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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.

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author
; ; ; ; and
organization
publishing date
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},
}