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Research ArticleENDOCRINE AND DIABETES

Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

Hye-Lim Noh, Yunying Hu, Tae-Sik Park, Thomas DiCioccio, Andrew J. Nichols, Kazue Okajima, Shunichi Homma and Ira J. Goldberg
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 496-503; DOI: https://doi.org/10.1124/jpet.108.136283
Hye-Lim Noh
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Yunying Hu
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Tae-Sik Park
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Thomas DiCioccio
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Andrew J. Nichols
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Kazue Okajima
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Shunichi Homma
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Ira J. Goldberg
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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 μg/ml; placebo-treated mice had plasma fructose levels of 12.08 ± 7.4 μg/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.

Footnotes

  • This study was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grants P01-HL54591, U01-HL087945]; and by Alinea Pharmaceuticals.

  • The data presented here have appeared in abstract form: Noh HL, Hu Y, Park TS, DiCioccio T, Nichols AJ, Okajima K, Homma S, and Goldberg IJ (2007) Regulation of plasma fructose and mortality in mice by the aldose reductase inhibitor lidorestat. In 67th American Diabetes Scientific Sessions; 2007 22–26 June; Chicago, IL. American Diabetes Association, Alexandria, VA.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.136283.

  • ABBREVIATIONS: AR, aldose reductase; hAR, human AR; STZ, streptozotocin; LDL, low-density lipoprotein; Ldlr(-/-), LDL receptor-deficient; ARI, aldose reductase inhibitor; CCD, cholesterol-containing diet; PCR, polymerase chain reaction; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; TSP, thrombospondin; MMP, matrix metalloproteinase; FK, fructose kinase.

    • Received January 7, 2008.
    • Accepted October 22, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleENDOCRINE AND DIABETES

Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

Hye-Lim Noh, Yunying Hu, Tae-Sik Park, Thomas DiCioccio, Andrew J. Nichols, Kazue Okajima, Shunichi Homma and Ira J. Goldberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 496-503; DOI: https://doi.org/10.1124/jpet.108.136283

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Research ArticleENDOCRINE AND DIABETES

Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

Hye-Lim Noh, Yunying Hu, Tae-Sik Park, Thomas DiCioccio, Andrew J. Nichols, Kazue Okajima, Shunichi Homma and Ira J. Goldberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 496-503; DOI: https://doi.org/10.1124/jpet.108.136283
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