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Research Article Free access | 10.1172/JCI1256

Mechanisms of insulin resistance in experimental hyperinsulinemic dogs.

P D Miles, S Li, M Hart, O Romeo, J Cheng, A Cohen, K Raafat, A R Moossa, and J M Olefsky

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

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Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

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Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

Find articles by Hart, M. in: PubMed | Google Scholar

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

Find articles by Romeo, O. in: PubMed | Google Scholar

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

Find articles by Cheng, J. in: PubMed | Google Scholar

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

Find articles by Cohen, A. in: PubMed | Google Scholar

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

Find articles by Raafat, K. in: PubMed | Google Scholar

Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

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Department of Surgery, University of California, San Diego, La Jolla, California 92093, USA.

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Published January 1, 1998 - More info

Published in Volume 101, Issue 1 on January 1, 1998
J Clin Invest. 1998;101(1):202–211. https://doi.org/10.1172/JCI1256.
© 1998 The American Society for Clinical Investigation
Published January 1, 1998 - Version history
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Abstract

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 micromol/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 (t1/2a) for arterial insulin was the same for both groups, whereas the t1/2a 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.

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