Administration of Ascorbic Acid and an Aldose Reductase Inhibitor (Tolrestat) in Diabetes: Effect on Urinary Albumin Excretion

Abstract

The important role of ascorbic acid (AA) as an anti-oxidant is particularly relevant in diabetes mellitus where plasma concentrations of AA are reduced. This study was conducted to evaluate the effects of treatment with AA or an aldose reductase inhibitor, tolrestat, on AA metabolism and urinary albumin excretion in diabetes. Blood and urine samples were collected at 0, 3, 6, 9, and 12 months from 20 diabetic subjects who were randomized into two groups to receive either oral AA 500 mg twice daily or placebo. Systolic and diastolic blood pressures, HbA_1c, plasma lipids, urinary albumin, and total glycosaminoglycan excretion were measured at all time points, and heparan sulphate (glycosaminoglycan) was measured at 0 and 12 months. The same parameters, as well as urinary AA excretion, were determined at 0 and 3 months for 16 diabetes subjects receiving 200 mg tolrestat/day. AA treatment increased plasma AA (ANOVA, F ratio = 12.1, p = 0.004) and reduced albumin excretion rate (AER) after 9 months (ANOVA, F ratio = 3.2, p = 0.03), but did not change the other parameters measured. Tolrestat lowered plasma AA (Wilcoxon’s signed-rank test, p < 0.05), but did not change AER or the other parameters measured. The ability of AA treatment to decrease AER may be related to changes in extracellular matrix or improvement in oxidative defence mechanism. Unlike the rat model of diabetes, inhibition of aldose reductase did not normalize plasma AA or AER in humans. In fact, tolrestat reduced the plasma AA concentration, a phenomenon which may be due to increased utilization of AA. Dietary supplementation of AA in diabetic subjects may have long-term benefits in attenuating the progression of diabetic complications.

Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials

“…When data were reported as subgroups without an overall effect, subgroups were used in the analysis (34,36). In a sensitivity analysis, we included trials with incomplete reporting of BP or BP variance after an assumption of no effect of supplementation on BP (36,(40)(41)(42)(43)(44)(45)(46)(47)(48). See Supplemental Tables 2 and 3 under "Supplemental data" in the online issue for characteristics of these trials and details of our imputation methodology.…”

Low plasma concentrations of diet-derived antioxidants in association with microalbuminuria in Indigenous Australian populations

“…Intervention studies have provided some evidence for a link between oxidant stress and renal damage. In one group of Type I and II diabetic patients, long-term treatment with ascorbate reduced albumin excretion rate [53], and in another similar group α-lipoic acid prevented progression of albuminuria [54]. None of these studies have looked specifically at the role of carotenoids or carotenoid-rich diets.…”

Mesangial cell protein kinase C isozyme activation in the diabetic milieu

“…In diabetic animal models and human studies where aldose reductase inhibitors were used to treat or prevent diabetic nephropathy, the outcomes remain controversial (44,50,51,52). We have demonstrated that treatment of STZ-diabetic rats with tolrestat prevents glomerular hyperfiltration, glomerular hypertrophy, and increased microalbuminuria but does not prevent fractional mesangial expansion in the first 12 wk of diabetes (15).…”