Regulation of plasma fructose and mortality in mice by the aldose reductase inhibitor lidorestat.
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 patients.
Noh
Hye-Lim
HL
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Hu
Yunying
Y
Park
Tae-Sik
TS
DiCioccio
Thomas
T
Nichols
Andrew J
AJ
Okajima
Kazue
K
Homma
Shunichi
S
Goldberg
Ira J
IJ
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001686:Biological Phenomena / Q000187:drug effects; D001769:Blood / Q000187:drug effects* / Q000378:metabolism; D001786:Blood Glucose / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005632:Fructose / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D013311:Streptozocin; D013844:Thiazoles / Q000494:pharmacology*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D013844:Thiazoles; D005632:Fructose; D013311:Streptozocin; C500848:lidorestat; D000449:Aldehyde Reductase