Muscle capillary basement membrane in juvenile diabetes mellitus

Calculations of the minimum rather than the average basement membrane thickness of muscle capillaries established that widening of this structure was only rarely encountered in juvenile-onset diabetes of 1–6 yr duration. The basement membrane was usually, but not always, thickened, however, in childhood-onset diabetes present for 7 or more yr. The presence or absence of basement membrane thickening did not appear to be related to age at onset of diabetes, the degree of hyperglycemia in an oral glucose tolerance test, any residual ability to secrete insulin, the type, dosage or schedule of insulin therapy, history of ketoacidosis and shocking, blood pressure, or the state of the kidneys. However, each of the patients with an increase in the width of the basement membrane of muscle capillaries did have microaneurysms. Our data are consonant with the hypothesis that thickening of the basement membrane generally appears toward the end of the first decade following the diagnosis. Since duration and age tend to be related, such thickening was more common in the older persons with juvenile-onset diabetes. Also, in such patients serum creatinine tended to be higher and proteinuria was more frequent, two variables known to be influenced by duration of diabetes and increased chronologic age.     

Sulfonylurea-induced decrease of muscle capillary basement membrane thickness in diabetes

Three muscle biopsies were performed in 53 overt type 2 diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an increased capillary basement membrane width in muscle. Thirty-five patients received glipizide and 18 received placebo. In the patients receiving placebo, the mean of the muscle capillary basement membrane width increased from 158.7 +/- 11.5 nm (SEM) to 170.9 +/- 14.7 nm (P = NS), but in those receiving glipizide the value decreased from 192.9 +/- 13.2 nm to 161.0 +/- 10.2 nm (P = 0.02). Plasma glucose and glycosylated hemoglobin A1 decreased significantly (P less than 0.001) after 2 years in patients receiving glipizide. In 15, mean glycosylated hemoglobin A1 reached a normal range, and mean basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). These findings are consistent with the hypothesis that effective response to oral medication can decrease the basement membrane thickening, suggesting that diabetic microangiopathy is not necessarily progressive.     

Improved diabetes control reduces skeletal muscle capillary basement membrane width in insulin-dependent diabetes mellitus

We studied the relationship between the control of blood glucose and the width of skeletal muscle capillary basement membrane in 54 insulin-dependent diabetic patients. After initial measurement of levels of glycosylated hemoglobin and the width of skeletal muscle capillary basement membrane, the patients were divided into two groups: an intensive treatment group of 30 patients who were treated with continuous subcutaneous insulin infusion and a control group of 24 patients who continued to receive conventional treatment, usually two daily injections of insulin. Both groups have been followed prospectively for periods of time up to 4 years. Within 1 year the intensive treatment group had a significant decrease in glycosylated hemoglobin levels as compared to baseline values reflecting improved control of blood glucose. This level of glycosylated hemoglobin was stable over the remainder of the follow-up period. This group also had a significant reduction in the width of skeletal muscle capillary basement membrane within 1 year and it persisted for the 4 years of observation. The control group of patients had no significant change in their level of glycosylated hemoglobin and the width of the skeletal muscle capillary basement membrane tended to increase with time. It this result in skeletal muscle capillaries applies to those of retinal and renal tissue, meticulous diabetic control for a prolonged period of time may be beneficial in preventing the progression of the microvascular complications of diabetes mellitus.     

Correlation between erythrocyte aldose reductase activity and the width of skeletal-muscle capillary basement membrane in insulin-dependent diabetes mellitus

Thickening of capillary basement membrane has been demonstrated in diabetic subjects, and it is considered to be the characteristic pathological lesion of diabetic microvascular disease. There are studies reporting the effects of inhibitors of aldose reductase, the first enzyme of the polyol pathway, on the thickening of the capillary basement membrane. These observations indicate a significant role of the polyol pathway in the development of microvascular disease. However, it is unknown whether or not there is any correlation between the thickness of the capillary basement membrane and the activity of aldose reductase in diabetic patients. To clarify this issue, we measured the width of skeletal-muscle basement membrane and erythrocyte aldose reductase activity in 27 insulin-dependent diabetic and 8 nondiabetic individuals. The results showed that both the aldose reductase activity and the width of capillary basement membrane were increased in diabetic patients as compared to nondiabetic individuals (6.89 ± 0.38 versus 5.15 ± 0.60 mL/mU erythrocytes, p < 0.05 and 2257 ± 166 versus 1136 ± 69 Å, p < 0.0001, respectively) (means ± SE), but marked variability was observed in both the enzyme activity and the basement membrane thickness among the diabetic patients. There was a significant correlation between the capillary basement membrane thickness and the activity of erythrocyte aldose reductase (r = 0.51, p < 0.01) in diabetic patients. Our data suggest that the polyol pathway plays an important role in thickening of capillary basement membrane in diabetic individuals, and the variability in aldose reductase activity seen among diabetic patients may result in the varying susceptibility to the development of diabetic microvascular disease.     

