The permissive effects of glucose on receptor-operated potentiation of insulin secretion from mouse islets: a role for ERK1/2 activation and cytoskeletal remodelling

J. E. Bowe*, A. Chander, B. Liu, S. J. Persaud, P. M. Jones

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Aims/hypothesis
Glucose plays two distinct roles in regulating insulin secretion from beta cells—an initiatory role, and a permissive role enabling receptor-operated secretagogues to potentiate glucose-induced insulin secretion. The molecular mechanisms underlying the permissive effects of glucose on receptor-operated insulin secretion remain uncertain. We have investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and consequent cytoskeletal remodelling in this process.

Methods
Insulin release was measured from groups of isolated mouse islets using static incubation experiments and subsequent radioimmunoassay of samples. ERK1/2 activation was measured by western blotting of islet protein samples for both phosphorylated and total ERK1/2. Rhodamine–phalloidin staining was used to measure filamentous actin in dispersed primary beta cells.

Results
Inhibition of ERK1/2 blocked potentiation of glucose-induced insulin release by the receptor-operated secretagogues kisspeptin, A568, exendin-4 and JWH015, although the agonists alone had minimal effects on ERK1/2 activation, suggesting a permissive rather than causal role for ERK1/2 activation in receptor-operated insulin release. Following pharmacological activation of ERK1/2 all agonists caused a significant increase in insulin release from islets incubated with sub-stimulatory levels of glucose. ERK1/2 inhibition significantly reduced the glucose-dependent decreases in filamentous actin observed in primary beta cells, while pharmacological dissociation of actin filaments enabled all receptor-operated secretagogues tested to significantly stimulate insulin release from islets at a sub-stimulatory glucose concentration.

Conclusions/interpretation
Glucose-induced ERK1/2 activation in beta cells mediates the permissive effects of stimulatory glucose concentrations on receptor-operated insulin secretagogues, at least in part through effects on actin depolymerisation and cytoskeletal remodelling.
Original languageEnglish
Pages (from-to)783-791
Number of pages9
JournalDiabetologia
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Actin
  • Beta cell
  • ERK1/2
  • G-protein coupled receptor agonists
  • Islet
  • Insulin secretion
  • PANCREATIC BETA-CELLS
  • CALCIUM-SENSING RECEPTOR
  • MAP KINASE PATHWAYS
  • PROTEIN-KINASE
  • RAT ISLETS
  • SYNAPSIN-I
  • CANNABINOID RECEPTORS
  • ACTIN CYTOSKELETON
  • REGULATED KINASES
  • LANGERHANS

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