Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice.
(2008) In Journal of Molecular Endocrinology 40(2). p.93-100- Abstract
- Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from... (More)
- Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from HFD-fed mice at 8.3 mM glucose was reduced compared with islets from control mice fed a normal diet due to increased basal insulin secretion. However, GSIS increased in islets from HFD-fed exendin-4-treated animals (0.124+/-0.012 ng/h per islet in HFD-Ex-4 versus 0.062+/-0.010 in HFD, P=0.006). Furthermore, the insulin response to forskolin was increased (2.7+/-0.3 in HFD-Ex-4 versus 2.0+/-0.2 ng/h per islet in HFD, P=0.011) and PKAcat expression was increased, while PKAreg was reduced in islets from exendin-4-treated mice. In contrast, protein expression of PKBalpha, Pdx-1, and caspase 3/7 activity was not affected by exendin-4 treatment. We conclude that GLP-1 receptor activation in HFD-fed mice has durable effects on GSIS, in association with augmented signaling through the PKA pathway. These effects are seen beyond those induced by circulating exendin-4 already after 2 weeks of once-daily treatment in mice, whereas markers for islet proliferation and apoptosis were unaffected by this treatment. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1042471
- author
- Sörhede Winzell, Maria LU and Ahrén, Bo LU
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Islets of Langerhans: drug effects, Islets of Langerhans: cytology, Insulin: secretion, Fatty Acids: pharmacology, Fatty Acids: administration & dosage, Cyclic AMP-Dependent Protein Kinases: metabolism, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits: metabolism, Cell Proliferation: drug effects, Caspase 7: metabolism, Caspase 3: metabolism, Body Weight: drug effects, Apoptosis: drug effects, Biological Markers: metabolism, Islets of Langerhans: enzymology, Islets of Langerhans: secretion, Peptides: administration & dosage, Peptides: pharmacology, Venoms: administration & dosage, Venoms: pharmacology
- in
- Journal of Molecular Endocrinology
- volume
- 40
- issue
- 2
- pages
- 93 - 100
- publisher
- Society for Endocrinology
- external identifiers
-
- pmid:18234911
- wos:000253379700010
- pmid:18234911
- scopus:39549097312
- ISSN
- 1479-6813
- DOI
- 10.1677/JME-07-0121
- language
- English
- LU publication?
- yes
- id
- bc36cb0e-2105-4b62-9695-e96da9833a45 (old id 1042471)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/18234911?dopt=Abstract
- date added to LUP
- 2016-04-04 09:21:30
- date last changed
- 2024-01-12 12:25:54
@article{bc36cb0e-2105-4b62-9695-e96da9833a45,
abstract = {{Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from HFD-fed mice at 8.3 mM glucose was reduced compared with islets from control mice fed a normal diet due to increased basal insulin secretion. However, GSIS increased in islets from HFD-fed exendin-4-treated animals (0.124+/-0.012 ng/h per islet in HFD-Ex-4 versus 0.062+/-0.010 in HFD, P=0.006). Furthermore, the insulin response to forskolin was increased (2.7+/-0.3 in HFD-Ex-4 versus 2.0+/-0.2 ng/h per islet in HFD, P=0.011) and PKAcat expression was increased, while PKAreg was reduced in islets from exendin-4-treated mice. In contrast, protein expression of PKBalpha, Pdx-1, and caspase 3/7 activity was not affected by exendin-4 treatment. We conclude that GLP-1 receptor activation in HFD-fed mice has durable effects on GSIS, in association with augmented signaling through the PKA pathway. These effects are seen beyond those induced by circulating exendin-4 already after 2 weeks of once-daily treatment in mice, whereas markers for islet proliferation and apoptosis were unaffected by this treatment.}},
author = {{Sörhede Winzell, Maria and Ahrén, Bo}},
issn = {{1479-6813}},
keywords = {{Islets of Langerhans: drug effects; Islets of Langerhans: cytology; Insulin: secretion; Fatty Acids: pharmacology; Fatty Acids: administration & dosage; Cyclic AMP-Dependent Protein Kinases: metabolism; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits: metabolism; Cell Proliferation: drug effects; Caspase 7: metabolism; Caspase 3: metabolism; Body Weight: drug effects; Apoptosis: drug effects; Biological Markers: metabolism; Islets of Langerhans: enzymology; Islets of Langerhans: secretion; Peptides: administration & dosage; Peptides: pharmacology; Venoms: administration & dosage; Venoms: pharmacology}},
language = {{eng}},
number = {{2}},
pages = {{93--100}},
publisher = {{Society for Endocrinology}},
series = {{Journal of Molecular Endocrinology}},
title = {{Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice.}},
url = {{http://dx.doi.org/10.1677/JME-07-0121}},
doi = {{10.1677/JME-07-0121}},
volume = {{40}},
year = {{2008}},
}