Advanced

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.

Ahrén, Bo LU ; Winzell, Maria Sorhede; Wierup, Nils LU ; Sundler, Frank LU ; Burkey, Bryan and Hughes, Thomas E (2007) In Regulatory Peptides 143(1-3). p.97-103
Abstract
Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin... (More)
Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
islet amyloid polypeptide, DPP4, insulin secretion, mice, vildagliptin, glucose tolerance
in
Regulatory Peptides
volume
143
issue
1-3
pages
97 - 103
publisher
Elsevier
external identifiers
  • wos:000249459100013
  • scopus:34547673164
ISSN
1873-1686
DOI
10.1016/j.regpep.2007.03.008
language
English
LU publication?
yes
id
086e84b0-8a8b-4dda-99a0-25d168437130 (old id 168420)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17482289&dopt=Abstract
date added to LUP
2007-06-26 16:30:29
date last changed
2017-07-30 03:31:24
@article{086e84b0-8a8b-4dda-99a0-25d168437130,
  abstract     = {Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.},
  author       = {Ahrén, Bo and Winzell, Maria Sorhede and Wierup, Nils and Sundler, Frank and Burkey, Bryan and Hughes, Thomas E},
  issn         = {1873-1686},
  keyword      = {islet amyloid polypeptide,DPP4,insulin secretion,mice,vildagliptin,glucose tolerance},
  language     = {eng},
  number       = {1-3},
  pages        = {97--103},
  publisher    = {Elsevier},
  series       = {Regulatory Peptides},
  title        = {DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.},
  url          = {http://dx.doi.org/10.1016/j.regpep.2007.03.008},
  volume       = {143},
  year         = {2007},
}