sorbinil and Diabetes-Mellitus--Type-2

Recently, aldose reductase inhibitors (ARIs) have been registered in several countries for the improvement of glycaemic control. However, their efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more effective than normoglycaemia, and so their potential benefits and limitations should be considered relative to the effects of prolonged euglycaemia. The clinical effects of ARIs can be put into perspective by assessing the effects of improved glycaemic control attained in randomised trials of intensive insulin treatment [such as the Diabetes Control and Complications Trial (DCCT)] and after pancreatic transplantation. Although direct comparison of these 3 interventions is hampered by differences in patient populations, duration and methods of follow-up and in the potency of ARIs, the effects of these 3 metabolic interventions and their course in time appear remarkably similar. For neuropathy, all 3 interventions induce an increase in average motor nerve conduction velocity of approximately 1 m/sec during the first months of treatment. At the same time, improvement of painful symptoms may occur. These changes probably largely represent a metabolic amelioration of the condition of the nerves. Around the second year of treatment with all 3 forms of metabolic improvement, an acceleration of nerve conduction of a similar magnitude occurs, with signs of structural nerve regeneration and some sensory recuperation. Experience with ARIs in nephropathy is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found during short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences between intensive insulin regimens, pancreatic transplantation and ARIs in effects on retinopathy. Retinopathy often temporarily deteriorates in the early phases of improved glycaemic control, but this is not noted with ARIs. New microaneurysm formation was slightly reduced in a single long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normoglycaemia trials of similar duration. However, the pharmacodynamic effects on inhibiting the polyol pathway differ among ARIs, and the half-life of the inhibiting effect of sorbinil may have been too short for a complete reduction of polyol pathway activity.

Topics: Adult; Aged; Aldehyde Reductase; Cross-Sectional Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Insulin; Islets of Langerhans Transplantation; Middle Aged; Naphthalenes; Pancreas Transplantation; Treatment Outcome

Topics: Adult; Aldehyde Reductase; Aneurysm; Capillaries; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Edema; Humans; Imidazoles; Imidazolidines; Laser Therapy; Neovascularization, Pathologic; Retinal Diseases; Retinal Vessels; Sorbitol; Vitrectomy

Three clinical trials to evaluate the efficacy of the aldose reductase inhibitor sorbinil in improving or preventing diabetic neural function have either been completed or are currently in progress. In the first study from Seattle and Chicago, motor and sensory nerve conduction velocities (NCV) were evaluated in 39 insulin- and noninsulin-dependent, glycemic-stable diabetic patients in a randomized, double-blind, crossover trial. During the 9 weeks of treatment with 250 mg/d of sorbinil, there was a faster nerve conduction velocity of all 3 nerves tested when compared with the placebo period: peroneal motor NCV (+0.70 +/- 0.24 m/s; means +/- SEM; P less than 0.008), median motor NCV (+0.66 +/- 0.27 m/s; P less than 0.005), and median sensory NCV (+1.16 +/- 0.50 m/s; P less than 0.035). Conduction velocity for all 3 nerves declined significantly within 3 weeks following cessation of the drug. These effects of sorbinil were unrelated to glycemic control, which was constant during the study. Although the effects of sorbinil in improving nerve conduction velocity were small, the findings suggest that the polyol-pathway activity contributes to slowed nerve conduction velocity in diabetics. The second study is a seven-center, double-blind, randomized, 12-month trial of 210 to 280 diabetic patients with clinical signs, symptoms, and objective measurements of neuropathy. The trial has a common-core protocol with end-point evaluations of scored neural signs, symptoms, and neural measurements. Two unique neural tests were designed and validated for use in this trial: thermal and tactile perception thresholds of the fingers and toes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Neural Conduction; Neurons; Random Allocation

37 patients with diabetic neuropathy were randomized into 2 equal groups and given daily doses of 200 mg or 50 mg of Sorbinil - a potent aldose-reductase inhibitor - in a double-blind 4-week period between 2 periods on placebo. The purpose was to assess the role of the drug on various neurophysiological parameters and its clinical effect. No difference was shown either in the placebo periods compared to Sorbinil treatment or between the 2 groups on the neurophysiological parameters but there was a statistically significant effect on overall subjective well-being. The drug had no side-effects in the present study.

