Advanced

Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes

Gandasi, Nikhil R.; Yin, Peng; Omar-Hmeadi, Muhmmad; Ottosson Laakso, Emilia LU ; Vikman, Petter LU and Barg, Sebastian LU (2018) In Cell Metabolism 27(2). p.4-478
Abstract

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression... (More)

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D. Insulin secretion is disturbed in type 2 diabetes (T2D). Gandasi et al. show that insulin granule docking to the plasma membrane is necessary for exocytosis and sustained insulin secretion and that this process is dysregulated in T2D.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biphasic secretion, dense core vesicle, docking, exocytosis, genome-wide association, GLP-1, insulin secretion, priming, somatostatin, type 2 diabetes
in
Cell Metabolism
volume
27
issue
2
pages
4 - 478
publisher
Cell Press
external identifiers
  • scopus:85044734403
ISSN
1550-4131
DOI
10.1016/j.cmet.2017.12.017
language
English
LU publication?
yes
id
fdad7259-5fec-46ec-b498-ce63a7581163
date added to LUP
2018-04-11 13:38:40
date last changed
2019-05-21 04:03:38
@article{fdad7259-5fec-46ec-b498-ce63a7581163,
  abstract     = {<p>Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D. Insulin secretion is disturbed in type 2 diabetes (T2D). Gandasi et al. show that insulin granule docking to the plasma membrane is necessary for exocytosis and sustained insulin secretion and that this process is dysregulated in T2D.</p>},
  author       = {Gandasi, Nikhil R. and Yin, Peng and Omar-Hmeadi, Muhmmad and Ottosson Laakso, Emilia and Vikman, Petter and Barg, Sebastian},
  issn         = {1550-4131},
  keyword      = {biphasic secretion,dense core vesicle,docking,exocytosis,genome-wide association,GLP-1,insulin secretion,priming,somatostatin,type 2 diabetes},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {4--478},
  publisher    = {Cell Press},
  series       = {Cell Metabolism},
  title        = {Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes},
  url          = {http://dx.doi.org/10.1016/j.cmet.2017.12.017},
  volume       = {27},
  year         = {2018},
}