title: Reversal of in vitro hepatic insulin resistance in chronic pancreatitis by pancreatic polypeptide in the rat.
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 microliters 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 microU/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 less than 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.
authors.affiliation: Department of Surgery, State University of New York Health Science Center, Brooklyn 11203.
authors.forename: J A
authors.initials: JA
authors.lastname: Goldstein
authors.forename: J D
authors.initials: JD
authors.lastname: Kirwin
authors.forename: N E
authors.initials: NE
authors.lastname: Seymour
authors.forename: J E
authors.initials: JE
authors.lastname: Trachtenberg
authors.forename: E A
authors.initials: EA
authors.lastname: Rademaker
authors.forename: D K
authors.initials: DK
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002908:Chronic Disease; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids; D010191:Pancreatic Polypeptide / Q000494:pharmacology*; D010195:Pancreatitis / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D009829:Oleic Acids; D019301:Oleic Acid; D010191:Pancreatic Polypeptide; D005934:Glucagon; D005947:Glucose