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Measuring Relative Insulin Secretion using a Co-Secreted Luciferase Surrogate
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A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion

Makoto Shigeto1,2, Chae Young Cha3, Patrik Rorsman3

  • 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK. shigeto@med.kawasaki-m.ac.jp.

Journal of Molecular Medicine (Berlin, Germany)
|January 19, 2017
PubMed

Insights

Glucagon-like peptide-1 (GLP-1) at physiological concentrations stimulates insulin secretion via a novel protein kinase C (PKC) pathway, distinct from the established protein kinase A (PKA) pathway. This discovery offers insights into GLP-1

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • Glucagon-like peptide-1 (GLP-1) is an endogenous hormone crucial for glucose regulation.
  • GLP-1 receptor agonists are established antidiabetic therapies.
  • The canonical cAMP-Epac2-PKA-KATP channel pathway is widely accepted for GLP-1-stimulated insulin secretion, based on high-concentration studies.

Purpose of the Study:

  • To review and contrast the signaling mechanisms of GLP-1 at physiological (pM) versus pharmacological (nM) concentrations.
  • To highlight the recently discovered PKA-independent pathway activated by physiological GLP-1 levels.
  • To explore how differential signaling might explain diverse GLP-1 functions.

Main Methods:

  • Review of recent in vitro studies on isolated islets and beta cells.
  • Analysis of GLP-1 effects at nanomolar (1-100 nM) and picomolar (1-10 pM) concentrations.
  • Investigation of signaling components including cAMP, PKA, PKC, PLC, Ca2+ channels, and KATP channels.

Main Results:

  • Physiological GLP-1 concentrations stimulate insulin secretion, depolarization, and Ca2+ influx independently of PKA and cAMP.
  • These low-concentration effects are mediated by PKC, GLP1R, PLC, and involve DAG elevation and altered Ca2+ and TRPM channel activity.
  • Pharmacological GLP-1 concentrations activate the canonical cAMP-PKA pathway.

Conclusions:

  • GLP-1 utilizes distinct intracellular signaling pathways at physiological and pharmacological concentrations.
  • The PKA-independent pathway activated by physiological GLP-1 is crucial for insulin secretion.
  • Understanding these differential pathways may elucidate GLP-1's diverse roles in the central nervous system and periphery.
Keywords:
GLP-1Insulin secretionKATP channelPKAPKCTRP channels

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