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Research ArticleEndocrine and Diabetes

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler, Andrew G. Reaume and Michael S. Saporito
Journal of Pharmacology and Experimental Therapeutics July 2012, 342 (1) 23-32; DOI: https://doi.org/10.1124/jpet.112.192187
Alexander R. Ochman
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Christopher A. Lipinski
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Jeffrey A. Handler
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Andrew G. Reaume
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Michael S. Saporito
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Abstract

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15–22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.112.192187.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    T2D
    type 2 diabetes
    TZD
    thiazolidinediones
    PPAR
    peroxisome proliferator-activated receptor
    MLR-1023
    2(1H)-pyrimidinone, 5-(3-methylphenoxy)
    IRS-1
    insulin receptor substrate-1
    OGTT
    oral glucose tolerance test
    ELISA
    enzyme-linked immunosorbent assay
    PBS
    phosphate-buffered saline
    GIR
    glucose infusion rate
    AUC
    area under the curve
    DPP-IV
    dipeptidyl peptidase-4
    GLP-1
    glucagon-like peptide
    STZ
    streptozotocin.

  • Received January 18, 2012.
  • Accepted March 16, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 1
1 Jul 2012
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Research ArticleEndocrine and Diabetes

MLR-1023 Is a Novel Insulin Receptor Potentiator

Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler, Andrew G. Reaume and Michael S. Saporito
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 23-32; DOI: https://doi.org/10.1124/jpet.112.192187

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Research ArticleEndocrine and Diabetes

MLR-1023 Is a Novel Insulin Receptor Potentiator

Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler, Andrew G. Reaume and Michael S. Saporito
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 23-32; DOI: https://doi.org/10.1124/jpet.112.192187
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