Capillary Basement Membrane Width Research Articles

Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats.

We examined the effects of aminoguanidine and methylguanidine on vascular dysfunction, glomerular structural changes, and indexes of early and late nonenzymatic glycation in 7-month streptozotocin-induced diabetic rats. Kidney weight, glomerular volume, fractional mesangial volume, glomerular capillary basement membrane width, and urinary albumin excretion were increased in diabetic rats. Diabetes also 1) increased vascular albumin permeation twofold in retina, sciatic nerve, aorta, skin, and kidney; 2) decreased renal collagenase-soluble collagen; 3) increased collagen-associated fluorescence in kidney and skin but not in aorta; and 4) increased glycated hemoglobin levels and aortic pentosidine levels. Aminoguanidine reduced albuminuria by 70% after 4 months, and both guanidines 1) normalized aortic pentosidine levels and renal collagenase-soluble collagen, 2) had no effect on glycated hemoglobin levels or collagen-associated fluorescence (in aorta, kidney, or skin), and 3) had little or no effect on regional albumin permeation. These discordant effects of aminoguanidine on diabetes-induced vascular changes versus parameters of nonenzymatic glycation are consistent with a multifactorial pathogenesis of diabetic complications, including roles for metabolic imbalances independent of nonenzymatic glycation. To the extent that glomerular matrix accumulation and increased regional albumin permeation in chronically diabetic rats are sequelae of nonenzymatic glycation, these findings point to an important role for early glycation reactions and products.

Endurance exercise training decreases capillary basement membrane width in older nondiabetic and diabetic adults.

The objectives of these studies were to 1) evaluate the relationships among age, glucose intolerance, and skeletal muscle capillary basement membrane (CBM) width (CBMW) and 2) determine the effects of exercise training on CBMW by comparing values of young (28 +/- 4 yr) and older (63 +/- 7 yr) athletes with those of age-matched sedentary control subjects and by measuring CBMW in older men and women before and after a 9-mo endurance-exercise training program. CBMW was measured in tissue samples obtained from the gastrocnemius muscle. CBMW in sedentary 64 +/- 3-yr-old subjects was 25% thicker than in sedentary 24 +/- 3-yr-old subjects. CBMW was similar in young and older athletes and was thinner than the CBMW of age-matched sedentary control subjects. There were no differences in CBMW among older sedentary individuals with normal or impaired glucose tolerance or mild non-insulin-dependent diabetes mellitus. Nine months of endurance exercise training reduced CBMW in older men and women by 30-40%, to widths that were not different from those of the young subjects; this response was independent of glucose tolerance status. These findings suggest that habitual exercise prevents the thickening of the skeletal muscle CBM that is characteristic of advancing age. Moreover, the thickening of the CBM appears to be readily reversed as a result of exercise training, even in older individuals.

Dietary myo-inositol supplementation does not prevent retinal and glomerular vascular structural changes in chronically diabetic rats

To assess effects of dietary myo-inositol supplementation on diabetes-induced vascular structural lesions, diabetes was induced in Sprague-Dawley rats with streptozotocin; one-third of these rats was fed a 2% myo-inositol diet for 9 months, one-third was left untreated for 5 months then treated with myo-inositol for the last 4 months, and one-third was untreated for the entire 9 months. Controls included untreated and myo-inositol-treated groups. Weight gain was impaired and plasma glucose, glycosylated hemoglobin, food consumption, urine volume, and albuminuria were increased significantly in diabetic versus age-matched control rats. Plasma myo-inositol levels were increased approximately fivefold in controls and approximately six- to eightfold in diabetic rats treated with myo-inositol. In general, myo-inositol did not affect any of the above parameters in control or diabetic rats. Retinal capillary basement membrane width (CBMW) was increased significantly (∼50% versus controls) after 9 months of diabetes. In the control group myo-inositol increased CBMW to the level of untreated diabetic rats; myo-inositol had no effect on CBMW in each diabetic group. The number of retinal capillaries containing pericyte nuclei and pericyte capillary coverage were increased in untreated as well as myo-inositol-treated diabetic rats and in the myo-inositol-treated control group. Glomerular CBMW was increased after 5 and 9 months of diabetes versus age-matched controls, and was increased even more by myo-inositol. Mesangial fractional volume of the glomerulus was increased 36% by diabetes and was decreased slightly but significantly by myo-inositol. These results indicate that diets supplemented with 2% myo-inositol (1) cause capillary basement membrane (CBM) thickening and pericyte changes in retinal capillaries of normal rats, (2) are ineffective in preventing or reversing diabetes-induced retinal CBM thickening, and (3) cause further thickening of glomerular CBM in diabetic rats.

