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- Title
Lidorestat, an Inhibitor of Aldose Reductase, Improves Mortality in Diabetic Human All Transgenic Mice.
- Authors
Hye Lim Noh; Yunying Hu; Dicioccio, A. Thomas; Nichols, Andrew J.; Goldberg, Ira J.
- 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 feeding mice with lidorestat, an AR inhibitor (ARI) at 25 mg/kg/day, affected mortality and/or vascular lesions in streptozotocin (STZ) induced diabetic human AR (hAR)/LDL receptor-deficient (Ldlr-/-) mice. A line of mice expressing hAR via a histocompatilibity antigen crossed onto the Ldlr-/- background were made diabetic at age 12 weeks with low dose STZ treatment. Four weeks later the diabetic animals (glucose >360 mg/dl) 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. Mice receiving ARI had plasma fructose levels of 5.2 ± 2.3 ug/mL, placebo treated mice had plasma fructose levels of 10.38 ± 7.5 ug/mL, p< 0.01. After 6 weeks, hAR/Ldlr-/- mice on the placebo-containing diet had greater mortality (69%, n = 9/26 vs 94%, n = 1/21, p<0.05). The mortality rate in the ARI treated group was similar to that in non-hAR-expressing mice. Among the causes of death mice there was evidence of GI ischemia (black bowel) and CVA (hemiplegia). Therefore, in a blinded study, diabetic hAR-expressing mice have increased mortality that is 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.
- Publication
Diabetes, 2007, Vol 56, pA149
- ISSN
0012-1797
- Publication type
Academic Journal