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Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane.

Olofsson, Charlotta LU ; Collins, Stephan; Bengtsson, Martin LU ; Eliasson, Lena LU ; Salehi, S Albert LU ; Shimomura, Kenju; Tarasov, Andrei; Holm, Cecilia LU ; Ashcroft, Frances and Rorsman, Patrik (2007) In Diabetes 56(7). p.1888-1897
Abstract
Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K-ATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca-i(2+]) +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)induced inhibition of secretion was not associated with any major changes in [Ca2+](i) or islet ATP content. Palmitate... (More)
Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K-ATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca-i(2+]) +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)induced inhibition of secretion was not associated with any major changes in [Ca2+](i) or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced V-induced secretion by up to 60%. Basal (1 mmol/l glucose) K-ATP channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secre tory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased tran script levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
56
issue
7
pages
1888 - 1897
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000247768000017
  • scopus:34347382713
ISSN
1939-327X
DOI
10.2337/db06-1150
language
English
LU publication?
yes
id
e1019600-6c78-4fd9-b8ec-d5451b7d71e6 (old id 167378)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17456851&dopt=Abstract
date added to LUP
2007-07-18 14:07:29
date last changed
2017-06-11 04:23:38
@article{e1019600-6c78-4fd9-b8ec-d5451b7d71e6,
  abstract     = {Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K-ATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca-i(2+]) +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)induced inhibition of secretion was not associated with any major changes in [Ca2+](i) or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced V-induced secretion by up to 60%. Basal (1 mmol/l glucose) K-ATP channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secre tory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased tran script levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore.},
  author       = {Olofsson, Charlotta and Collins, Stephan and Bengtsson, Martin and Eliasson, Lena and Salehi, S Albert and Shimomura, Kenju and Tarasov, Andrei and Holm, Cecilia and Ashcroft, Frances and Rorsman, Patrik},
  issn         = {1939-327X},
  language     = {eng},
  number       = {7},
  pages        = {1888--1897},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane.},
  url          = {http://dx.doi.org/10.2337/db06-1150},
  volume       = {56},
  year         = {2007},
}