Received for publication January 7, 2008.
Revised October 21, 2008.
Accepted for publication October 22, 2008.

Regulation of plasma fructose and mortality in mice by the aldose reductase inhibitor lidorestat

Abstract

Aldose reductase (AR), an enzyme widely believed to be involved in the aberrant metabolism of glucose and development of diabetic complications, is expressed at low levels in the mouse. We studied whether expression of human AR (hAR), its inhibition with lidorestat, an AR inhibitor (ARI), and the presence of streptozotocin (STZ)-induced diabetes altered plasma fructose, mortality and/or vascular lesions in LDL receptor-deficient (Ldlr-/-) mice. Mice were made diabetic at 12 weeks of age with low dose STZ treatment. Four weeks later the diabetic animals (glucose >20mmol/l) were blindly assigned to a 0.15% cholesterol diet with or without ARI. After 4 and 6 weeks there were no significant differences in body weights or plasma cholesterol, triglyceride, and glucose levels between the groups. Diabetic Ldlr-/- mice receiving ARI had plasma fructose levels of 5.2 ± 2.3 µg/mL, placebo treated mice had plasma fructose levels of 12.08 ± 7.4 µg/mL, p< 0.01. Fructose metabolizing enzymes, fructose kinase and adolase B, were increased in hAR expressing mice. After 6 weeks, hAR/Ldlr-/- mice on the placebo-containing diet had greater mortality (31%, n = 9/26 vs 6%, n = 1/21, p<0.05). The mortality rate in the ARI treated group was similar to that in non-hAR-expressing mice. Therefore, diabetic hAR-expressing mice had increased fructose and greater mortality that was corrected by inclusion of lidorestat, an ARI, in the diet. If similar effects are found in humans, such treatment could improve clinical outcome in diabetic patients.

Key words: aldose reductase, aldose reductase inhibitor, cholesterol diet, diabetes, heart fucntion, plasma fructose