Hironobu Kakuta

Effect of Niceritrol on Streptozocin-Induced Diabetic Neuropathy in Rats

Niceritrol, a drug with peripheral tissue vasodilatory and serum lipid-lowering activity, was administered for 2 mo to rats with streptozocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue. A markedly lower value of ∼ 47% in sciatic nerve blood flow (SNBF) was detected in an untreated diabetic (DC) group than in a nondiabetic control group (CC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol, and fructose values were observed in the sciatic nerve and serum lipids. In contrast, a niceritrol-treated diabetic (DN) group had significantly higher SNBF, MNCV, and sciatic nerve myo-inositol values and lower serum triglyceride levels than group DC. No differences between these two groups were noted in glucose, sorbitol, and fructose levels in the sciatic nerve, or in cholesterol and glucose in serum. These findings suggest that niceritrol has a clear inhibitory effect on the development of delayed MNCV in the diabetic rat, which may be due to reduced nerve blood flow and/or decreased nerve myo-inositol levels.

Effects of a fructose-rich diet and the aldose reductase inhibitor, ONO-2235, on the development of diabetic neuropathy in streptozotocin-treated rats

SummaryStreptozotocin-diabetic rats were maintained on a 72% fructose diet for 4 weeks and some were treated with an aldose reductase inhibitor (either alrestatin: 0.9 g · kg−1 · day−1 or ONO-2235: 50 mg · kg−1 · day−1). Fructose feeding significantly influenced the development of impaired motor nerve conduction velocity in the diabetic rats and this effect was positively correlated with sorbitol accumulation in the sciatic nerve of diabetic rats maintained on a fructose-rich diet. Treatment with ONO-2235, a new aldose reductase inhibitor, prevented both slowing of motor nerve conduction velocity and elevation of nerve sorbitol concentration. On the other hand, erythrocyte sorbitol levels were significantly correlated to those of the sciatic nerve (r=0.86, p<0.001) and the retina (r=0.91, p<0.001) in these animals. Thus, our findings suggest that increased polyol pathway activity may be related to the pathogenesis of diabetic neuropathy and erythrocyte sorbitol concentrations may prove a useful indicator for the presence of diabetic complications.

Long‐term Effect of Acarbose on Glycaemic Control in Non‐insulin‐dependent Diabetes Mellitus: A Placebo‐controlled Double‐blind Study

The efficacy and safety of acarbose therapy (100 mg tds for 24 weeks) was investigated in a placebo‐controlled double‐blind study in patients with non‐insulin dependent diabetes mellitus who could not achieve satisfactory glycaemic control by diet alone. In the acarbose group, the 2 h postprandial blood glucose and haemoglobin A1 levels decreased significantly from 14.0 mmol l−1 to 11.3 mmol l−1 and from 11.1 % to 9.7 %, respectively. In the placebo group, the 2 h postprandial blood glucose (14.4 mmol l−1 to 14.2 mmol l−1) and the hemoglobin A1 level (10.3% to 9.9%) showed no significant changes. A 75 g oral glucose tolerance test was performed before and after the study, the difference not being significant in either the acarbose group or the placebo group. The incidence of side‐effects (mainly gastrointestinal symptoms such as flatulence and abdominal distension) was high at 78.9 % in the acarbose group and 61.1 % in the placebo group. However, there was no significant difference between the groups, and side‐effects in the acarbose group tapered during the trial, suggesting that some at least were not related to the drug. From these findings, it was concluded that acarbose is an effective new treatment for diet treated non‐insulin‐dependent diabetic patients.

Effects of Beraprost Sodium and Insulin on the Electroretinogram, Nerve Conduction, and Nerve Blood Flow in Rats with Streptozotocin-Induced Diabetes

The effect of a prostacyclin analog, beraprost sodium, on the electroretinogram, motor nerve conduction velocity, and nerve blood flow was determined in rats with streptozotocin-induced diabetes and was compared with the effect of insulin. Beraprost sodium (0.01 mg · kg−1 · day−1 for 8 weeks) significantly shortened the peak latency of the electroretinogram b-wave, increased tail nerve conduction velocity, and increased sciatic nerve blood flow in diabetic rats (P < 0.0003, 0.0001, and 0.0001 vs. untreated diabetic rats, respectively). This was accompanied by a significant increase in the 6-keto-prostaglandin F1α content of the thoracic aorta and a marked increase in the cAMP content of the sciatic nerve. Beraprost sodium had no effect on the sorbitol and fructose contents of the sciatic nerve and retina, but insulin (8–10 U/day) significantly reduced both parameters. These findings suggest that beraprost sodium may be useful for prevention of vascular and neural dysfunction in the retina and peripheral nerve.

