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Research ArticleEndocrine and Diabetes

Modeling Diabetes Disease Progression and Salsalate Intervention in Goto-Kakizaki Rats

Yanguang Cao, Debra C. DuBois, Hao Sun, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics December 2011, 339 (3) 896-904; DOI: https://doi.org/10.1124/jpet.111.185686
Yanguang Cao
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Debra C. DuBois
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Hao Sun
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Richard R. Almon
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William J. Jusko
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Abstract

Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and β-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 15 weeks with an upsurge of more than 100 mg/dl. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics by using a population method in S-ADAPT. Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and β-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on β-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. In addition, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats.

Footnotes

  • This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM57980] and the University of Buffalo-Pfizer Strategic Alliance.

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

    doi:10.1124/jpet.111.185686.

  • ABBREVIATIONS:

    T2DM
    type 2 diabetes mellitus
    GK
    Goto-Kakizaki
    WKY
    Wister-Kyoto
    NF
    nuclear factor
    IL
    interleukin
    BW
    body weight
    LBM
    lean body mass
    SE%
    relative standard error.

  • Received July 1, 2011.
  • Accepted September 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 3
1 Dec 2011
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Research ArticleEndocrine and Diabetes

Modeling Diabetes Progression and Salsalate Intervention

Yanguang Cao, Debra C. DuBois, Hao Sun, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 896-904; DOI: https://doi.org/10.1124/jpet.111.185686

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Research ArticleEndocrine and Diabetes

Modeling Diabetes Progression and Salsalate Intervention

Yanguang Cao, Debra C. DuBois, Hao Sun, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 896-904; DOI: https://doi.org/10.1124/jpet.111.185686
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