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Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice.

Sörhede Winzell, Maria LU and Ahrén, Bo LU (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)
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organization
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Contribution to journal
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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
  • Scopus:39049112002
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
2008-03-06 14:05:43
date last changed
2016-10-13 04:29:05
@misc{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},
  keyword      = {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    = {ARRAY(0x828bbb0)},
  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},
  volume       = {40},
  year         = {2008},
}