; P<0.001).Capillary pressure was clearly elevated in the patients with overt or incipient nephropathy as compared with the matched normal subjects (Table 2). The pressure was also higher in the group with diabetes of short duration than in the matched normal subjects. The values in the three subgroups of diabetic patients were not significantly different. The development of nephropathy, either incipient or overt, was accompanied by an increase in both mean brachial-arterial pressures (P<0.001) and hemoglobin A1 values (P = 0.006). The mean skin temperature did not differ in the three subgroups. In these 29 diabetic patients we found a weak relation between capillary pressure and skin temperature (Rs = 0.38, P = 0.04) but no relation with mean blood pressure (Rs = 0.04, P = 0.85), blood glucose (Rs = 0.18, P = 0.34), duration of disease (Rs = 0.31, P = 0.10), age (Rs = 0.17, P = 0.26), or hemoglobin A1 (Rs = 0.23, P = 0.24). However, capillary pressure was related to hemoglobin A1 in the diabetic patients in the short-duration group (Rs = 0.86, P = 0.01).
Capillary-pressure values in the patients studied a second time after improvement in glycemic control are shown in Figure 3Figure 3
Nail-Fold Capillary Pressures in Patients with Type I Diabetes, before and after a Three-Month Period of Improved Glycemic Control.. Their median hemoglobin A1 value decreased from 9.6 percent (range, 8.7 to 12.4 percent) to 8.4 percent (range, 8.0 to 10.4 percent) (P = 0.02 by the Wilcoxon signed-rank test). The median skin temperatures were 30°C (range, 24 to 32) and 29°C (range, 24 to 32), respectively, before and after the period of improved glycemic control (P not significant). The median capillary-pressure values were 20.0 mm Hg (range, 18.5 to 21.7) before and 17.8 mm Hg (range, 14.1 to 20.3; P = 0.02) after the three-month period. There were no differences in ambient blood glucose concentration (the average of the blood glucose concentrations before and after the capillary-pressure measurements) or mean arterial blood pressure between the two studies.Discussion
We found that the capillary pressure in the skin capillaries of patients with Type I diabetes was higher than that in normal subjects matched for age and sex. These results differ from those of an earlier study in which capillary pressure in diabetic men was not increased. However, it is more difficult to detect an increase in men, because the values in normal men are higher and therefore more similar to the values in diabetic patients; furthermore, the manometric technique used in that study is both less sensitive and less accurate than the one we used.21 , 22
Capillary pressure was elevated less than one year after diagnosis. The elevation is therefore likely to represent an early functional change and not to be the result of microvascular disease itself. The role of poor glycemic control in this early elevation of capillary pressure remains to be established, but changes in microvascular flow were influenced by glycemic control at this stage of the disease process.
The capillary pressure in the patients with incipient and overt nephropathy was no higher than in the patients who had had diabetes for less than one year, although each subgroup was small. The lack of an additional elevation of capillary pressure in the patients with overt nephropathy and elevated blood pressure would suggest that adaptation to the raised brachial-artery pressure had occurred. In the diabetic patients with overt nephropathy and hypertension, transmission of the elevated arterial pressure to the capillaries may be reduced by changes in resistance in the early part of the arteriolar tree. Such changes may be structural — for example, involving an increase in the thickness of the vessel wall relative to the lumen size, with the result that the pressures at the distal precapillary arterioles are similar to those encountered in early diabetes. Indeed, it would be surprising if structural changes in the small vessels did not occur in diabetes, in a manner analogous to the findings in essential hypertension,23 a condition in which structural autoregulation in the resistance vessels restricts the distal transmission of the elevated arterial pressure.
There is little sex-related difference in the expression of microvascular complications in diabetes.24 If the absolute level of capillary pressure is the most relevant variable in the causation of microvascular disease, one might anticipate that the values in men and women with diabetes would be similar, as we found, in contrast to the difference between the male and female normal subjects. Current evidence supports a role for sex hormones in the regulation of vascular function,25 but the nature of the interplay between the metabolic disturbance of diabetes and sex-hormone secretion is not known.
A complex relation between capillary pressure and metabolic control is to be expected in view of the complex relation between microvascular complications and metabolic control.10 , 26 27 28 The finding of a correlation between capillary pressure and hemoglobin A1 in the patients who had had diabetes for less than one year, but not in the patients with nephropathy, is in keeping with clinical studies in which improvement in glycemic control was accompanied by a reduction in microvascular complications in patients with an early stage of diabetes, but not in those with overt nephropathy.28 The relation between capillary pressure and metabolic control in the cross-sectional study is strongly supported by our findings of a reduction in capillary pressure with improvement in glycemic control.
It is not possible, from the measurement of capillary pressure at a single point, to determine whether changes in precapillary or post-capillary resistance cause the elevated capillary pressure. Measurements of blood flow in this capillary bed have revealed no significant differences between diabetic patients and normal subjects, although there was a trend toward increased blood flow in the diabetic patients.29 To accommodate both increased or maintained flow and raised pressure, precapillary vasodilatation must occur, in keeping with the interpretation of indirect studies in other organs in humans.2 In support of this hypothesis, we recently demonstrated raised pressure around the whole capillary loop in diabetes.30 The cause of precapillary vasodilatation remains speculative, but changes in endothelial function,31 32 33 blood rheology,34 neural35 or humoral36 control mechanisms, and vascular smooth-muscle function37 and a direct effect of glucose38 have been implicated.
Raised capillary pressure may promote microvascular sclerosis39; indeed, basement-membrane thickening around capillaries increases progressively with the distance below the heart.12 Furthermore, patients with other disease states associated with increased hydrostatic pressure, such as cardiac failure, have capillary sclerosis.12 Besides possibly promoting basement-membrane thickening, the small increase in capillary pressure could also increase net capillary filtration and possibly the rate of escape of serum albumin.40 Future studies need to be directed at determining the mechanism and reversibility of the capillary hypertension.
Supported by the Wellcome Trust.
Source Information
From the University of Exeter, Postgraduate Medical School, Barrack Rd., Exeter EX2 5EQ, United Kingdom, where reprint requests should be addressed to Dr. Sandeman.
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