Regulation of plasma fructose and mortality in mice by the aldose reductase
inhibitor lidorestat.
Authors Noh HL, Hu Y, Park TS, DiCioccio T, Nichols AJ, Okajima K, Homma S, Goldberg IJ
Submitted By Ira Goldberg on 2/8/2009
Status Published
Journal The Journal of pharmacology and experimental therapeutics
Year 2009
Date Published 2/1/2009
Volume : Pages 328(2) : 496 - 503
PubMed Reference 18974362
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, which is an AR inhibitor (ARI), and the presence of
streptozotocin (STZ)-induced diabetes altered plasma fructose, mortality, and/or
vascular lesions in low-density lipoprotein (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 > 20 mM) 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 microg/ml; placebo-treated mice had plasma
fructose levels of 12.08 +/- 7.4 microg/ml, p < 0.01, despite the induction of
fructose-metabolizing enzymes, fructose kinase and adolase B. After 6 weeks,
hAR/Ldlr(-/-) mice on the placebo-containing diet had greater mortality (31%, n
= 9/26 versus 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

Investigators with authorship
Ira GoldbergNew York University School of Medicine


Akr1b3aldo-keto reductase family 1, member B3 (aldose reductase)
Akr1b7aldo-keto reductase family 1, member B7
Arandrogen receptor
Fdxrferredoxin reductase
Akr1b8aldo-keto reductase family 1, member B8
Cyp19a1cytochrome P450, family 19, subfamily a, polypeptide 1