The effect of aldose reductase inhibition with ponalrestat on the width of the capillarly basement membrane in diabetes mellitus

Abstract

There is evidence to suggest that hyperglycemia is required for the development of the microvascular complications of diabetes. However, the precise mechanism by which hyperglycemia might cause diabetic complications is not completely clear. One possibility is the increased activity of the polyol pathway. Capillary basement membrane thickness is a hallmark histological finding in diabetic microangiopathy. Previous studies in experimental models of diabetes have related the polyol pathway with the thickness of basement membrane in retinal capillaries. To study the effect of aldose reductase inhibition with ponalrestat on the width of the skeletal muscle capillary basement membrane in subjects with diabetes, we measured the capillary basement membrane width in 55 subjects with diabetes in a double masked, placebo controlled randomized trial over a period of 18 months. Twenty-nine patients received ponalrestat (two 300 mg tablets daily) and twenty-six received placebo tablets. The age, sex distribution, type and duration of diabetes were similar in both groups. The glycosylated hemoglobin remained at a constant level throughout the study in both groups. The baseline capillary basement membrane width of the ponalrestat group was 3134 ± 146 Å, it was 3074 ± 226 Å at month 12 and 2548 ± 182 Å at month 18 ( P < 0.001 vs baseline value). The placebo group also had a significant reduction in the width of the capillary basement membrane, from a baseline value of 3026 ± 147 Å to 2818 ± 144 Å at month 12 and 2618 ± 156 Å at month 18 ( P < 0.001 vs baseline value). There was no statistical difference in the capillary basement membrane width between the two groups at any time point. In conclusion, our study showed no effect on skeletal muscle basement membrane width following 18 months of treatment with the aldose reductase inhibitor, ponalrestat, as compared to placebo. It is possible that in the skeletal muscle capillaries the thickening of the capillary basement membrane width induced by diabetes is mediated by mechanisms other than the polyol pathway.