Reversal of in vitro hepatic insulin resistance in chronic pancreatitis by pancreatic polypeptide in the rat

Jeffrey A. Goldstein, Jon D. Kirwin, Neal E. Seymour, Jeffrey E. Trachtenberg, Edward A. Rademaker, Dana K. Andersen

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Abstract

In vitro isolated liver perfusion in a rat model of chronic pancreatitis (CP) has been shown to demonstrate hepatic resistance to insulin. The ability of pancreatic polypeptide (PP) to reverse the resistance to insulin on glucagon-stimulated hepatic glucose production was therefore investigated in this model. CP was induced in 250 to 300 gm Sprague-Dawley rats by infusion of 50 Al of 99% oleic acid into the pancreas via the common bile duct. After 6 to 8 weeks, isolated liver perfusion was performed on livers from both CP rats and sham-operated control animals (n = 12, 14), both with and without PP administration. Glucagon infusion (100 pg/ml for 30 minutes) produced a five- to sixfold increase in hepatic glucose production. The integrated hepatic glucose output (IHGO) response to glucagon alone was comparable in pancreatic and sham-operated animals; during period 1 (0 to 10 minutes) IHGO was 7.1 ± 0.5 mg/gm-min for sham-operated controls (n = 8) and 7.1 ± 0.4 mg/gm-min for pancreatitic animals (n = 6) without PP treatment. Animals that received PP (100 ng intraperitoneally 5 hours before liver harvest and perfusion with 4.2 ng/ml from 10 to 30 minutes) demonstrated an IHGO for period 1 for the sham (n = 6) and pancreatitic animals (n = 6) of 5.6 ± 0.6 and 4.8 ± 0.8 mg/gm-min, respectively. Insulin infusion (100 μU/ml added to perfusate from 10 to 30 minutes) in CP livers without PP revealed impaired responsiveness to insulin; the ratio of period 3 (20 to 30 minutes)/period 1 IHGO was 110% ± 5% in CP livers compared with 77% ± 5% in sham controls (p < 0.01). In contrast, PP treatment restored hepatic responsiveness to insulin to control levels; the period 3/period 1 IHGO was 75% ±13% in CP livers treated with PP, which was indistinguishable from the 67% ±9% response seen in sham-operated control animals. These data provide the first in vitro evidence of a primary hepatic glucoregulatory role of PP. Therefore PP deficiency may contribute to altered glucose metabolism through the induction of a reversible hepatic resistance to insulin.

Original languageEnglish (US)
Pages (from-to)1128-1133
Number of pages6
JournalSurgery
Volume106
Issue number6
StatePublished - Dec 1989

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ASJC Scopus subject areas

  • Surgery

Cite this

Goldstein, J. A., Kirwin, J. D., Seymour, N. E., Trachtenberg, J. E., Rademaker, E. A., & Andersen, D. K. (1989). Reversal of in vitro hepatic insulin resistance in chronic pancreatitis by pancreatic polypeptide in the rat. Surgery, 106(6), 1128-1133.