The effect of aldose reductase inhibition with ponalrestat on the width of the capillary basement membrane in diabetes mellitus

There is evidence to suggest that hyperglycemia is required for the development of the microvascular complications of diabetes. However, the precise mechanism by which hyperglycemia might cause diabetic complications is not completely clear. One possibility is the increased activity of the polyol pathway. Capillary basement membrane thickness is a hallmark histological finding in diabetic microangiopathy. Previous studies in experimental models of diabetes have related the polyol pathway with the thickness of basement membrane in retinal capillaries. To study the effect of aldose reductase inhibition with ponalrestat on the width of the skeletal muscle capillary basement membrane in subjects with diabetes, we measured the capillary basement membrane width in 55 subjects with diabetes in a double masked, placebo controlled randomized trial over a period of 18 months. Twenty-nine patients received ponalrestat (two 300 mg tablets daily) and twenty-six received placebo tablets. The age, sex distribution, type and duration of diabetes were similar in both groups. The glycosylated hemoglobin remained at a constant level throughout the study in both groups. The baseline capillary basement membrane width of the ponalrestat group was 3134 +/- 146 A, it was 3074 +/- 226 A at month 12 and 2548 +/- 182 A at month 18 (P less than 0.001 vs baseline value). The placebo group also had a significant reduction in the width of the capillary basement membrane, from a baseline value of 3026 +/- 147 A to 2818 +/- 144 A at month 12 and 2618 +/- 156 A at month 18 (P less than 0.001 vs baseline value). There was no statistical difference in the capillary basement membrane width between the two groups at any time point.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retinal capillary basement membrane thickness in diabetic mice genetically modified at the haptoglobin locus

BACKGROUND: Individuals with diabetes mellitus (DM) homozygous for the haptoglobin (Hp) 1 allele are at decreased risk of retinopathy as compared to DM individuals with the Hp 2 allele. We sought to recapitulate these findings in DM mice genetically modified at the Hp locus. METHODS: An early morphological characteristic of the microangiopathy seen in diabetic retinal disease is retinal capillary basement membrane (RCBM) thickening. RCBM thickness as assessed by electron microscopy was performed on a total of 12 eyes taken from three mice in each of the four study groups (three eyes from C57Bl/6 Hp 1 and C57Bl/6 Hp 2 mice with and without streptozotocin-induced diabetes). RESULTS: The non-parametric Kruskal-Wallis ANOVA test demonstrated that there was a highly significant difference between the four groups of mice (P < 0.0001). Mann-Whitney tests for specific pair-wise comparisons demonstrated that there was no significant difference in the RCBM thickness between Hp 1 and Hp 2 mice (p = 0.70) or between DM Hp 1 and non-DM Hp 1 mice (p = 0.42). However, induction of diabetes resulted in a marked increase in RCBM thickness in Hp 2 mice compared to non-DM Hp 2 mice (p = 0.0004) and compared to DM Hp 1 mice (p = 0.0005). CONCLUSIONS: A highly significant increase in RCBM thickness was observed in DM mice with the Hp 2 genotype. These data provide important support for association studies done in humans showing an increased prevalence of diabetic retinopathy in individuals with the Hp 2 genotype.     

Prevention of glomerular basement membrane thickening by aminoguanidine in experimental diabetes mellitus

The etiology of diabetic glomerulopathy appears to be related, at least in part, to the degree of hyperglycemia, the resultant nonenzymatic glycosylation of proteins, and the eventual formation of advanced glycosylation end products in long-lived structural proteins. To investigate the relationship between the glomerular basement membrane (GBM) changes of diabetic nephropathy and the formation of advanced glycosylation end products, we studied control rats, diabetic rats, and control and diabetic rats who received aminoguanidine, a compound that pharmacologically inhibits formation of advanced glycosylation end products. After 9 months, rat weight was smaller and kidney weight larger in both diabetic groups compared with both control groups. GBM width was increased in the diabetic group compared with the control group. Aminoguanidine administration to diabetic rats ameliorated this increase in GBM. Thus, aminoguanidine administration from the onset of experimental diabetes prevented the widening of the GBM that is typical of diabetes.     

