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

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

Author information

1
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA.
2
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA.
3
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Program in Developmental Biology and Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37235, USA.
4
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Program in Developmental Biology and Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37235, USA. Electronic address: guoqiang.gu@vanderbilt.edu.
5
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA. Electronic address: irina.kaverina@vanderbilt.edu.

Abstract

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

PMID:
31303487
DOI:
10.1016/j.cub.2019.06.032

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