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Pontus Dunér

Assistant researcher

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Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion

Author

  • Fariborz Parandeh
  • Stefan Amisten
  • Gaurav Verma
  • Israa Mohammed Al-Amily
  • Pontus Dunér
  • Albert Salehi

Summary, in English

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.

Department/s

  • Diabetes - Islet Patophysiology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Molecular Metabolism
  • Islet cell physiology
  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis

Publishing year

2020

Language

English

Pages

15245-15252

Publication/Series

The Journal of biological chemistry

Volume

295

Issue

45

Document type

Journal article

Publisher

ASBMB

Topic

  • Endocrinology and Diabetes

Keywords

  • diabetes
  • G protein–coupled receptor
  • GPCR
  • hormone
  • insulin secretion
  • islet
  • pancreas
  • purine
  • purinoceptor

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • Diabetes - Molecular Metabolism
  • Islet cell physiology
  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis

ISBN/ISSN/Other

  • ISSN: 1083-351X