sorbinil and Diabetic-Angiopathies

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

A 2-year randomized placebo-controlled double-blind trial of 250 mg day-1 of the aldose reductase inhibitor Sorbinil in severe symptomatic chronic peripheral neuropathy was performed in 21 diabetic patients. Due to adverse reactions 8 patients completed the trial on Sorbinil and 6 patients on placebo. Despite differences in baseline neurophysiological parameters, duration of diabetes, and presence of retinopathy between the placebo and treatment groups, there were no initial differences in in vitro platelet aggregation, albumin excretion rate (AER) or muscle capillary basement membrane thickness. After 2 years the median deterioration in AER in the placebo group was 18.4 micrograms min-1 (range 2.6-64.8 micrograms min-1). This deterioration was significant (p less than 0.03). The change in AER in the Sorbinil group was +1.25 (-10.7 to +20.4) micrograms min-1, an insignificant change. In vitro platelet responsiveness to collagen and adenosine diphosphate (ADP) increased in the placebo group (median change max% collagen + 8 (+2 to +30)%; ADP +4.5 (0 to +20)% compared with a fall in the Sorbinil treated patients (median change; collagen -17.5 (-2 to -40)%, p less than 0.05; ADP, -4 (0 to -25)%, p less than 0.05). Muscle capillary basement membrane thickness was measured in only 3 patients in each group and did not alter significantly during the trial. All 12 neurophysiological measurements showed no significant changes between the treatment and placebo groups. The data suggest that aldose reductase inhibition has effects on platelet reactivity and microalbuminuria.

Topics: Aldehyde Reductase; Basement Membrane; Blood Pressure; Capillaries; Clinical Trials as Topic; Diabetic Angiopathies; Diabetic Neuropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Muscles; Neural Conduction; Perception; Random Allocation; Regional Blood Flow; Sugar Alcohol Dehydrogenases

Diabetic microangiopathy is characterized by a thickening of capillary basement membranes associated with type IV collagen accumulation. An increase in type IV collagen content of the aortic wall is also observed in macroangiopathy. In order to analyse the importance of the polyol pathway in the development of the collagen metabolism alterations seen in diabetic angiopathy and their prevention by aldose reductase inhibitors, we have studied the effects of sorbinil on the high glucose-induced stimulation of type IV collagen biosynthesis in human umbilical vein endothelial cells. Primary cultures were exposed to high glucose (16.7 mmol/l), with and without 0.11 mmol/l sorbinil, for 3 or 6 days after beginning of confluence. We measured the soluble type IV collagen secreted into the culture medium and the insoluble type IV collagen accumulated in the extracellular matrix and cells, by ELISA. We also studied [14C]proline incorporation into the newly synthesized collagenous and total proteins in the culture supernatant and in the extracellular matrix and cell fraction. High glucose decreased the number of cells and increased the amount of type IV collagen in the culture supernatant and in the extracellular matrix and cell fraction. It also increased proline incorporation into the newly synthesized collagenous and total proteins in the culture supernatant and in the extracellular matrix and cell fraction. Sorbinil corrected all these high glucose-induced alterations. The corrective effects of sorbinil on the proliferation and on type IV collagen metabolism of endothelial cells cultured in high glucose may be attributed to prevention of polyol pathway dysregulation.

Topics: Aldehyde Reductase; Animals; Carbon Radioisotopes; Cell Survival; Cells, Cultured; Collagen; Culture Media, Serum-Free; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Glucose; Humans; Imidazoles; Imidazolidines; Osmolar Concentration; Proline; Proteins; Umbilical Veins

The underlying etiology of diabetic microvascular disease remains unknown. To examine the potential contribution of basic fibroblast growth factor (bFGF), which is an angiogenic factor, and insulin-like growth factor-I (IGF-I) to the development of diabetic microvascular disease, bFGF and IGF-I mRNA levels were measured in tissues of control, diabetic, and insulin-treated diabetic rats. Diabetes was induced in rats by intravenous injection of streptozotocin (STZ) 65 mg/kg, and the rats were maintained for 21 days. bFGF mRNA levels increased threefold in the eyes of diabetic versus control rats, whereas a consistent change in bFGF mRNA levels was not observed in other tissues. In contrast, IGF-I mRNA levels decreased in the eyes and other tissues, including kidney, lung, and skeletal muscle, of diabetic as compared with control rats. Insulin treatment prevented the diabetes-induced increase in bFGF and decrease in IGF-I mRNA levels. Acidic FGF (aFGF) mRNA levels were unchanged in eyes from diabetic versus control rats. In partially purified retinas, diabetes increased bFGF mRNA levels twofold as compared with levels in control retinas, whereas IGF-I mRNA levels decreased to 58% of control levels in retinas from diabetic rats. Insulin treatment again prevented the diabetes-induced increase in IGF-I mRNA levels in the retina but had no effect on the diabetes-induced increase in bFGF mRNA levels. bFGF peptide levels were minimally increased in diabetic versus control retinas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Retinopathy; Eye; Fibroblast Growth Factor 2; Fructose; Glucose; Imidazoles; Imidazolidines; Inositol; Insulin-Like Growth Factor I; Kidney; Lens, Crystalline; Lung; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sorbitol; Streptozocin

