(5-(3-thienyl)tetrazol-1-yl)acetic-acid and Diabetes-Mellitus--Type-2

To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.

Topics: 2,3-Diphosphoglycerate; Aldehyde Reductase; Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dietary Sucrose; Enzyme Inhibitors; Erythrocytes; Humans; Hyperglycemia; Male; Neural Conduction; Platelet Aggregation; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Regional Blood Flow; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Tetrazoles; Thiophenes

In an animal model of human non-insulin dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima Fatty (OLETF) rats were fed with sucrose for 8 weeks to obtain severe hyperglycemia. The effects of sucrose administration on peripheral nerve functions, motor nerve conduction velocity (MNCV) and coefficient of variance of R-R interval (CVR-R), were investigated with concomitant measuring of sciatic nerve blood flow (SNBF), ADP-induced platelet aggregation and polyol content in the sciatic nerves. The effects of an aldose reductase inhibitor, TAT, on these parameters were also studied. Administration of sucrose to OLETF rats caused significant body weight reduction and remarkable hyperglycemia. Sucrose-fed OLETF rats demonstrated significantly delayed MNCV, decreased CVR-R, reduced SNBF and increased platelet aggregation activity to ADP. Sorbitol and fructose accumulation, and myo-inositol depletion in sciatic nerves were observed only in sucrose-fed OLETF rats. These abnormalities were all ameliorated by the treatment with TAT. These observations suggest that the sucrose-fed OLETF rat is a useful animal model for studying the pathogenesis of diabetic neuropathy in human NIDDM, and that an aldose reductase inhibitor is a useful therapeutic agent for the treatment of diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Enzyme Inhibitors; Insulin; Lipids; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymers; Rats; Regional Blood Flow; Sciatic Nerve; Sucrose; Tetrazoles; Thiophenes

To investigate the role of increased polyol pathway activity and hemodynamic deficits in the pathogenesis of diabetic retinopathy in non-insulin-dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human NIDDM, were given water with or without 30% sucrose and some of them were fed laboratory chow containing 0.03% cilostazol, an anticoagulant, or 0.05% [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT), an aldose reductase inhibitor, for 8 wk. Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic controls. The peak latencies of oscillatory potentials of the electroretinogram in sucrose-fed OLETF rats were significantly prolonged compared with those in OLETF rats without sucrose feeding and LETO rats. There was a marked increase in platelet aggregability and a significant decrease in erythrocyte 2,3-diphosphoglycerate in sucrose-fed OLETF rats. Cilostazol significantly improved these parameters without changes in retinal levels of sorbitol and fructose. TAT, however, ameliorated all of these parameters. These findings confirm that the sucrose-fed OLETF rat is a useful animal model of retinopathy in human NIDDM and suggest that cilostazol improved diabetic retinopathy by modifying vascular factors, not by altering polyol pathway activity.

Topics: 2,3-Diphosphoglycerate; Aldehyde Reductase; Animals; Anticoagulants; Blood Glucose; Body Weight; Cilostazol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dietary Sucrose; Electroretinography; Enzyme Inhibitors; Fructose; Humans; Insulin; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Retina; Sorbitol; Tetrazoles; Thiophenes; Triglycerides