Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling

  1. Peter C. Butler1
  1. 1Larry Hillblom Islet Research Center, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
  2. 2Department of Information Engineering, University of Padova, Padova, Italy
  3. 3Howard Hughes Medical Institute, Division of Endocrinology, Children’s Hospital, Boston, Massachusetts
  4. 4Department of Internal Medicine and Sealy Center on Aging, University of Texas Medical Branch, Galveston, Texas
  1. Corresponding author: Peter C. Butler, pbutler{at}mednet.ucla.edu.

Abstract

Insulin is secreted as discrete insulin secretory bursts at ∼5-min intervals into the hepatic portal vein, these pulses being attenuated early in the development of type 1 and type 2 diabetes mellitus (T2DM). Intraportal insulin infusions (pulsatile, constant, or reproducing that in T2DM) indicated that the pattern of pulsatile insulin secretion delivered via the portal vein is important for hepatic insulin action and, therefore, presumably for hepatic insulin signaling. To test this, we examined hepatic insulin signaling in rat livers exposed to the same three patterns of portal vein insulin delivery by use of sequential liver biopsies in anesthetized rats. Intraportal delivery of insulin in a constant versus pulsatile pattern led to delayed and impaired activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase (Gck). We further established that hepatic Gck expression is decreased in the HIP rat model of T2DM, a defect that correlated with a progressive defect of pulsatile insulin secretion. We conclude that the physiological pulsatile pattern of insulin delivery is important in hepatic insulin signaling and glycemic control. Hepatic insulin resistance in diabetes is likely in part due to impaired pulsatile insulin secretion.

Footnotes

  • Received October 14, 2011.
  • Accepted April 4, 2012.

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