These experiments were undertaken to assess the effects of combined treatment with insulin (designed to partially restore metabolic control) and sorbinil (an aldose reductase inhibitor [ARI]) versus the effects of sorbinil alone or of two insulin regimens providing different degrees of glycemic control on diabetes-induced metabolic derangements and vascular function. Streptozocin-diabetic rats were divided into the following five groups: (1) untreated (D); (2) treated with approximately 1 U NPH insulin/100 g body weight/d administered in one subcutaneous (SC) injection (DI-1); (3) treated with the same total daily dose of insulin administered in two SC injections (DI-2); (4) treated with approximately 0.2 mmol sorbinil in the diet/kg body weight/d (DS); and (5) treated with once-daily insulin plus sorbinil (DSI-1). Two groups of nondiabetic rats, untreated (C) and sorbinil-treated (CS), served as controls. Metabolic parameters were unaffected by sorbinil treatment in controls and diabetics, whereas insulin administration in the diabetics virtually normalized body growth, food consumption, urine volume, and plasma glucose levels, and markedly decreased hemoglobin A1 (HbA1) levels. Two daily injections were more effective than one in improving metabolic control as measured by HbA1 levels. Regional vascular 131I-albumin permeation was increased about twofold to threefold by diabetes in ocular tissues, sciatic nerve, aorta, diaphragm, and new granulation tissue; it was decreased (but not normalized) by insulin treatment in accordance with improved metabolic control, and was completely normalized by sorbinil. 131I-albumin kidney clearance, as well as urinary albumin and IgG excretion, were markedly increased in diabetic rats and were significantly decreased but not completely normalized by sorbinil and by twice-daily insulin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Drug Therapy, Combination; Imidazoles; Imidazolidines; Insulin; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.

Topics: Aldehyde Reductase; Amino Acid Oxidoreductases; Animals; Arginine; Benzothiazoles; Blood Pressure; Body Weight; Capillary Permeability; Citrulline; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Glycation End Products, Advanced; Guanidines; Imidazoles; Imidazolidines; Inositol; Iodine Radioisotopes; Male; Methylguanidine; Naphthalenes; Nitric Oxide Synthase; omega-N-Methylarginine; Phthalazines; Rats; Rats, Sprague-Dawley; Retina; Sciatic Nerve; Serum Albumin, Bovine; Sorbitol; Thiazoles; Uvea

We have found a defect in the ouabain-sensitive Na+, K+-ATPase (Na+ pump, EC 3.6.1.37) of erythrocytes from streptozocin diabetic rats. This defect was accompanied by an increase in cell volume and osmotic fragility and a decrease in the cytosolic K+/Na+ ratio. There was also a doubling in the time needed for diabetic erythrocytes to pass through 4.7-micron channels in a polycarbonate filter. Our data are consistent with a primary defect in the erythrocyte Na+ pump and secondary changes in cell volume, osmotic fragility, K+/Na+ ratio, and cell filterability. All were reversed or prevented in vivo by insulin or the aldose reductase inhibitor Sorbinil. Protein kinase C agonists (phorbol ester and diacylglycerol) and agonist precursor (myoinositol) reversed the Na+ pump lesion, suggesting that protein kinase C-dependent phosphorylation of the 100-kDa subunit regulates Na+ pump activity and that insulin can influence erythrocyte protein kinase C activity. Ouabain inhibition of the erythrocyte Na+ pump also produced increases in cell size and reductions in rates of filtration. Theoretical treatment of the volume changes also predicts reduction in filterability as a consequence of cell swelling. We suggest that enlarged erythrocytes could play a role in the evolution of the microvascular changes of diabetes mellitus.

Topics: Adenosine Triphosphate; Animals; Cytosol; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Erythrocyte Deformability; Erythrocyte Indices; Erythrocytes; Hematocrit; Imidazoles; Imidazolidines; Insulin; Kinetics; Male; Osmotic Fragility; Ouabain; Phosphorylation; Potassium; Protein Kinase C; Rats; Rats, Inbred Strains; Sodium; Sodium Channels; Sodium-Potassium-Exchanging ATPase; Sorbitol

In a recently developed animal model, we investigated the pathogenesis of diabetic vascular disease and demonstrated that 125I-albumin permeation is markedly increased in new "granulation tissue" vessels formed in subcutaneous tissue after the onset of diabetes. The studies described in this report were undertaken to examine the effects of an aldose reductase inhibitor on diabetes-induced increases in vascular permeability in this animal model. 125I-albumin permeation was assessed 3 weeks after the subcutaneous implantation of sterile preweighed polyester fabric (to stimulate angiogenesis) in diabetic male Sprague-Dawley rats, in controls, and in diabetic rats given sorbinil approximately 12 or approximately 25 mg/kg/d mixed in ground rat chow. Sorbinil administration prevented the diabetes-induced increase in vascular permeability by approximately 60% at the lower dose and by approximately 80% at the higher dose without affecting body weight or plasma glucose levels. Diabetes-induced changes in tissue levels of sorbitol, myo-inositol, scyllo-inositol, and chiro-inositol were also prevented by the high dose of sorbinil (data were not obtained for the lower dose). These observations are consistent with evidence linking diabetic cataracts and neuropathy to imbalances in sorbitol/inositol metabolism and support the hypothesis that diabetic vascular disease as well as neuropathy and cataracts are mediated by excess metabolism of glucose through the polyol pathway. Furthermore, these observations suggest that increased vascular permeability associated with diabetic microangiopathy in humans may be prevented by inhibitors of aldose reductase without the need to normalize blood glucose levels.

Topics: Adolescent; Animals; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Granulation Tissue; Humans; Imidazoles; Imidazolidines; Inositol; Male; Rats; Rats, Inbred Strains; Sorbitol; Stereoisomerism