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.

Discordant effects of the aldose resuctase inhibitor, sorbinil, on vascular structure and function in chronically diabetic and galactosemic rats

Effects of sorbinil, an aldose reductase inhibitor, were examined on renal glomerular structure, urinary albumin and IgG excretion, and vascular albumin permeation in eyes and aorta of 8-month diabetic, galactose-fed, and age-matched control rats. Sorbinil was added to the diet of one-half of the rats in each group at the time of induction of diabetes and galactosemia. Weight gain was impaired in diabetic and galactose-fed rats versus controls and was improved slightly in corresponding sorbinil-treated groups. Plasma glucose and glycosylated hemoglobin levels, food consumption, and 24-hr urine volume were increased in diabetic rats and were unaffected by sorbinil treatment. Food consumption and glycosylated hemoglobin levels were increased in galactose-fed rats, although the increases were smaller than in diabetic rats; glycosylated hemoglobin levels were decreased by sorbinil. Diabetes- and galactosemia-induced increases in albumin permeation in eyes and aorta were prevented by sorbinil. Urinary excretion of albumin and IgG was increased by diabetes and decreased by sorbinil, although differences between the two diabetic groups were not statistically significant for albumin. Galactosemia was associated with an increase in urinary albumin and IgG excretion that did not reach statistical significance. Glomerular capillary basement membrane width (GBMW) was increased in diabetic versus agematched control rats but was unaffected by galactose feeding. GBMW was increased in controls fed sorbinil and glomerular capillary basement membrane thickening in diabetic rats was not prevented by sorbinil. The fractional volume of the glomerulus occupied by mesangium (V vmes) was increased in diabetic and galactose fed rats versus agematched controls, and was unaffected by sorbinil. The explanation for the discordant effects of sorbinil on generalized vascular dysfunction versus glomerular structural changes remains unclear.

The effect of aldose reductase inhibition with ponalrestat on the width of the capillarly 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 Å, it was 3074 ± 226 Å at month 12 and 2548 ± 182 Å at month 18 ( P < 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 Å to 2818 ± 144 Å at month 12 and 2618 ± 156 Å at month 18 ( P < 0.001 vs baseline value). There was no statistical difference in the capillary basement membrane width between the two groups at any time point. In conclusion, our study showed no effect on skeletal muscle basement membrane width following 18 months of treatment with the aldose reductase inhibitor, ponalrestat, as compared to placebo. It is possible that in the skeletal muscle capillaries the thickening of the capillary basement membrane width induced by diabetes is mediated by mechanisms other than the polyol pathway.

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.

Delay of progression of diabetic microangiopathy

Three muscle biopsies were performed in 53 overt type II diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an abnormally increased capillary basement membrane width in muscle. Thirty-five subjects received glipizide and 18, placebo. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups ( P = NS). In the subjects receiving placebo, the mean width of the muscle capillary basement membrane increased ( P = NS), but in those receiving glipizide, the mean decreased from 193 ± 13 nm (SEM) to 161 ± 10 nm ( P = .02). Fasting plasma glucose and glycosylated hemoglobin A 1 significantly decreased ( P < .001) after two years in those receiving glipizide. In 15 subjects, mean glycosylated hemoglobin A 1 reached the normal range, and mean muscle capillary basement membrane width decreased to a level close to that found in subjects without diabetes ( P = NS). Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a 2-year significant decrease of muscle glucosyltransferase (synthesis) activity ( P < .01) in the glipizide-treated subjects as opposed to a significant increase ( P < .001) in those receiving placebo. Muscle N-acetyl-β-glucosaminidase activity (degradation) was statistically increased ( P < .001) in those subjects taking glipizide, but decreased in those taking placebo ( P < .001).

Salivary glands in long-term alloxan-diabetic rats. A quantitative light and electron-microscopic study.