Nerve function and blood flow in Otsuka Long-Evans Tokushima Fatty rats with sucrose feeding: effect of an anticoagulant

To investigate the pathogenesis of diabetic neuropathy in non-insulin-dependent diabetes mellitus, Otsuka Long-Evans Tokushima Fatty rats, an animal model of non-insulin-dependent diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka rats were fed with or without sucrose and/or cilostazol, an anticoagulant, for 8 weeks. Sucrose-fed diabetic rats showed a delayed motor nerve conduction velocity, decreased R-R interval variability of electrocardiogram, reduced sciatic nerve blood flow, increased platelet aggregability and a decreased erythrocyte 2,3-diphosphoglycerate concentration compared with non-sucrose-fed diabetic rats and non-diabetic rats. These abnormalities were significantly prevented by treatment with cilostazol without changes in the nerve tissue levels of polyols. These findings indicate that sucrose-fed Otsuka Long-Evans Tokushima Fatty rats may be a useful animal model of neuropathy in non-insulin-dependent diabetes mellitus, and that cilostazol may prevent the development of diabetic neuropathy by modifying vascular factors.

Effect of a potent new aldose reductase inhibitor, (5(3-thienyl)tetrazol- 1 -yl)acetic acid (TAT), on diabetic neuropathy in rats

(5-(3-Thienyl)tetrazol-1-yl)acetic acid (TAT), a novel potent aldose reductase inhibitor, was administered for 4 weeks to rats with streptozotocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue and erythrocyte sorbitol content was estimated. Sciatic nerve blood flow (SNBF) was markedly lower (about 43.4%) in untreated diabetic (DC) rats than in non-diabetic controls (NC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol and fructose values were observed in the sciatic nerve, accompanied by a markedly higher sorbitol concentration in erythrocytes. In contrast, TAT-treated diabetic groups (DT-10, DT-40 and DT-200) had significantly higher SNBF, MNCV and sciatic nerve myo-inositol values and lower sciatic nerve sorbitol and fructose levels and erythrocyte sorbitol concentration than the DC group. There were good correlations between SNBF and MNCV (r = 0.672, P < 0.001) and between SNBF and erythrocyte sorbitol (r = 0.455, P < 0.003). These findings suggest that both vascular and metabolic factors play an important role in diabetic neuropathy and the effect of aldose reductase inhibitors on diabetic neuropathy may be mediated by at least these two factors.

Prevention of abnormalities in motor nerve conduction and nerve blood-flow by a prostacyclin analog, beraprost sodium, in streptozotocin-induced diabetic rats

The effects of the prostacyclin analog beraprost sodium on motor nerve function and nerve blood-flow were examined in streptozotocin-induced diabetic rats. Oral administration of beraprost sodium 0.1 mg/kg/day for 8 wks significantly (P < 0.001) improved caudal motor nerve conduction velocity and sciatic nerve blood-flow, both of which are impaired in diabetic rats. Beraprost sodium did not affect glucose, sorbitol, or fructose levels in the sciatic nerve. However, a decreased content of cyclic AMP in the sciatic nerve and higher level of thromboxane B2 in the thoracic aorta of diabetic rats, as compared with those in normal rats, were reversed by the treatment with beraprost sodium (P < 0.01). Results suggest that beraprost sodium may have value in treating diabetic neuropathy, mainly by improving endoneurial blood-flow.

Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy An Open-Label Pilot Study

ObjectiveTo evaluate the effects of fidarestat (SNK-860) on vibration perception threshold, as measured by C64 quantitative tuning fork (64Hz) analysis, as well as its effects on subjective symptoms in patients with diabetic polyneuropathy.Design and settingOpen-label, prospective study conducted at 12 hospitals in the central area of Honshu, Japan.InterventionsFidarestat was administered at a dosage of 1mg once daily after breakfast for 28 weeks.Main outcome measuresVibration perception threshold of upper and lower extremities was determined using a C64 quantitative tuning fork, and measured at baseline and after 12 and 28 weeks of treatment. Subjective symptoms, including numbness, spontaneous pain and hypoaesthesia, were evaluated every 4 weeks.ResultsSubjective symptoms were evaluated in 22 patients, and vibration perception threshold data were available for 19 patients. Vibration perception threshold at baseline was negatively correlated with the severity of the following subjective symptoms: numbness in the upper limbs, and numbness, coldness and hot flushes, smarting pain causing difficulty walking and hypoaesthesia in the lower limbs. During treatment with fidarestat, vibration perception threshold increased significantly in the upper (p = 0.0017) and lower (p = 0.0001) limbs. The following symptoms were also significantly improved: severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness. Adverse events occurred in four patients.ConclusionAdministration of fidarestat after breakfast was effective in significantly alleviating some symptoms of diabetic polyneuropathy. The C64 quantitative tuning fork analysis is useful in the diagnosis of diabetic polyneuropathy, and as a measure of the severity of the neuropathological symptoms of this condition.

Effects of propionyl-L carnitine and insulin on the electroretinogram, nerve conduction and nerve blood flow in rats with streptozotocin-induced diabetes

The effect of an analogue ofl-carnitine, propionyl-l-carnitine, on the electroretinogram, motor nerve conduction velocity and nerve blood flow was determined in rats with streptozotocin-induced diabetes, and was compared with the effects of insulin alone or combined therapy. Oral administration of propionyl-l-carnitine (3 g/kg daily for 4 weeks) significantly increased caudal nerve motor conduction velocity and sciatic nerve blood flow in diabetic rats. There were no differences in the effects of insulin (8–10 U daily for 4 weeks), propionyl-l-carnitine and combined therapy. Although propionyl-l-carnitine significantly shortened the peak latency of the electroretinogram b-wave in diabetic rats, its effect was far weaker than that of insulin or combined therapy, with combined therapy producing the greatest improvement. These effects of propionyl-l-carnitine were accompanied by a decrease of serum lipid levels, an increase of the sciatic nerve carnitine content, and no changes of the tissue (nerve and retinal) sorbitol andmyo-inositol concentrations. In contrast, insulin significantly reduced the tissue sorbitol content and markedly increasedmyo-inositol. These findings suggest that propionyl-l-carnitine may improve diabetic neuropathy and retinopathy without influencing the polyol pathway, and that this beneficial effect may be mediated through the amelioration of microcirculation and tissue carnitine content, thus probably increasing fatty acid oxidation.

Effect of an aldose reductase inhibitor, SNK‐860, on deficits in the electroretinogram of diabetic rats

To determine the effect of an aldose reductase inhibitor, SNK‐860, on the worsening of the electroretinogram (ERG) during a diabetic state, rats with streptozotocin‐induced diabetes were administered SNK‐860 (1 or 4 mg kg‐1 orally) daily for 4 weeks. The effectiveness of SNK‐860 in prolonging the peak latencies of oscillatory potentials in the b‐wave of the electroretinogram of diabetic rats varied between these different waveform components (designated O1, O2 and O3). SNK‐860 (4 mg kg‐1 day‐1) either completely or partially prevented the prolonged peak latencies at O1 and sigma(O1 + O2 + O3). The drug failed to shorten the latency of the O2 and O3 components, and produced only a modest reduction in retinal levels of sorbitol and fructose, with no increase in myo‐inositol. There was a significant correlation between the state of the ERG (components O1 and sigma(O1 + O2 + O3)) and the retinal levels of sorbitol and fructose (P < 0.01), but not of myo‐inositol. It is concluded that a better understanding of the mechanism by which SNK‐860 acts may provide new insight into the pathogenesis of hyperglycaemic retinal dysfunction and help to establish effective therapy for diabetic retinopathy.