Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion
Parandeh, Fariborz LU ; Amisten, Stefan LU ; Verma, Gaurav LU ; Mohammed Al-Amily, Israa LU ; Dunér, Pontus LU and Salehi, Albert LU
(2020)
In The Journal of biological chemistry
295(45).
p.15245-15252
- Abstract
Type-2 diabetes (T2D) is a global disease caused by the inability of pancreatic β-cells to secrete adequate insulin. However, the molecular mechanisms underlying the failure of β-cells to respond to glucose in T2D remains unknown. Here, we investigated the relative contribution of UDP-glucose (UDP-G), a P2Y14-specific agonist, in the regulation of insulin release using human isolated pancreatic islets and INS-1 cells. P2Y14 was expressed in both human and rodent pancreatic β-cells. Dose-dependent activation of P2Y14 by UDP-G suppressed glucose-stimulated insulin secretion (GSIS) and knockdown of P2Y14 abolished the UDP-G effect. 12-h pretreatment of human islets with pertussis-toxin (PTX) improved GSIS and prevented the inhibitory... (More)
Type-2 diabetes (T2D) is a global disease caused by the inability of pancreatic β-cells to secrete adequate insulin. However, the molecular mechanisms underlying the failure of β-cells to respond to glucose in T2D remains unknown. Here, we investigated the relative contribution of UDP-glucose (UDP-G), a P2Y14-specific agonist, in the regulation of insulin release using human isolated pancreatic islets and INS-1 cells. P2Y14 was expressed in both human and rodent pancreatic β-cells. Dose-dependent activation of P2Y14 by UDP-G suppressed glucose-stimulated insulin secretion (GSIS) and knockdown of P2Y14 abolished the UDP-G effect. 12-h pretreatment of human islets with pertussis-toxin (PTX) improved GSIS and prevented the inhibitory effect of UDP-G on GSIS. UDP-G on GSIS suppression was associated with suppression of cAMP in INS-1 cells. UDP-G decreased the reductive capacity of nondiabetic human islets cultured at 5 mm glucose for 72 h and exacerbated the negative effect of 20 mm glucose on the cell viability during culture period. T2D donor islets displayed a lower reductive capacity when cultured at 5 mm glucose for 72 h that was further decreased in the presence of 20 mm glucose and UDP-G. Presence of a nonmetabolizable cAMP analog during culture period counteracted the effect of glucose and UDP-G. Islet cultures at 20 mm glucose increased apoptosis, which was further amplified when UDP-G was present. UDP-G modulated glucose-induced proliferation of INS-1 cells. The data provide intriguing evidence for P2Y14 and UDP-G's role in the regulation of pancreatic β-cell function.
(Less)
- author
- Parandeh, Fariborz
LU
; Amisten, Stefan
LU
; Verma, Gaurav
LU
; Mohammed Al-Amily, Israa
LU
; Dunér, Pontus
LU
and Salehi, Albert
LU
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- diabetes, G protein–coupled receptor, GPCR, hormone, insulin secretion, islet, pancreas, purine, purinoceptor
- in
- The Journal of biological chemistry
- volume
- 295
- issue
- 45
- pages
- 8 pages
- publisher
- ASBMB
- external identifiers
-
- scopus:85095862048
- pmid:32855238
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.RA120.012929
- language
- English
- LU publication?
- yes
- id
- 85deb91c-cc55-4eb5-a19b-678f3d371724
- date added to LUP
- 2020-11-24 15:24:43
- date last changed
- 2021-03-03 04:26:29
@article{85deb91c-cc55-4eb5-a19b-678f3d371724,
abstract = {<p>Type-2 diabetes (T2D) is a global disease caused by the inability of pancreatic β-cells to secrete adequate insulin. However, the molecular mechanisms underlying the failure of β-cells to respond to glucose in T2D remains unknown. Here, we investigated the relative contribution of UDP-glucose (UDP-G), a P2Y14-specific agonist, in the regulation of insulin release using human isolated pancreatic islets and INS-1 cells. P2Y14 was expressed in both human and rodent pancreatic β-cells. Dose-dependent activation of P2Y14 by UDP-G suppressed glucose-stimulated insulin secretion (GSIS) and knockdown of P2Y14 abolished the UDP-G effect. 12-h pretreatment of human islets with pertussis-toxin (PTX) improved GSIS and prevented the inhibitory effect of UDP-G on GSIS. UDP-G on GSIS suppression was associated with suppression of cAMP in INS-1 cells. UDP-G decreased the reductive capacity of nondiabetic human islets cultured at 5 mm glucose for 72 h and exacerbated the negative effect of 20 mm glucose on the cell viability during culture period. T2D donor islets displayed a lower reductive capacity when cultured at 5 mm glucose for 72 h that was further decreased in the presence of 20 mm glucose and UDP-G. Presence of a nonmetabolizable cAMP analog during culture period counteracted the effect of glucose and UDP-G. Islet cultures at 20 mm glucose increased apoptosis, which was further amplified when UDP-G was present. UDP-G modulated glucose-induced proliferation of INS-1 cells. The data provide intriguing evidence for P2Y14 and UDP-G's role in the regulation of pancreatic β-cell function.</p>},
author = {Parandeh, Fariborz and Amisten, Stefan and Verma, Gaurav and Mohammed Al-Amily, Israa and Dunér, Pontus and Salehi, Albert},
issn = {1083-351X},
language = {eng},
number = {45},
pages = {15245--15252},
publisher = {ASBMB},
series = {The Journal of biological chemistry},
title = {Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion},
url = {http://dx.doi.org/10.1074/jbc.RA120.012929},
doi = {10.1074/jbc.RA120.012929},
volume = {295},
year = {2020},
}