Fifty untreated diabetic animals were compared with 58 age-matched non-diabetic controls. Reduced salivary gland weight was evident after one month's diabetes and this was unchanged after 12 months of diabetes. Submandibular/sublingual gland weight was proportional to the reduced body weight in the diabetic rats. Parotid gland weight, however, was proportionally more reduced. Only diabetic rats had lipid inclusions in the acinar cells of their submandibular glands and the morphometrically estimated amount of inclusions was positively correlated to the blood glucose level. Acinar cell size was significantly increased in long-term diabetic rats as compared with short-term diabetic rats and controls. Capillary basement membrane width was significantly increased in long-term diabetic rats compared with age-matched controls and with short-term diabetic rats. Thus, both the degree and duration of diabetes have a major effect on salivary gland morphology in alloxan diabetic rats.

Relationship of muscle capillary basement membrane thickness and diabetic retinopathy.

We examined the relationship between the thickness of the quadriceps muscle capillary basement membrane and diabetic retinopathy. Basement membrane thickness was measured in two groups of patients with long-standing type II diabetes mellitus. One group of patients (N = 13) had no evidence of diabetic retinopathy on fluorescein angiography, whereas the other (N = 12) had proliferative microvascular disease. All the patients were male, and both groups were of similar ages, duration of diabetes, serum creatinines, and glycemic control as reflected by HbA1 levels. Mean muscle capillary basement membrane width (+/- SE) of the patients with proliferative retinopathy (3346 +/- 262) was significantly greater (P less than .05) than that observed in the patients without retinopathy (2660 +/- 177). The results of this study suggest that there is a relationship between capillary basement membrane thickness in skeletal muscle and the severity of microangiopathy in the eye. However, there was a substantial overlap between the two groups, indicating that for any individual patient the measurement of muscle capillary basement width will probably not be useful in identifying the presence or absence of retinopathy.

Kidney morphology in experimental hyperglycemia.

To evaluate the role of hyperglycemia in the pathogenesis of diabetic nephropathy, the kidneys from dogs experimentally galactosemic for 5 yr have been compared with the kidneys from age-matched normal dogs and dogs with alloxan-induced diabetes for 5 yr. The width of glomerular capillary basement membrane and the quantity of plasma protein immunohistochemically demonstrable in the basement membrane were supranormal in the galactosemics, as they were in the diabetics. In contrast, kidney weight, mesangial volume, and the prevalence of obliterated glomeruli, glomerular exudates, and mesangial nodules in the galactosemic animals were comparable to those of normal animals and clearly were less than observed in the insulin-deficient diabetic animals. These galactosemic dogs are known to have developed a retinopathy morphologically indistinguishable from that of diabetic patients and dogs. Thus, galactosemia sufficient to produce diabetic-like lesions in the glomerular basement membrane and retina was found to be nevertheless insufficient to elicit several renal abnormalities that are typical of diabetes. The polyol concentration in erythrocytes was greater than normal in the galactosemics and the diabetics and was greatest in the galactosemics. The absence of mesangial expansion, glomerular obliteration, and nephromegaly in galactose-fed dogs raises the possibility that these abnormalities in diabetes are not a result of excessive polyol pathway activity.

Effect of glycemic control on microvascular complications in patients with type I diabetes mellitus

The relation between the control of blood glucose levels and the progression of early diabetic retinopathy and the width of skeletal muscle capillary basement membrane was studied in 54 insulin-dependent diabetic patients. After initial ophthalmologic evaluation including seven-field fundus photography and fluorescein angiography and measurement of levels of glycosylated hemoglobin and width of skeletal muscle capillary basement membrane, the patients were divided into two groups: an experimental 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 injections of insulin daily. After a mean follow-up period of 31.4 months, the experimental group had a significant decrease in glycosylated hemoglobin levels as compared with baseline values (mean ± SEM, 7.2 ± 0.3 percent versus 10.1 ± 0.4 percent), reflecting improved control of blood glucose levels. The conventional treatment group had no change in glycosylated hemoglobin levels after a mean of 33.5 months of follow-up. With use of either a modified Early Treatment Diabetic Retinopathy Study grading system or macular microaneurysm counts, the experimental treatment group showed significantly less progression of retinopathy (p <0.05). The skeletal muscle capillary basement membrane width was significantly reduced only in the experimental treatment group with stable or improved retinopathy and was unchanged in the control group. There was a tendency for skeletal muscle capillary basement membrane width to increase in thickness over time in those patients whose retinopathy worsened irrespective of treatment. It is concluded that meticulous diabetic control may slow the progression of early diabetic retinopathy. Changes in skeletal muscle capillary basement membrane width may reflect the course of diabetic retinopathy.

