Role of phosphatidylinositol 3-kinase gamma in the beta-cell: Interactions with glucagon-like peptide-1
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/406157
- author
- Li, LX ; MacDonald, Patrick LU ; Ahn, DS ; Oudit, GY ; Backx, PH and Brubaker, PL
- organization
- publishing date
- 2006
- 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
- 2022-02-11 02:37:20
@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 < 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.}},
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}},
}