Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance and deranged glucose morphology.
Härndahl, Linda LU ; Wierup, Nils LU ; Enerbäck, Sven ; Mulder, Hindrik LU
; Manganiello, Vincent C
; Sundler, Frank
LU
; Degerman, Eva
LU
; Ahrén, Bo
LU
and Stenson Holst, Lena
(2004)
In Journal of Biological Chemistry
279(15).
p.15214-15222
- Abstract
- The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin... (More)
- The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/120015
- author
- Härndahl, Linda
LU
; Wierup, Nils
LU
; Enerbäck, Sven
; Mulder, Hindrik
LU
; Manganiello, Vincent C
; Sundler, Frank
LU
; Degerman, Eva
LU
; Ahrén, Bo
LU
and Stenson Holst, Lena
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 279
- issue
- 15
- pages
- 15214 - 15222
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000220594700088
- scopus:2442423329
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M308952200
- language
- English
- LU publication?
- yes
- id
- 5c964935-3efc-480b-a55c-f0bf6347a2a8 (old id 120015)
- alternative location
- http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14736883&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
- date added to LUP
- 2016-04-01 12:30:10
- date last changed
- 2024-01-08 22:42:24
@article{5c964935-3efc-480b-a55c-f0bf6347a2a8,
abstract = {{The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.}},
author = {{Härndahl, Linda and Wierup, Nils and Enerbäck, Sven and Mulder, Hindrik and Manganiello, Vincent C and Sundler, Frank and Degerman, Eva and Ahrén, Bo and Stenson Holst, Lena}},
issn = {{1083-351X}},
language = {{eng}},
number = {{15}},
pages = {{15214--15222}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance and deranged glucose morphology.}},
url = {{http://dx.doi.org/10.1074/jbc.M308952200}},
doi = {{10.1074/jbc.M308952200}},
volume = {{279}},
year = {{2004}},
}