Tissue magnesium status in diabetes mellitus

Summary Leucocyte and erythrocyte magnesium was assayed in 17 healthy subjects and 17 insulin dependent diabetic patients. Plasma magnesium concentration (mean±standard error of mean) was significantly lower in the diabetic patients (0.80±0.02 mmol/l), compared with the healthy subjects (0.90±0.02 mmol/l, p < 0.001), but the leucocyte and erythrocyte magnesium content was not significantly different in the diabetic patients (34.5±0.8 and 6.2±0.2 mmol/kg dry solids) compared with the healthy subjects (35.5±0.8 and 6.5±0.11 mmol/kg dry solids). In a separate study skeletal muscle obtained by needle biopsy was also assayed. Plasma magnesium in 10 diabetic patients (0.74±0.01 mmol/l) was significantly lower than in 16 healthy subjects (0.85±0.02 mmol/l, p < 0.001), but there was no significant difference in the mean muscle magnesium content (43.0±0.7 compared with 40.7±0.9 mmol/kg dry solids in the diabetic patients).     

Cerebral cortical capillary basement membrane thickening in galactosaemic rats

Summary Wistar-Kyoto rats fed a diet containing 30% by weight galactose for 15–21 months developed significant thickening of the endothelial basement membranes of capillaries from the frontal cortex of the cerebrum, by comparison with cerebral capillary basement membranes from animals on a standard diet (p<0.001), or animals receiving a diet containing 30% galactose together with 250 mg/kg diet of the aldose reductase inhibitor, Sorbinil (0.001<p<0.01). The effect was similar to that which we have reported previously in the retinal capillaries of these animals. Spontaneously hypertensive rats on the high-galactose diet showed modest cerebral capillary basement membrane thickening (0.02<p<0.05) only for one of the measurement protocols utilised, and the process was not prevented by Sorbinil. Biochemical assays of retina, cerebral cortex, and blood serum from Wistar-Kyoto and spontaneously hypertensive rats maintained on the Sorbinil regimen showed that the drug did cross the blood-retinal and blood-brain barriers. Similar to our previous study on the retinal capillaries, we observed no degeneration of pericyte or endothelial cell cytoplasm, and no alteration in the pericyte/endothelial cell nuclear ratio in the cerebral capillaries of galactosaemic animals, by comparison with controls. Based on immunocytochemical studies in the human retina, it has been claimed that aldose reductase is present in capillary pericytes but absent in the endothelial cells. However, we observe a considerably smaller pericyte/ endothelial cell nuclear ratio in the capillaries of the cerebral cortex of the rat, by comparison with those of the retina. Also, pericyte coverage of the cerebral cortical capillaries is much less than that of the retinal capillaries of these animals. Therefore, it appears that the biochemical process(es) responsible for basement membrane thickening are unlikely to reside within the pericytes.     

Growth hormone enhances basement membrane thickening in experimental diabetes

Summary Injection of porcine growth hormone (200 μg) or saline 5 days a week for 16 to 20 weeks in streptozotocin-diabetic rats showed that compared to saline growth hormone produced a 2 1/2-fold larger increase in glomerular capillary basement membrane thickness (2p=0.027). The possible significance of this effect of an elevated level of growth hormone for diabetic microangiopathy is discussed.     

Fluorescence angiography of the paramacular retinal vessels and altered glomerular basement membrane in children with juvenile onset diabetes mellitus

Summary Eighteen diabetic children aged between 8.5 and 16.5 years (mean 12.5 years) who had been diabetic for 1 to 10 years (mean 4.1 years) were examined for their urinary glomerular basement membrane (GBM) antigen excretion by means of immunoelectrophoresis and for alterations of the retinal vessels by fluorescence angiography. None of these patients showed albuminuria or hypertension. As compared to 40 healthy controls aged between 5 and 17 years, altered GBM antigen mobility (alpha-1) was found in 9 out of these 18 diabetics, whereas the remaining 9 children had normal GBM antigen mobility (alpha-2). Pathological fluorescence angiography findings on the other hand were evident in 7 children with altered GBM mobility, but only in 4 diabetics with normal GBM antigen mobility. This trend reflects the similarity of biochemical and functional characteristics of basement membranes in the retinal and kidney vessels supporting the well established association of vascular changes in both organs in patients with diabetes mellitus. GBM antigen excretion into urine could be useful for detecting early microvascular alterations in the kidneys in juvenile diabetics where diagnosis of early glomerulosclerosis is important.     

