High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor.
Tan, Chanyuan LU ; Voss, Ulrikke LU ; Svensson, Siv LU ; Erlinge, David LU
and Olde, Björn
LU
(2013)
In Purinergic Signalling
9(1).
p.67-79
- Abstract
- While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC)... (More)
- While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y(13)-specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y(13) receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y(13) plays an important role in beta cell apoptosis and suggest that autocrine/paracrine mechanisms, related to ADP and P2Y(13) receptors, contribute to glucolipotoxicity. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3049720
- author
- Tan, Chanyuan
LU
; Voss, Ulrikke
LU
; Svensson, Siv
LU
; Erlinge, David
LU
and Olde, Björn
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Purinergic Signalling
- volume
- 9
- issue
- 1
- pages
- 67 - 79
- publisher
- Springer
- external identifiers
-
- wos:000314723400009
- pmid:22941026
- scopus:84873745779
- pmid:22941026
- ISSN
- 1573-9546
- DOI
- 10.1007/s11302-012-9331-6
- language
- English
- LU publication?
- yes
- id
- 41236d16-654b-426e-97cf-f0d31511c053 (old id 3049720)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22941026?dopt=Abstract
- date added to LUP
- 2016-04-01 09:54:49
- date last changed
- 2022-03-16 05:19:11
@article{41236d16-654b-426e-97cf-f0d31511c053,
abstract = {{While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y(13)-specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y(13) receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y(13) plays an important role in beta cell apoptosis and suggest that autocrine/paracrine mechanisms, related to ADP and P2Y(13) receptors, contribute to glucolipotoxicity.}},
author = {{Tan, Chanyuan and Voss, Ulrikke and Svensson, Siv and Erlinge, David and Olde, Björn}},
issn = {{1573-9546}},
language = {{eng}},
number = {{1}},
pages = {{67--79}},
publisher = {{Springer}},
series = {{Purinergic Signalling}},
title = {{High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor.}},
url = {{http://dx.doi.org/10.1007/s11302-012-9331-6}},
doi = {{10.1007/s11302-012-9331-6}},
volume = {{9}},
year = {{2013}},
}