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Elevated basal insulin secretion in type 2 diabetes caused by reduced plasma membrane cholesterol

Nagaraj, Vini LU ; Kazim, Abdulla S. LU ; Helgeson, Johan; Lewold, Clemens; Barik, Satadal; Buda, Pawel LU ; Reinbothe, Thomas M. LU ; Wennmalm, Stefan; Zhang, Enming LU and Renström, Erik LU (2016) In Molecular Endocrinology 30(10). p.1059-1069
Abstract

Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect... (More)

Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca2+ spike frequency and Ca2+ influx and explained by enhanced single Ca2+ channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Endocrinology
volume
30
issue
10
pages
11 pages
publisher
The Endocrine Society
external identifiers
  • scopus:84990062867
  • wos:000391208200010
ISSN
0888-8809
DOI
10.1210/me.2016-1023
language
English
LU publication?
yes
id
e329277f-5552-441d-b4c1-9c7c46bf650c
date added to LUP
2016-10-21 12:02:46
date last changed
2017-10-22 05:20:50
@article{e329277f-5552-441d-b4c1-9c7c46bf650c,
  abstract     = {<p>Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca<sup>2+</sup> spike frequency and Ca<sup>2+</sup> influx and explained by enhanced single Ca<sup>2+</sup> channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.</p>},
  author       = {Nagaraj, Vini and Kazim, Abdulla S. and Helgeson, Johan and Lewold, Clemens and Barik, Satadal and Buda, Pawel and Reinbothe, Thomas M. and Wennmalm, Stefan and Zhang, Enming and Renström, Erik},
  issn         = {0888-8809},
  language     = {eng},
  month        = {10},
  number       = {10},
  pages        = {1059--1069},
  publisher    = {The Endocrine Society},
  series       = {Molecular Endocrinology},
  title        = {Elevated basal insulin secretion in type 2 diabetes caused by reduced plasma membrane cholesterol},
  url          = {http://dx.doi.org/10.1210/me.2016-1023},
  volume       = {30},
  year         = {2016},
}