Pancreatic α- And β-cellular Clocks Have Distinct Molecular Properties and Impact on Islet Hormone Secretion and Gene Expression

Genes Dev. 2017 Feb 15;31(4):383-398. doi: 10.1101/gad.290379.116. Epub 2017 Mar 8.

Abstract

A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and β-cellular clocks are oscillating with distinct phases in vivo and in vitro. Diurnal transcriptome analysis in separated α and β cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and β-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.

Keywords: RNA sequencing; circadian clock; insulin/glucagon secretion; mouse α cells and β cells; single-cell bioluminescence–fluorescence time-lapse microscopy.

MeSH terms

  • Animals
  • Cells, Cultured
  • Circadian Clocks / drug effects
  • Circadian Clocks / physiology*
  • Colforsin / pharmacology
  • Enzyme Activators / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation* / drug effects
  • Glucagon / blood
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / physiology*
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Models, Animal
  • Sequence Analysis, RNA
  • Time Factors

Substances

  • Enzyme Activators
  • Insulin
  • Colforsin
  • Glucagon