Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling

Aleksey V. Matveyenko, David Liuwantara, Tatyana Gurlo, David Kirakossian, Chiara Dalla Man, Claudio Cobelli, Morris F. White, Kyle D. Copps, Elena Volpi, Satoshi Fujita, Peter C. Butler

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2269-2279
Number of pages11
JournalDiabetes
Volume61
Issue number9
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Matveyenko, A. V., Liuwantara, D., Gurlo, T., Kirakossian, D., Dalla Man, C., Cobelli, C., White, M. F., Copps, K. D., Volpi, E., Fujita, S., & Butler, P. C. (2012). Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling. Diabetes, 61(9), 2269-2279. https://doi.org/10.2337/db11-1462