Mechanisms of insulin resistance in experimental hyperinsulinemic dogs

Philip D.G. Miles, Shujun Li, Marquis Hart, Oreste Romeo, Jean Cheng, Aaron Cohen, Karim Raafat, A. R. Moossa, Jerrold M. Olefsky

Research output: Contribution to journalArticle

49 Scopus citations


This study was undertaken to characterize the insulin resistance and the mechanism thereof caused by chronic hyperinsulinemia produced in dogs by surgically diverting the veins of the pancreas from the portal vein to the vena cava. Pancreatic venous diversion (PVD, n = 8) caused a sustained increase in arterial insulin and decrease in portal insulin concentration compared with the control group (n = 6). Hyperinsulinemic euglycemic clamps were conducted 4 wk after surgery. The increase in the glucose disposal rate (GDR) was significantly less in the PVD group (39.0±5.0 vs. 27.9±3.2 μmol/kg/min, P < 0.01) compared with the control group, but the suppression of hepatic glucose production by insulin was similar for both groups. Muscle insulin receptor tyrosine kinase activity (IR-TKA) increased from 6.2±0.4 to 20.3±2.7 in the control group, but from 5.8±0.5 to only 12.7±1.7 fmol P/fmol IR in the PVD group (P < 0.01). With respect to the periphery, the time to half-maximum response (t( 1/4 )a) for arterial insulin was the same for both groups, whereas the t( 1/4 )a for lymph insulin (30±3 vs. 40±4 min, P < 0.05) and GDR (29±3 vs. 66±10 min, P < 0.01) were greater for the PVD group. Chronic hyperinsulinemia led to marked peripheral insulin resistance characterized by decreased insulin-stimulated GDR, and impaired activation of GDR kinetics due, in part, to reduced IR-TKA. Transendothelial insulin transport was impeded and was responsible for one third of the kinetic defect in insulin-resistant animals, while slower intracellular mechanisms of GDR were responsible for the remaining two thirds.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalJournal of Clinical Investigation
Issue number1
StatePublished - Jan 1 1998


  • Glucose clamp
  • Hyperinsulinemia
  • Insulin kinetics
  • Insulin resistance
  • Transendothelial insulin transport

ASJC Scopus subject areas

  • Medicine(all)

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