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Title: Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat

Abstract

In type 2 diabetes (T2DM) {beta}-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3 {+-} 3.8%) than ZF rats (48.8 {+-} 22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0 {+-} 17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.

Authors:
; ; ;  [1];  [2];  [3]; ;  [4]; ;  [1];  [5]
  1. University of British Columbia, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC (Canada)
  2. Institute of Molecular Biotechnology, Vienna (Austria)
  3. HRI, Diabetes Center, University of California San Francisco, CA (United States)
  4. Probiodrug AG, Biocenter, Halle (Saale) (Germany)
  5. University of British Columbia, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC (Canada), E-mail: mcintoch@interchange.ubc.ca
Publication Date:
OSTI Identifier:
21032954
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 362; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2007.08.115; PII: S0006-291X(07)01822-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL RECOVERY; GLUCOSE; GLYCOSIDES; HYPERGLYCEMIA; KETONES; PANCREAS; POLYPEPTIDES; RATS; RECEPTORS; SENSITIVITY

Citation Formats

Piteau, Shalea, Olver, Amy, Kim, Su-Jin, Winter, Kyle, Pospisilik, John Andrew, Lynn, Francis, Manhart, Susanne, Demuth, Hans-Ulrich, Speck, Madeleine, Pederson, Raymond A., and McIntosh, Christopher H.S.. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.08.115.
Piteau, Shalea, Olver, Amy, Kim, Su-Jin, Winter, Kyle, Pospisilik, John Andrew, Lynn, Francis, Manhart, Susanne, Demuth, Hans-Ulrich, Speck, Madeleine, Pederson, Raymond A., & McIntosh, Christopher H.S.. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. United States. doi:10.1016/j.bbrc.2007.08.115.
Piteau, Shalea, Olver, Amy, Kim, Su-Jin, Winter, Kyle, Pospisilik, John Andrew, Lynn, Francis, Manhart, Susanne, Demuth, Hans-Ulrich, Speck, Madeleine, Pederson, Raymond A., and McIntosh, Christopher H.S.. 2007. "Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat". United States. doi:10.1016/j.bbrc.2007.08.115.
@article{osti_21032954,
title = {Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat},
author = {Piteau, Shalea and Olver, Amy and Kim, Su-Jin and Winter, Kyle and Pospisilik, John Andrew and Lynn, Francis and Manhart, Susanne and Demuth, Hans-Ulrich and Speck, Madeleine and Pederson, Raymond A. and McIntosh, Christopher H.S.},
abstractNote = {In type 2 diabetes (T2DM) {beta}-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3 {+-} 3.8%) than ZF rats (48.8 {+-} 22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0 {+-} 17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.},
doi = {10.1016/j.bbrc.2007.08.115},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 362,
place = {United States},
year = 2007,
month =
}
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