Regulation of Glucose-Dependent Golgi-Derived Microtubules by cAMP/EPAC2 Promotes Secretory Vesicle Biogenesis in Pancreatic β Cells

Curr Biol. 2019 Jul 22;29(14):2339-2350.e5. doi: 10.1016/j.cub.2019.06.032. Epub 2019 Jul 11.


The microtubule (MT) network is an essential regulator of insulin secretion from pancreatic β cells, which is central to blood-sugar homeostasis. We find that when glucose metabolism induces insulin secretion, it also increases formation of Golgi-derived microtubules (GDMTs), notably with the same biphasic kinetics as insulin exocytosis. Furthermore, GDMT nucleation is controlled by a glucose signal-transduction pathway through cAMP and its effector EPAC2. Preventing new GDMT nucleation dramatically affects the pipeline of insulin production, storage, and release. There is an overall reduction of β-cell insulin content, and remaining insulin becomes retained within the Golgi, likely because of stalling of insulin-granule budding. While not preventing glucose-induced insulin exocytosis, the diminished granule availability substantially blunts the amount secreted. Constant dynamic maintenance of the GDMT network is therefore critical for normal β-cell physiology. Our study demonstrates that the biogenesis of post-Golgi carriers, particularly large secretory granules, requires ongoing nucleation and replenishment of the GDMT network.

Keywords: EPAC; Golgi; cytoskeleton; dense-core granules; diabetes; insulin biogenesis; insulin granule; insulin secretion; microtubule nucleation; pancreatic beta cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cyclic AMP / metabolism*
  • Glucose / metabolism
  • Golgi Apparatus / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Insulin-Secreting Cells / physiology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microtubules / metabolism*
  • Organelle Biogenesis*
  • Secretory Vesicles / metabolism*


  • Guanine Nucleotide Exchange Factors
  • Rapgef4 protein, mouse
  • Cyclic AMP
  • Glucose