Glycemic control and bone age are independently associated with muscle capillary basement membrane width in diabetic children after puberty.

This study was undertaken to examine the possible relationships between muscle capillary basement membrane width (CBMW) and glycemic control, bone age, chronologic age, and duration of diabetes in young patients with insulin-dependent diabetes mellitus (IDDM) during different stages of pubertal development. We studied 49 males and 43 females (age, 7-20 yr) with IDDM for up to 16 yr for whom bone age and glycosylated hemoglobin (HbA1c) data were available at the time of right quadriceps muscle biopsy. Based on pubic hair Tanner stage, subjects were assigned to prepubertal (Tanner I), pubertal (Tanner II and III), and postpubertal (Tanner IV and V) groups. In 30 pubertal and prepubertal subjects, none of the variables studied was significantly correlated with CBMW. This is attributable in part to the small number of subjects in each group. In 62 postpubertal subjects, CBMW was correlated with age (r = .27, P = .03), bone age (r = .43, P = .0005), and postpubertal duration of diabetes (r = .38, P = .003) but not total duration of diabetes. In the postpubertal subjects, CBMW was correlated with HbA1c at the time of biopsy (r = .31, P = .01) but correlated more strongly with the mean of HbA1c values obtained during the 1- and 2-yr periods before biopsy (r = .37, P = .01, and r = .54, P = .03, respectively). An analysis of covariance revealed that the slopes for the regression of loge CBMW on HbA1c differed significantly (P = .02) among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle capillary basement membrane width in patients with vacor-induced diabetes mellitus.

Muscle capillary basement membrane width is a sensitive marker for the presence of diabetic microangiopathy. Studies have indicated that genetic factors and alterations in glucose metabolism influence muscle capillary basement membrane width. To define the role of these factors we have measured muscle capillary basement membrane thickness in controls, insulin dependent diabetics, and individuals with diabetes secondary to the ingestion of Vacor, a rat poison, which results in hyperglycemia. Hemoglobin A1 concentrations were increased in both diabetic groups, but hemoglobin A1 levels and the duration of diabetes were similar in the two diabetic groups. The muscle capillary basement membrane width was increased to a similar extent in the insulin-dependent diabetics (control, 1,781 +/- 46 vs. IDD, 2,287 +/- 144 A, P less than 0.001) and in the Vacor diabetic group (2,320 +/- 149 A, P less than 0.001). In the insulin-dependent diabetic group, 63% of the patients had a muscle capillary basement membrane width greater than two standard deviations above the mean of the controls, while in the Vacor diabetic group this figure was 56%. Despite the relatively short duration of diabetes (6.2 +/- 0.3 yr), 44% of the Vacor diabetic patients had retinopathy and 28% had proteinuria. The present study provides strong evidence that even in the absence of genetic diabetes mellitus, hyperglycemia or some other abnormality related to insulin lack can cause microvascular changes.

Enzyme activities as a predictor of diabetic vasculopathy

Forty-one patients with chemical diabetes had three oral glucose tolerance tests and underwent muscle biopsy three times over a period of three years. Twenty-three received glipizide and 18 placebo. Those taking placebo had an increase in the mean muscle capillary basement membrane width (p = 0.01), but those taking glipizide showed a decrease (p = 0.01) to values no different from those of nondiabetic subjects. Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a three-year decrease (not significant) in muscle glucosyltransferase activity in the glipizide-treated patients, but a statistically significant difference (p <0.01) comparing the adjusted means of the two treatment groups. N-acetyl-beta-glucosaminidase activity was significantly increased in muscle from baseline values (p <0.01), with adjusted means also significantly different (p <0.01). The data suggest that changes in basement membrane and enzyme activities are correlated, and the latter may be a predictor to follow the development, progression, or regression of diabetic vasculopathy.

Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus.

