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 (approximately 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.

Interactions between hypertension and diabetes on vascular function and structure in rats.

Regional 125I-albumin permeation and glomerular structural changes were assessed in male Sprague-Dawley rats with diabetes and/or hypertension. All rats underwent unilateral nephrectomy 2 weeks after induction of diabetes with streptozotocin. At the same time, one-half of the nondiabetic and diabetic animals were placed on 1% saline drinking water and given weekly intramuscular injections of deoxycorticosterone acetate to induce hypertension (systolic blood pressure greater than 150 mm Hg). Vascular permeability studies were performed after 1 and 3 months of hypertension. Hypertension, alone or in combination with diabetes, had no effect on weight gain, plasma glucose, or food consumption, but did increase 24-h urine volume in nondiabetics. In normotensive diabetics and in nondiabetic hypertensive rats, vascular 125I-albumin permeation was increased in eyes, aorta, and new granulation tissue (formed in a subcutaneous fabric implant), and glomerular basement membranes were thickened without any change in the fractional volume of the glomerulus occupied by mesangium. Urinary albumin and IgG excretion in nondiabetic hypertensive rats was increased much more than in normotensive diabetics. Hypertension and diabetes were additive in their effects on 125I-albumin permeation in eyes, aorta, and granulation tissue, and on glomerular basement membrane thickening, but were synergistic in their effects on urinary albumin excretion and mesangial fractional volume. The magnitude of the increase in vascular albumin permeation and urinary albumin and IgG excretion between and 1 and 3 months was much larger in diabetic hypertensive rats than in rats with hypertension or diabetes alone. Neither diabetes nor hypertension, alone or in combination, had any effect on albumin permeation in skeletal muscle, skin, heart, or brain. These findings demonstrate that hypertension and diabetes increase vascular albumin permeation in rats preferentially in tissues that correspond to sites of clinically significant vascular disease in human diabetics. They also attest to an important interaction between blood pressure-induced and diabetes-induced increases in vascular permeability in these tissues and in structural changes in the glomerular vasculature.

Discordant effects of the aldose reductase 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 age-matched 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 (Vvmes) was increased in diabetic and galactose fed rats versus age-matched controls, and was unaffected by sorbinil.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of degenerative changes in retinal and uveal capillary pericytes in diabetic rats.

Ultrastructural morphometric techniques were used to quantify pericyte degeneration in retinal and uveal capillaries of streptozotocin-diabetic rats in order to assess the suitability of this small rodent model of diabetes for studies of the pathogenesis of microvascular eye disease in diabetic humans. Male, Sprague-Dawley rats were killed by intraaortic perfusion of fixative 6 and 9 mos after induction of diabetes with 50 mg/kg streptozotocin. No differences were evident between diabetics and age-matched controls in capillary circumference, numbers of endothelial cells per capillary, and capillary cytoplasmic area of retinal, choroidal, and iridial vessels. Capillary basement membrane width and the percentage of the capillary circumference covered by pericytes were increased in retinas of diabetic vs age-matched control rats after 9 mos of diabetes (P less than 0.05), but no differences were evident in the number of pericyte processes per capillary and the percentage of vessels with pericyte nuclei. No differences in pericyte distributions were observed between control and diabetic rats in the choriocapillaris and iris after 9 mos of diabetes. These findings indicate that retinal capillary basement membrane thickening precedes any evidence of pericyte degenerative changes and suggest that pericyte degeneration analogous to that associated with human diabetic microangiopathy does not occur in this experimental animal model.

Pathomorphologic aspects of muscular tissue in diabetes mellitus.

Biopsy specimens from the myocardium were examined in a series of 145 patients who had elected coronary arterial bypass grafting. The patients were divided into three groups; 1) overtly diabetic (OD) patients; 2) chemically diabetic (CD) patients, who demonstrated impaired glucose tolerance only when stressed with a sugar load; and 3) normoglycemic, nondiabetic (ND) patients, who served as a control group. Tissue plugs from the left anterior apical segment of the heart and from the quadriceps femoris in 71 patients, for comparative evaluation, were prepared for ultrastructural examination. Findings were as follows: 1) Myocardial hypertrophy and interstitial fibrosis were twin characteristic abnormalities, seen in all but two of the biopsy specimens; capillary endothelial changes, the third most common abnormality, were present in approximately half of these specimens, regardless of the patients' metabolic status. 2) In patients matched by sex, age, weight, blood pressure, preoperative myocardial ventricular function, and coronary arterial integrity, capillary basal laminar thickening represented a pathomorphologic hallmark, distinguishing structural alterations in the diabetic from those in the normoglycemic patient. 3) Although clear-cut and statistically significant thickening of basal laminae was noticeable in OD patients, a) in the quadriceps markedly increased laminar thickening was present in a number of ND patients, rendering interpretation of this change in skeletal muscle as pathognomonic for diabetes doubtful; and b) within cardiac muscle this increase in laminar width was less than that seen in skeletal muscle, leaving the functional implications of this alteration in doubt. 4) Early but statistically significant increases in capillary basal laminar thickening were observed in the myocardium of CD patients; these patients demonstrated impaired glucose tolerance only when stressed with a sugar load, without exhibiting overt diabetic manifestations. 5) In this group of highly selected patients with epicardial coronary arterial disease, the histopathologic profile of the diabetic myocardium did not include distinctive abnormalities sufficient to warrant the designation of "diabetic cardiomyopathy," indicating that coronary arterial bypass grafting can be recommended for the diabetic patient who requires this procedure.

Quadriceps and myocardial capillary basal laminae. Their comparison in diabetic patients.

Quadriceps and myocardial biopsy specimens were obtained from 24 patients undergoing elective coronary arterial bypass grafting. Patients were divided into those with chemical diabetes (CD) (with incidentally discovered elevated glucose levels when stressed), overt diabetes (OD) (who required insulin support), and euglycemic nondiabetics (ND). Specimens from the quadriceps femoris and left anterior apical segment of the heart were examined ultrastructurally, with particular attention to the evaluation of capillary basal laminar thickness, using morphometric techniques. Results indicate (1) an increased, though statistically insignificant, thickening of capillary basal laminae in the quadriceps of CD and OD patients, in contrast with statistically significant laminar thickening in the diabetic myocardium; (2) early, mild laminar thickening in quadriceps and myocardium of the asymptomatic CD group; and (3) two characteristic patterns of basal laminar contours, homogeneous and lamellated, the latter being seen prominently in the quadriceps of diabetic patients in frequent association with pericapillary edema. These findings support the concept that basal laminar thickening in the diabetic is associated with deranged carbohydrate metabolism.

Mitigating effects of ICRF-159 (razoxane) on a daunomycin-induced cardiomyopathy in mice.

In an attempt to induce in mice the cardiomyopathy associated with daunomycin treatment and to ameliorate this disorder by a protective pretreatment with ICRF-159 (razoxane), young male BDF 1 mice were injected with daunomycin, 6 mg/kg, in multiple doses. A second group of mice were pretreated by injection with razoxane, 200 mg/kg, 24 hours before each daunomycin administration. Within three weeks of the third daunomycin injection one half of the unprotected mice were moribund and were sacrificed. Mice pretreated with razoxane survived the length of the experiment without exhibiting any disabilities. Myocardial tissue of all mice was processed for light and electron microscopic examination. The myocardial ultrastructure of daunomycin-toxic mice showed foci of incipient changes, characterized by sarcoplasmic translucency, vacuolation of membrane-limited components, degeneration of mitochondria and lysosomal aggregates. Evaluation of mice pretreated with razoxane either failed to reveal ultrastructural alterations or demonstrated only minimal changes in the myocardium.