Physiological Consequences of Phasic Insulin Release in the Normal Animal

  1. Alan D. Cherrington1,
  2. Dana Sindelar2,
  3. Dale Edgerton1,
  4. Kurt Steiner3 and
  5. Owen P. McGuinness1
  1. 1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
  2. 2Department of Eli Lilly and Company, Indianapolis, Indiana
  3. 3Department of Biological Research, Wyeth Ayerst Laboratories, Radnor, Pennsylvania

    Abstract

    The dose-response relationship between the hepatic sinusoidal insulin level and glucose production by the liver is such that a half-maximally effective concentration is at or slightly below the hormone levels seen basally after an overnight fast. In the normal individual, the direct effect of the hormone on the hepatocyte is far more important in restraining glucose production than its indirect effect mediated via a suppression of lipolysis. Because insulin regulates the liver in a direct fashion, its effect occurs within several minutes. Thus, the speed with which insulin works and the sensitivity of the liver to it predict that first-phase insulin release should have a significant effect in quickly suppressing hepatic glucose production. On the other hand, nonhepatic tissues are much less sensitive to insulin and respond slowly as a result of the need for insulin to cross the endothelial barrier. As a result, first-phase insulin is unlikely to significantly alter peripheral glucose disposal. Simulation studies in humans and dogs in which the effects of first-phase insulin were simulated confirmed the aforementioned predictions. In addition, they confirmed the ability of second-phase insulin release to have significant effects on both glucose production and utilization.

    Footnotes

    • Address correspondence and reprint requests to alan.cherrington{at}mcmail.vanderbilt.edu.

      Accepted for publication 12 June 2001.

      FFA, free fatty acid

      A.D.C. holds stock options in OSI/Tanabe, Entelos Metabasis, and Nobex; acts as a consultant for Bayer Diagnostics, Inhale Therapeutics, AMDG, and Entelos; and serves on advisory boards for Nobex Corporation, OSI/Tanabe, and Metabasis. D.S. holds stock in Eli Lilly. K.S. holds stock in Pfizer and Bristol-Myers Squibb.

      The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.

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