To distinguish metabolic from genetic factors in the development of microangiopathy in diabetes, we evaluated biopsy specimens of kidney and quadriceps muscle from seven pairs of identical twins who were discordant for Type I (insulin-dependent) diabetes mellitus. Two of the diabetic patients had clinical diabetic nephropathy, including hypertension, marked albuminuria, and a substantially reduced creatinine clearance; the other five had normal renal function and only minor clinical indications of complications. All the twins of the diabetic patients had normal glomerular basement membrane widths and normal fractional volumes of the glomerular mesangium. Values for glomerular basement membrane width, tubular basement membrane width, and mesangial volume in each diabetic twin exceeded the values in the respective sibling (P less than or equal to 0.0035), even if the value in the diabetic twin lay within established normal ranges. Values for muscle capillary basement membrane width in the diabetic twins did not differ from those in their siblings (P = 0.5). Our observations suggest that the metabolic abnormalities of diabetes are necessary, if not sufficient, for the development of glomerular abnormalities. We also conclude that in diabetic patients, alterations in muscle capillary basement membrane width do not necessarily accompany pathologic lesions in the kidney.

Skeletal muscle basement membrane in maturity-onset diabetes in the young.

We have studied skeletal muscle capillary basement membrane width (CBMW) and intensity of skeletal muscle extracellular basement membrane staining for albumin and IgG in eight families with maturity-onset diabetes in the young (MODY). Ninety-two MODY patients were identified. Sixty-three of these patients, 33 relatives with nondiagnostic oral glucose tolerance studies, and 61 normoglycemic relatives were studied for glucose and insulin. Twenty-six of these MODY patients, 20 normoglycemic relatives, and 16 unrelated normal controls had skeletal muscle capillary morphologic studies. The muscle capillary basement membrane was significantly increased in MODY patients younger than 40 yr when compared with unrelated normal subjects and relatives of the same age (P less than 0.001). However, in these families, the CBMW of MODY patients showed no significant thickening with age (slope = 0.45, P less than 0.14), as expected and seen in the normal subjects and in the normoglycemic relatives of the patients (slope = 1.21, P less than 0.001). The slope derived from the linear regression of age and CBMW in MODY patients (0.45 +/- 0.29) was significantly less (P less than 0.05) than that of the nondiabetic subjects (1.21 +/- 0.19). The mean intensity of skeletal muscle extracellular basement membrane staining for albumin was higher in MODY patients (1.1 +/- 0.15) than in unrelated normal subjects (0.7 +/- 0.1, P less than 0.025) and normal MODY family members (0.6 +/- 0.08, P less than 0.01). The unexpected absence of basement membrane thickening with age in the MODY patients may explain the paucity of vascular complications that have been reported by some.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle capillary basement membrane width and its relationship to diabetes mellitus in monozygotic twins

Muscle capillary basement membrane width and its relationship to diabetes mellitus in monozygotic twins

Increase in capillary basement membrane width in parents of children with type I diabetes mellitus. Association with HLA-DR4.

Hereditary factors related to HLA antigens are known to play a role in determining risk for the development of type I diabetes. In the present investigation, asymptomatic first degree relatives of diabetic patients were investigated to determine whether any abnormalities could be associated with the HLA haplo-types. Muscle biopsies were performed to obtain measurements of the width of the capillary basement membranes in 16 type I diabetic children, 20 of their unaffected siblings, and 38 parents. Only two diabetic children had capillary basement membranes greater than 2000 Å. The mean width of the capillary basement membranes was not different in affected compared with unaffected siblings. In contrast, the capillary basement membranes in the parents were considerably larger, with 14 of the 38 parents (37%) having measurements greater than 2000 Å. Moreover, the width of the capillary basement membranes in the parents correlated with the presence of the antigen HLA-DR4. The mean capillary basement membrane width in DR4 positive parents was 2026 ± 350 Å; that of DR4 negative parents was 1642 ± 333 Å. The difference was highly significant (P &amp;lt; 0.001). There was no correlation of capillary basement membrane width with HLA-DR3. The results suggest that a risk factor for type I diabetes associated with HLA-DR4 was associated in parents of type I diabetic patients with an asymptomatic increase in capillary basement membrane width in the absence of any clinical evidence of diabetes. The possible role of these abnormalities in the pathogenesis of type I diabetes and of the vascular complications of the disease require further study.