Pim3 negatively regulates glucose-stimulated insulin secretion

Gregory Vlacich, Martijn C. Nawijn, Gene C. Webb, Donald F. Steiner*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

Abstract

Pancreatic beta-cell response to glucose stimulation is governed by tightly regulated signaling pathways which have not been fully characterized. A screen for novel signaling intermediates identified Pim3 as a glucose-responsive gene in the beta-cell, and here, we characterize its role in the regulation of beta-cell function. Pim3 expression in the beta-cell was first observed through microarray analysis on glucose-stimulated murine insulinoma (MIN6) cells where expression was strongly and transiently induced. In the pancreas, Pim3 expression exhibited similar dynamics and was restricted to the beta-cell. Perturbation of Pim3 function resulted in enhanced glucose-stimulated insulin secretion, both in MIN6 cells and in isolated islets from Pim3(-/-) mice, where the augmentation was specifically seen in the second phase of secretion. Consequently, Pim3(-/-) mice displayed an increased glucose tolerance in vivo. Interestingly, Pim3(-/-) mice also exhibited increased insulin sensitivity. Glucose stimulation of isolated Pim3(-/-) islets resulted in increased phosphorylation of ERK1/2, a kinase involved in regulating beta-cell response to glucose. Pim3 was also found to physically interact with SOCS6 and SOCS6 levels were strongly reduced in Pim3(-/-) islets. Overexpression of SOCS6 inhibited glucose-induced ERK1/2 activation, strongly suggesting that Pim3 regulates ERK1/2 activity through SOCS6. These data reveal that Pim3 is a novel glucose-responsive gene in the beta-cell that negatively regulates insulin secretion by inhibiting the activation of ERK1/2, and through its effect on insulin sensitivity, has potentially a more global function in glucose homeostasis.

Original languageEnglish
Pages (from-to)308-317
Number of pages10
JournalIslets
Volume2
Issue number5
DOIs
Publication statusPublished - 2010

Keywords

  • insulin secretion
  • beta-cell
  • signal transduction
  • Pim3
  • ERK
  • SOCS6
  • PANCREATIC BETA-CELLS
  • ACTIVATED PROTEIN-KINASE
  • PHOSPHOINOSITIDE 3-KINASE
  • GENE-TRANSCRIPTION
  • PHOSPHORYLATES BAD
  • MICE LACKING
  • B-CELLS
  • LANGERHANS
  • EXPRESSION
  • RECEPTOR

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