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A 52-week multicenter placebo-controlled double-blind parallel group study OBJECTIVE -The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.RESEARCH DESIGN AND METHODS -A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.RESULTS -Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.CONCLUSIONS -The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. Diabetes Care 24:1776 -1782, 2001D iabetic neuropathy is a degenerative disorder triggered by persistent hyperglycemia. The degenerative changes, consisting of axonal atrophy, demyelination, nerve fiber loss, and disordered nerve fiber repair, develop and progress even in the early stage of diabetes. Axonal atrophy, demyelination, and disordered repair can be clinically assessed as a decline in nerve conduction velocity. During hyperglycemia, nerve maturation secondary to nerve fiber loss is also disturbed. Abnormal excitement of these immaturely regenerated nerve fibers causes spontaneous pain, numbness, and paresthesia (1-3). In the majority of patients, these changes, characteristic of diabetic neuropathy, considerably deteriorate the quality of life.After the onset of subjective symptoms, only palliative treatments are currently available. Accordingly, early diagnosis and treatment before the onset of subjective symptoms is considered essential. Diabetic neuropathy is a long-term complication of diabetes that should not be underestimated, bec...

Apolipoprotein A-V (apoA-V) is a recently discovered apolipoprotein that appears to have a role in plasma triglyceride (TG) transport. We have developed an ELISA for apoA-V using monoclonal antibodies that has a lower limit of detection of 0.3 ng/ml and linearity up to 20 ng/ml. The ELISA was then used to quantify plasma apoA-V in 196 healthy subjects and 106 patients with insulin-resistant diabetes mellitus. In the healthy subjects, total apoA-V concentration was 179.2 ؎ 74.8 ng/ml, and it was greater in females than in males ( P Ͻ 0.005). It was correlated positively with the plasma HDL cholesterol ( r ‫؍‬ 0.32, P Ͻ 0.0001), apoA-I ( r ‫؍‬ 0.27, P ‫؍‬ 0.0001), and apoE ( r ‫؍‬ 0.18, P ‫؍‬ 0.011) concentrations and negatively with plasma TG concentration ( r ‫؍‬ ؊ 0.22, P ‫؍‬ 0.021). In relation to single nucleotide polymorphism 3 ( ؊ 1131C/T) of the apoA-V gene, apoA-V concentration was higher in the T/T type than in the C/C type ( P Ͻ 0.01). Plasma TG concentration was lower in the T/T type than in the C/C or C/T type ( P Ͻ 0.05). ApoA-V concentration was lower in the diabetic patients (69.4 ؎ 44.3 ng/ml; P Ͻ 0.01) than in the healthy controls. Plasma triglyceride (TG) levels are influenced by both genetic and environmental factors and are a major independent risk factor for coronary heart disease (1, 2). Plasma TG concentration is influenced by many factors. These include apolipoproteins A-I, A-IV, C-II, and C-III, LPL, LCAT, cholesteryl ester transfer protein, and phospholipid transfer protein (3-11). These factors and their associated gene-environment interactions are of importance in the pathogenesis of coronary heart disease.Apolipoprotein A-V (apoA-V) has recently been identified by comparative sequencing of human and mouse DNA and is located ‫ف‬ 27 kb distal to the apoA-IV gene in the APOA1/C3/A4 gene cluster on chromosome 11q23 (12). ApoA-V, shown to be expressed mostly in liver and independently named regeneration-associated protein 3, is upregulated after the early phase of liver regeneration after hepatectomy in rat (13). In mice overexpressing the human apoA-V gene, TG concentrations decreased by 50-70%, and in apoA-V gene knockout mice, plasma TG concentrations increased ‫ف‬ 4-fold (12-14). These results suggest that apoA-V expression may strongly influence, and be negatively associated with, plasma TG concentrations. ApoA-V both enhances lipoprotein lipase-mediated hydrolysis of plasma TG and inhibits hepatic VLDL-TG production (15). ApoA-V also stimulates the efflux of cholesterol from cells by a mechanism independent on the ABCA1 protein, as do other exchangeable apolipoproteins, such as apoA-I and apoA-IV (16). It was recently described that apoA-V mRNA is regulated by peroxisome proliferator-activated receptor ␣ agonists (17,18) and that the liver X receptor ligand T0901317 decreases apoA-V mRNA through the activation of sterol-regulatory element binding protein 1c (SREBP-1c) (19). These results raise the possibility that some TG-lowering agents, such as fenofibrate, may act by alte...

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Apolipoprotein (apo) J, clusterin, is ubiquitously expressed in many tissues, and is a component of high-density lipoproteins (HDLs).There is experimental evidence that it may be anti-atherogenic through its effects on cholesterol transport, smooth muscle cell proliferation and lipid peroxidation. HDLs containing apo J and apo A-carry paraoxonase (PON1), which protects low-density lipoproteins from oxidative modification; however, the extent to which apo J affects coronary heart disease (CHD) is not known. We have developed a sandwich ELISA that enables apo J to be assayed in the range of 13-200 g/mL. Serum apo J was 52.8 0.8 g/mL (mean SEM; range, 36.0-84.3 g/mL; n 92) in healthy Japanese men, and 49.3 0.5 g/mL (34.5-72.8; n 241) in healthy Japanese women. Multiple regression of these data and results from 67 men with CHD showed that apo J concentration was unrelated to age, sex or body mass index, but was positively related to serum PON1 (p 0.001) and apo B (p 0.02) concentrations. In women, it was also positively related to blood glucose (p 0.02). After adjusting for its associations with covariates, serum apo J averaged 5.4 g/mL, lower in CHD men than in controls (p 0.003). Type 2 diabetics had higher apo J concentrations (men, 83.1 3.4 g/mL, n 64; women, 64.0 2.3 g/mL, n 46) than healthy men and women (p 0.001). In these Type 2 diabetics, apo J concentration was unrelated to PON1 concentration, but was positively related to blood glucose (p 0.01). After adjustment for its relation to blood glucose, the mean apo J concentration was similar in diabetics and healthy subjects. These findings suggest that apo J may be anti-atherogenic in humans, and that its concentration is raised by Type 2 diabetes. J Atheroscler Thromb, 2006; 13:314-322.