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Role of phosphatidylinositol 3-kinase gamma in the beta-cell: Interactions with glucagon-like peptide-1

Li, LX ; MacDonald, Patrick LU ; Ahn, DS ; Oudit, GY ; Backx, PH and Brubaker, PL (2006) In Endocrinology 147(7). p.3318-3325
Abstract
Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-K gamma is known to be activated by G(beta gamma). Therefore, the role of PI3-K gamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-K gamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially... (More)
Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-K gamma is known to be activated by G(beta gamma). Therefore, the role of PI3-K gamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-K gamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially normalized by chronic Ex4 treatment (P < 0.05). In contrast, insulin content was increased in PBS- KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P < 0.05-0.01). Transfection of INS-1E beta-cells with small interferingRNAfor PI3-K gamma similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for beta-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS- KO mice (P < 0.05-0.001) and, although they were increased by Ex4 treatment of WT animals (P < 0.05), they were decreased in Ex4-KO mice (P < 0.05-0.01). These findings indicate that PI3-K gamma deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of beta-cell mass. These studies reveal a new role for PI3-K gamma as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal beta-cell function. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrinology
volume
147
issue
7
pages
3318 - 3325
publisher
Oxford University Press
external identifiers
  • wos:000238312400020
  • pmid:16574789
  • scopus:33745154535
ISSN
0013-7227
DOI
10.1210/en.2006-0155
language
English
LU publication?
yes
id
5e05c86d-c2d1-4266-8553-56619992d778 (old id 406157)
date added to LUP
2016-04-01 12:08:38
date last changed
2021-02-23 03:09:14
@article{5e05c86d-c2d1-4266-8553-56619992d778,
  abstract     = {Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-K gamma is known to be activated by G(beta gamma). Therefore, the role of PI3-K gamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-K gamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P &lt; 0.05), and this was partially normalized by chronic Ex4 treatment (P &lt; 0.05). In contrast, insulin content was increased in PBS- KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P &lt; 0.05-0.01). Transfection of INS-1E beta-cells with small interferingRNAfor PI3-K gamma similarly decreased glucose-stimulated insulin secretion (P &lt; 0.01) and increased insulin content. Basal values for beta-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS- KO mice (P &lt; 0.05-0.001) and, although they were increased by Ex4 treatment of WT animals (P &lt; 0.05), they were decreased in Ex4-KO mice (P &lt; 0.05-0.01). These findings indicate that PI3-K gamma deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of beta-cell mass. These studies reveal a new role for PI3-K gamma as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal beta-cell function.},
  author       = {Li, LX and MacDonald, Patrick and Ahn, DS and Oudit, GY and Backx, PH and Brubaker, PL},
  issn         = {0013-7227},
  language     = {eng},
  number       = {7},
  pages        = {3318--3325},
  publisher    = {Oxford University Press},
  series       = {Endocrinology},
  title        = {Role of phosphatidylinositol 3-kinase gamma in the beta-cell: Interactions with glucagon-like peptide-1},
  url          = {http://dx.doi.org/10.1210/en.2006-0155},
  doi          = {10.1210/en.2006-0155},
  volume       = {147},
  year         = {2006},
}