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Beta-Cell-Targeted Expression of a Dominant-Negative Mutant of Hepatocyte Nuclear Factor-1{alpha} in Mice: Diabetes Model with {beta}-Cell Dysfunction Partially Rescued by Nonglucose Secretagogues.

Sörhede Winzell, Maria LU ; Ahrén, Bo LU ; Wollheim, Claes B. and Pacini, Giovanni (2004) In Diabetes 53(suppl_3). p.92-96
Abstract
We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. At age 2-3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P=0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P=0.006). In islets incubated for 60 min, the insulin response to glucose (3.3-22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose... (More)
We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. At age 2-3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P=0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P=0.006). In islets incubated for 60 min, the insulin response to glucose (3.3-22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose secretagogues were only partially suppressed (to GLP-1 [100 nmol/l] by 40%, to carbachol [1 micromol/l] by 20%, and to palmitate [0.5 mmol/l] by 15%), whereas the response to depolarization by KCl (50 mmol/l) was not reduced. Finally, the IVGTT data insulin sensitivity in transgenic mice was not significantly different from that of wild-type mice. Thus, mice with targeted suppression of beta-cell HNF-1alpha represent a good diabetes model exhibiting severely impaired insulin secretion after glucose with marked glucose intolerance. In contrast, the insulin responses to nonglucose stimuli are not suppressed when the islet insulin content is taken into account. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
53
issue
suppl_3
pages
92 - 96
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000225460000015
ISSN
1939-327X
DOI
10.2337/diabetes.53.suppl_3.S92
language
English
LU publication?
yes
id
09f11490-d165-41ca-a505-4a4dfa3f019c (old id 130676)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15561929&dopt=Abstract
date added to LUP
2007-07-02 09:38:10
date last changed
2016-04-16 03:59:33
@article{09f11490-d165-41ca-a505-4a4dfa3f019c,
  abstract     = {We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. At age 2-3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P=0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P=0.006). In islets incubated for 60 min, the insulin response to glucose (3.3-22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose secretagogues were only partially suppressed (to GLP-1 [100 nmol/l] by 40%, to carbachol [1 micromol/l] by 20%, and to palmitate [0.5 mmol/l] by 15%), whereas the response to depolarization by KCl (50 mmol/l) was not reduced. Finally, the IVGTT data insulin sensitivity in transgenic mice was not significantly different from that of wild-type mice. Thus, mice with targeted suppression of beta-cell HNF-1alpha represent a good diabetes model exhibiting severely impaired insulin secretion after glucose with marked glucose intolerance. In contrast, the insulin responses to nonglucose stimuli are not suppressed when the islet insulin content is taken into account.},
  author       = {Sörhede Winzell, Maria and Ahrén, Bo and Wollheim, Claes B. and Pacini, Giovanni},
  issn         = {1939-327X},
  language     = {eng},
  number       = {suppl_3},
  pages        = {92--96},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Beta-Cell-Targeted Expression of a Dominant-Negative Mutant of Hepatocyte Nuclear Factor-1{alpha} in Mice: Diabetes Model with {beta}-Cell Dysfunction Partially Rescued by Nonglucose Secretagogues.},
  url          = {http://dx.doi.org/10.2337/diabetes.53.suppl_3.S92},
  volume       = {53},
  year         = {2004},
}