Aims: Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN.Methods: Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2 years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial.Results: Global glomerular sclerosis was negatively associated with sdNN (partial r = -0.35, p = 0.01) and LF (r = -032, p = 0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r = -0.28 to -0.42, p < 0.05); filtration surface density was positively associated with sdNN, LF, and HF (r = 0.31 to 0.38, p < 0.05); and cortical interstitial fractional volume was negatively associated with HF (r = -0.27, p = 0.04).Conclusions: CAN associates with DN lesions. Published by Elsevier Inc.

It was reported previously that dietary ascorbate (ASC) delays the development of galactose-induced cataract in guinea pigs compared to the rate which is observed in ASC-deficient animals. Experiments were conducted to explore the possible mechanism of this phenomenon. Guinea pigs were fed for a period of up to 4 weeks either a normal diet (1 g ASC/kg diet) or a scorbutic diet (< 0·04 g ASC/kg diet) combined with 10% galactose in the drinking water. After 2 weeks, levels of ASC in animals on the scorbutic diet decreased by 95% in the aqueous humor and by 78% in the lens. Slit lamp examination showed that galactose-induced vacuoles in the lens equator formed at a significantly faster rate in the scorbutic animals. However, examination of biochemical parameters in whole lenses of the two groups of animals after 2 weeks showed no significant differences with regard to accumulation of galactose and galactitol, decreases in the levels of myoinositol, taurine and GSH or changes in cation concentrations. In order to examine possible regional changes in the lenses, various parameters were studied in the lens capsule-epithelium. On day 4, the capsule epithelia of scorbutic animals on a galactose diet had a content of galactitol two-and-a-half times higher than that of normal galactose-fed animals. Scorbutic conditions also intensified the loss of Na+-K+ ATPase activity in the lens capsule-epithelium caused by galactose feeding. Oxidized glutathione was not detectable in the lens capsule epithelia of any of the animals studied. Hexose monophosphate shunt activity was elevated in lenses of normal galactose-fed animals during the first hour of culture after death whereas lenses of scorbutic galaclose-fed animals were not. Consistent with the in vivo findings, galactitol accumulation in dog lens epithelial cells exposed to 30 mM galactose was significantly inhibited by the presence of either ASC or dehydroascorbate (DHA) in the medium. Hexose monophosphate shunt activity in the cells was stimulated to two-and-a-half times its initial level by either 1 mM DHA or 30 mu galactose and slightly more than three-fold by a combination of the two challenges.The results suggest that decreased polyol accumulation in the lens epithelium of the normal galactose-fed guinea pig, which has a high level of ASC in the aqueous humor, accounts for the delay in onset of cataract compared to that for the ASC-deficient animal. It appears that when the lens epithelium is exposed to both high sugar and GSH-oxidants such as DHA and H2O2 (both of which are present in normal guinea pig aqueous humor as autoxidatlon products of ASC), NADPH is utilized to a greater extent by glutathione reductase for the reduction of GSSG compared to aldose reductase for the synthesis of polyol. This phenomenon is presumably a result of the relatively high Km of galactose for aldose reductase compared to the Km of GSSG for glutathione reductase. No evidence was found to indicate that oxidative stress contributed to the formation of epithelial vacuoles observed in the early stage of galactose cataract. While ASC inhibited the development of sugar cataract, it was by a pro-oxidant rather than an antioxidant mechanism, and involved a preferential consumption of NADPH associated with the reduction of DHA and H2O2.