Differential effects of type 2 (non-insulin-dependent) diabetes mellitus on pentosidine formation in skin and glomerular basement membrane

Summary Pentosidine is an advanced Maillard/glycation reaction product the formation of which in human skin is significantly increased in Type 1 (insulin-dependent) diabetes mellitus and correlates with the severity of diabetic complications. Preliminary data in a limited number of Type 2 (noninsulin-dependent) diabetic individuals showed that skin pentosidine was not significantly elevated, raising the question of whether statistical power was insufficient for differences to be revealed, or whether pentosidine did not form because biological factors intrinsic to Type 2 diabetes affected the advanced Maillard reaction altogether. To resolve this question, pentosidine levels were measured in 209 human skin samples obtained at autopsy and in purified glomerular basement membranes from 45 subjects of various ages, with and without Type 1 and Type 2 diabetes and uraemia. Pentosidine increased exponentially in skin but curvilinearly in glomerular basement membranes, and reached 75 and 50 pmol/mg collagen at projected 100 years, respectively. Skin levels were not significantly elevated in individuals with Type 2 diabetes (p>0.05). In contrast, pentosidine levels in glomerular basement membranes were elevated above the 95% confidence interval in the majority of diabetic patients regardless of the type of diabetes and in all individuals on haemodialysis. These data clearly demonstrate that the advanced Maillard reaction is indeed accelerated in Type 2 diabetes and strongly suggest that differences in pentosidine accumulation rates may be due to differences in collagen turnover. In diabetes and uraemia, accelerated Maillard reaction mediated protein crosslinking, as reflected by pentosidine, may contribute to decreased turnover of the extracellular matrix, sclerosis and thickening of basement membranes.     

Pathogenetic heterogeneity in retinal capillary basement membrane thickening in the diabetic BB-rat

Summary In the present study, we compared the effects of good blood glucose control and that of aldose reductase inhibitor (Statil) treatment on diabetic retinal capillary basement membrane thickening in the diabetic BB-rat. Aggressive insulin treatment maintaining euglycaemia for 4 months prevented the characteristic basement membrane thickening in both the superficial and deep capillary beds of the diabetic retina. Statil treatment of hyperglycaemic rats for the same length of time prevented basement membrane thickening in the deep capillary bed but not in the superficial capillaries.     

Relationship between nailfold capillary microscopy and salivary capillary basement membrane width in Raynaud's disease and progressive systemic sclerosis

To assess the relationship between a nailfold scleroderma pattern and histopathological data, we compared the results of nailfold capillaroscopy with capillary basement membrane width of labial salivary glands in 25 patients with either a Raynaud's disease (RD: 12 patients) or a progressive systemic sclerosis (PSS: 13 patients). The sensitivity of a capillaroscopic scleroderma pattern for capillary basement membrane thickness is of 75%. These results confirm the usefulness of in vivo capillary examination for the early diagnosis of PSS.     

The clinical utility of reticular basement membrane thickness measurements in asthmatic children

Objective: Reticular basement membrane (RBM) thickness is one of the pathological features of asthma and can be measured in endobronchial biopsies. We assessed the feasibility of endobronchial biopsies in a routine clinical setting and investigated the clinical value of RBM thickness measurements for asthma diagnosis in children. Methods: We included all children who underwent bronchoscopy with endobronchial mucosal biopsies for clinical reasons and divided them into three subgroups: (1) no asthma, (2) mild–moderate asthma, and (3) problematic severe asthma. Results: In 152/214 (71%) patients, mean age 9.5 years (SD 4.6; range 0.1–18.7) adequate biopsies were retrieved in which RBM thickness could be measured. Mean (SD) RBM thickness differed significantly among children without asthma, with mild–moderate asthma, and with problematic severe asthma (p?=?0.04), 4.68 (1.24)?µm, 4.56 (0.89)?µm, and 5.21 (1.10) µm respectively. This difference disappeared after adding exhaled nitric oxide to the multivariate model. Conclusions: This study confirms the difference in RBM thickness between children with and without asthma and between asthma severities in a routine clinical care setting. However, quantifying the RBM thickness appeared to have no added clinical diagnostic value for asthma in children.