Nobuo Sakamoto

Lipid peroxide level in plasma of diabetic patients.

Abstract Recently, one of the authors (1) devised a reliable method for the microdetermination of lipid peroxide in plasma. This has enabled us to study the plasma lipid peroxide level of patients suffering from diabetes. This paper deals with the data obtained with a large sample of patients, and the relation between the lipid peroxide level and the different features of the disease.

Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial

OBJECTIVE—We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS—Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) ≥40 m/s, and HbA1c ≤9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS—Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS—Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients

OBJECTIVE To determine whether long-term treatment with an angiotensinconverting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months. RESEARCH DESIGN AND METHODS Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20–300 mg/24 h, serum creatinine < 106.1 μM 1.2 mg/dl), supine systolic blood pressure (BP) <150 mmHg, supine diastolic BP <90 mmHg, and HbA1c <10% were divided into four groups. Twenty-six patients with normotension were divided at random into two groups; one group received enalapril (5 mg/day) (NE group), the other did not receive enalapril (NC group). In the same way, 26 other patients who were already well-controlled with nifedipine (30 mg/day) over a long-term period (4–6 years) were divided at random into two groups; one received enalapril (5 mg/day) (HE group), the other did not receive enalapril (HC group). RESULTS After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 ×/÷ 1.3 to 55.5 ×/÷ 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study. CONCLUSIONS Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.

Experimental atherosclerosis-like lesions induced by hyperinsulinism in Wistar rats.

To elucidate the possible role of hyperinsulinism in the etiology of diabetic macroangiopathy, we studied the long-term effects of insulin injection on the arterial wall of the rat both biochemically and histologically. Fifty male Wistar rats were divided into two groups. One group was subjected to daily injection of insulin-zinc suspension (20 U/kg), and the other group was treated with saline. After 1 yr, all the animals were killed, and the lipid contents in the intimal media of their aortas were determined. Parts of the ascending aortic tissues were further examined by use of either light or electron microscopy. The triglyceride content of the insulin-treated rat aortas was significantly (P < .05) increased compared with that of the saline-treated rat aortas. As determined by light microscopy, the intimas of the aortas from the insulin-treated rats were significantly (P < .001) thickened, and the subendothelial tissues consisted of eosinophilic fiber bundles, amorphous ground substances, and irregularly arranged cells. These cells were identified by electron microscopy as having smooth muscle cell origin. All these findings suggest that atherosclerosis like lesions could be induced by long-term insulin injection in the aortas of the rat and that hyperinsulinism plays a certain role in the development of diabetic macroangiopathy.

Effects of long-term enalapril treatment on persistent microalbuminuria in normotensive type 2 diabetic patients : results of a 4-year, prospective, randomized study

The beneficial effect of long‐term treatment with an angiotensin‐converting enzyme (ACE) inhibitor on urinary microalbumin excretion (UAE) and renal function was investigated in a 4 year, randomized prospective study in normotensive patients with non‐insulin‐dependent (Type 2) diabetes mellitus. Sixty‐two normotensive patients with Type 2 diabetes mellitus and microalbuminuria but normal renal function were randomized to receive either enalapril 5 mg day−1 or no treatment. In the enalapril‐treated patients, UAE was reduced from 115.4 ± 80.1 to 95.6 ± 61.7 mg 24 h−1 after 12 months (p<0.05) and to 75.3 ± 44.8 mg 24 h−1 after 48 months (p<0.001). In the untreated group, UAE increased slowly from 93.9 ± 69.9 to 150.0 ± 144.5 mg 24 h−1 after 48 months. No changes in creatinine clearance, blood pressure or HbA1C were seen in either group during the 4‐year period. In normotensive Type 2 diabetic patients with early stage of diabetic nephropathy, the ACE inhibitor enalapril may have a beneficial effect by decreasing microalbuminuria. This effect is long‐lasting and probably independent of the antihypertensive action of the drug.

Improvement of Glucose Tolerance in NIDDM by Clofibrate Randomized Double-Blind Study

A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects.A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects. These results suggest that clofibrate improves glucose tolerance in NIDDM subjects without a change in insulin receptors and that clofibrate increases insulin sensitivity through an unknown postreceptor mechanism.

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.

Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: Multicenter study

A number of diabetic patients with diabetic neuropathy were treated with epalrestat, an aldose reductase inhibitor, since this drug was launched into the market in Japan. More than 5000 patients with diabetic neuropathy who were treated with epalrestat for 3-12 months were treated to analyze the efficacy and the adverse reactions of the drug in this study. The improvement rates of subjective symptoms (i.e., spontaneous pain, numbness, coldness, and hypoesthesia) was 75% (slightly improved or better) and those of nerve function tests (i.e., motor nerve conduction velocity, sensory nerve-conduction velocity, and vibration threshold) 36%. Adverse drug reactions were encountered in 129 cases (2.5%) out of 5249 patients, none of which were severe ones. Although data are limited, they strongly suggest that epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.

A Case of Nephrotic Syndrome with Glomerular Lipoprotein Deposition with Capillary Ballooning and Mesangiolysis

A 33-year-old man with nephrotic syndrome and rapid deterioration of renal function showed curious glomerular morphological abnormalities. Ballooning of the glomerular capillaries due to a substance accumulated in the capillary lumina and mesangiolysis were prominent histological features. The deposits in the capillary lumen were positive for Sudan III staining, and also for beta-lipoprotein, apoprotein B and apoprotein E by immunofluorescent technique. The staining of beta-lipoprotein in a flower leaf pattern was a striking characteristic, while such staining was negative when studied in 20 patients with nephrotic syndrome who were used as controls. Based on these findings, the morphological abnormalities in this case were considered to be related to lipoprotein deposition in the glomeruli. This case is thought to be the first reported in a complete form in the literature which could be classified as a new kind of disease related to lipoprotein metabolism abnormalities.

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.