Nigishi Hotta

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.

Midkine Is Involved in Neutrophil Infiltration into the Tubulointerstitium in Ischemic Renal Injury

Midkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H2O2. Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk−/−) than in wild-type (Mdk+/+) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk−/− than in Mdk+/+ mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk−/− mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.

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.

A case of a dialysis patient with sclerosing peritonitis successfully treated with corticosteroid therapy alone

Sclerosing peritonitis (SCP) is a rare complication of peritoneal dialysis. Most of the patients with this serious complication have been treated in a symptomatic and conservative manner. Other patients have undergone risky surgical interventions. Recently it was reported that immunosuppressive therapy after renal transplantation was effective for this complication. A 56-year-old man developed sclerosing peritonitis 5 months after switching from peritoneal dialysis to hemodialysis because of ultrafiltration failure. The patient had ongoing inflammatory signs and symptoms, and corticosteroid therapy was commenced. His condition was dramatically improved within 1 week, and he is now well on an outpatient basis with the maintenance dosage of corticosteroid. This is the first report of a patient with peritoneal dialysis-related SCP who responded favorably to corticosteroid therapy alone.

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.

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.

Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333 531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication. [Diabetologia (2001) 44: 480–487]

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.