title: Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells.
abstract: For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In β cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional β cells of diabetic mice.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
authors.forename: Ruiying
authors.initials: R
authors.lastname: Hu
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Brissova
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Stein
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA. Electronic address: guoqiang.gu@vanderbilt.edu.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA. Electronic address: irina.kaverina@vanderbilt.edu.
authors.forename: Irina
authors.initials: I
authors.lastname: Kaverina
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000502:physiology*; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D007328:Insulin; D013549:Sweetening Agents; D005947:Glucose