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Cited by 41Pancreatic function and diabetesMetabolism, Diabetes, and CancerPhosphodiesterase function and regulation

Activators of PKA and Epac Distinctly Influence Insulin Secretion and Cytosolic Ca2+ in Female Mouse Islets Stimulated by Glucose and Tolbutamide

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Henquin, Jean-Claude, Nenquin, Myriam·2014·Endocrinology
DOI 10.1210/en.2014-1247PMC PMC4255079
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Abstract

Amplification of insulin secretion by cAMP is mediated by protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Using selective activators, we determined how each effector influences the cytosolic free Ca2+ concentration ([Ca2+]c) and insulin secretion in mouse islets. Alone PKA activator amplified glucose- and tolbutamide-induced insulin secretion, with a greater impact on second than first phase. Epac activator strongly amplified both phases in response to either secretagogue. Amplification was even greater when activators were combined. Although both activators similarly amplified glucose-induced insulin secretion, Epac activator was particularly efficient on tolbutamide-induced insulin secretion. That greater efficacy is attributed to higher [Ca2+]c rather than interaction of tolbutamide with Epac, because it was also observed during KCl stimulation. Moreover, in contrast to Epac activator, tolbutamide was inactive when insulin secretion was increased by gliclazide, and its effect on glucose-induced insulin secretion was unaffected by an inhibitor of Epac2. PKA activator increased [Ca2+]c during acute or steady-state glucose stimulation, whereas Epac activator had no effect alone or in combination. Neither activator affected [Ca2+]c response to tolbutamide or KCl. Metabolic (glucose-mediated) amplification of insulin secretion was unaffected by PKA activator. It was attenuated when insulin secretion was augmented by Epac activator but insensitive to Epac2 inhibitor, which suggests distinct although somewhat overlapping mechanisms. In conclusion, activators of PKA and Epac amplify insulin secretion by augmenting the action of Ca2+ on exocytosis and, for PKA only, slightly increasing glucose-induced [Ca2+]c rise. The influence of Epac seems more important than that of PKA during first phase.

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  • Enhanced RRP increased 1st phase insulin secretion in response to a subsequent challenge with glucose, tolbutamide or high [K+]o.

    “This enhanced 1st phase insulin secretion in response to a subsequent challenge with glucose, tolbutamide or high [K+]o (274), as expected if the size of the RRP determines 1st phase insulin secretion.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [274]

    The glucose- and tolbutamide-pretreatment Results sections report increased first-phase insulin secretion with Epac activation; the metabolic-amplification section also reports increased secretion during KCl stimulation. The paper does not establish that an enlarged readily releasable pool (RRP) caused these effects, and the cited KCl result is not identified as an increase specifically in first-phase secretion. Page numbers were not available in our copy. (LLM, conf=0.84)

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Cited by

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Authors
Henquin, J.-C., & Nenquin, M.
Affiliations
UCLouvain (BE)
Corresponding author
Henquin, Jean-Claude
ORCID
Henquin, Jean-Claude
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2014-09-01
Volume
155
Issue
9
Pages
3274-3287
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2014-1247
PMC
PMC4255079
OpenAlex
W2061806216
Cited by
41
References
1
Citations by year
2024: 1 · 2023: 4 · 2022: 2 · 2021: 6 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 2 · 2015: 7 · 2014: 1
FWCI
5.32
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Access to Libraries (submittedVersion)
Funders
Université Catholique de Louvain
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Keywords
protein kinase A, Epac, insulin secretion, intracellular calcium, pancreatic islets, tolbutamide, glucose stimulation, cAMP signaling, first-phase insulin secretion, second-phase insulin secretion, gliclazide, Epac2, exocytosis, female mice
MeSH terms
Insulin Secretion, Animals, Calcium, Cytosol, Female, Glucose, Insulin, Islets of Langerhans, Mice, Inbred C57BL, Tolbutamide, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Enzyme Activators, Guanine Nucleotide Exchange Factors, Mice

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