Topics: Aldehyde Reductase; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Female; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Sensory Thresholds; Sugar Alcohol Dehydrogenases; Touch; Visual Acuity

In two studies of patients with diabetes who did not have neurologic symptoms, nerve conduction velocity was increased either by an improvement in glucose control or by the administration of the aldose reductase inhibitor sorbinil. In a 1981 study by Graf et al, glycemic control and motor and sensory nerve conduction velocities were evaluated in 18 patients with non-insulin-dependent diabetes before and after one, three, six, and 12 months of antihyperglycemic therapy. There was an improvement in motor nerve conduction velocity (median motor, p less than 0.01; peroneal motor, p less than 0.05; and tibial motor, p less than 0.05), which was associated with the improvement in fasting plasma glucose levels after three months for some motor nerves (median motor: r = -0.62, p less than 0.01; peroneal motor: r = -0.50, p less than 0.05). A direct linear relationship between the change in fasting glucose and glycosylated hemoglobin levels and the change in median motor nerve conduction velocity after 12 months of antihyperglycemic therapy was also found. Thus, there was a tendency for those patients who had the greatest improvement in glycemic control to have the greatest improvement in motor nerve conduction velocity. The findings in the first study are consistent with the hypothesis that hyperglycemia contributes to slowed nerve conduction velocity. In a 1983 randomized, double-blind, crossover study by Judzewitsch et al, motor and sensory nerve conduction velocities were evaluated in 39 patients with insulin-dependent or non-insulin-dependent diabetes in whom glycemic control was stable. During nine weeks of treatment with 250 mg per day of sorbinil, nerve conduction velocity was faster in the three tested nerves when compared with the velocities during the placebo period (peroneal motor nerve conduction velocity: +0.70 +/- 0.24 m per second, mean +/- SEM, p less than 0.008; median motor nerve conduction velocity: +0.66 +/- 0.27 m per second, p less than 0.005; median sensory nerve conduction velocity: +1.16 +/- 0.50 m per second, p less than 0.035). Although the effect of an improvement in glycemic control and administration of sorbinil in increasing nerve conduction velocity in two groups of neurologically asymptomatic patients with diabetes was small, the findings are consistent with the hypothesis that polyol pathway activity contributes to slowed large-fiber nerve conduction velocity in these patients.

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Humans; Hypoglycemic Agents; Imidazoles; Imidazolidines; Male; Middle Aged; Neural Conduction; Peroneal Nerve; Random Allocation; Sugar Alcohol Dehydrogenases

Erythrocytes from diabetic patients before and after treatment with the aldose reductase inhibitor, sorbinil, were analyzed by a capillary gas chromatographic method for sorbitol and myo-inositol. The mean erythrocyte sorbitol level in the diabetic patients was significantly higher than in the control subjects (13.1 +/- 0.9 and 5.2 +/- 0.3 nmol/ml erythrocytes, respectively, mean +/- SEM, p less than 0.001). The mean erythrocyte myo-inositol level in diabetic patients was not different from that in control subjects (43.2 +/- 2.9 and 40.5 +/- 1.9 nmol/ml erythrocytes, respectively). Sorbinil treatment reduced the elevated sorbitol levels in the diabetic patients to normal or slightly below normal, but did not affect the erythrocyte myo-inositol concentration. It is concluded that the erythrocyte is not a suitable model to monitor a possible effect of sorbinil on myo-inositol concentration in less accessible tissues.

Topics: Adult; Aldehyde Reductase; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Erythrocytes; Female; Gas Chromatography-Mass Spectrometry; Humans; Imidazoles; Imidazolidines; Inositol; Male; Middle Aged; Sorbitol; Sugar Alcohol Dehydrogenases

Endoneurial microvascular abnormalities have been invoked in the pathogenesis of diabetic distal symmetric polyneuropathy. Detailed morphometric analysis of the endoneurial microvasculature was correlated with previously published data on nerve fiber morphometry and teased fiber analysis obtained from the same sural nerve biopsies. Biopsy specimens from neuropathic diabetic patients were obtained before and after 12 mo of aldose reductase inhibitor (ARI) treatment and compared to 15 carefully age-matched control subjects. Diabetic microvessels showed basement membrane thickening and loss of endothelial cell tight junctions. Microvascular density and the frequency of microvessels closed by endothelial cells increased with age in diabetic and control nerves and were unaffected by diabetes. The density of microvessels showing patent lumina did not differ between control and diabetic subjects and was not related to age or diabetes. Closed microvessels were composed of postcapillary venules that were otherwise devoid of ultrastructural abnormalities. We suggest that microvascular closure by endothelial cells may be a physiological condition and is unlikely to have any pathogenetic significance in diabetic neuropathy. Based on the current limited biopsy material, we conclude that 12 mo of ARI treatment that induced significant fiber repair and regeneration had no detectable effect on endoneurial microvascular abnormalities. These data suggest that endoneurial vascular pathology is not a rate-limiting factor in fiber damage or repair at this stage of diabetic neuropathy.

Topics: Adult; Aldehyde Reductase; Biopsy; Capillaries; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Endothelium, Vascular; Female; Humans; Imidazoles; Imidazolidines; Male; Microcirculation; Microscopy, Electron; Middle Aged; Nerve Fibers; Sural Nerve