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

Fariborz Parandeh1, Stefan Amisten1, Gaurav Verma1

  • 1Department of Clinical Science, Division of Islet Cell Physiology, UMAS University of Lund, Malmö, Sweden.

The Journal of Biological Chemistry
|August 29, 2020
PubMed

Insights

UDP-glucose (UDP-G) activates P2Y14 receptors, suppressing insulin secretion in type-2 diabetes (T2D). This study reveals UDP-G

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Type-2 diabetes (T2D) is characterized by impaired pancreatic beta-cell insulin secretion.
  • The precise molecular mechanisms causing beta-cell dysfunction in T2D remain incompletely understood.
  • UDP-glucose (UDP-G) and its receptor P2Y14 are implicated in cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of UDP-glucose (UDP-G) and its specific receptor P2Y14 in regulating insulin secretion from pancreatic beta-cells.
  • To elucidate the molecular mechanisms by which UDP-G affects beta-cell function and viability in the context of type-2 diabetes.

Main Methods:

  • Utilized human isolated pancreatic islets and INS-1 cells for experiments.
  • Assessed glucose-stimulated insulin secretion (GSIS) following P2Y14 activation with UDP-G.
  • Employed pertussis-toxin (PTX) pretreatment and P2Y14 knockdown to investigate signaling pathways.
  • Measured intracellular cAMP levels, cellular reductive capacity, cell viability, and apoptosis.
  • Examined the impact of UDP-G on glucose-induced proliferation of INS-1 cells.

Main Results:

  • P2Y14 is expressed in human and rodent pancreatic beta-cells.
  • UDP-G activation of P2Y14 dose-dependently suppressed GSIS; P2Y14 knockdown abolished this effect.
  • Pertussis-toxin (PTX) pretreatment improved GSIS and blocked UDP-G's inhibitory action.
  • UDP-G-induced suppression of GSIS correlated with reduced cAMP levels.
  • UDP-G diminished beta-cell reductive capacity and exacerbated glucose-induced cell death and apoptosis.
  • These detrimental effects were counteracted by a cAMP analog.
  • UDP-G modulated glucose-induced proliferation in INS-1 cells.

Conclusions:

  • P2Y14 receptor activation by UDP-glucose plays a significant role in suppressing insulin secretion.
  • UDP-G negatively impacts pancreatic beta-cell function and viability, potentially contributing to T2D pathogenesis.
  • Targeting the P2Y14/UDP-G pathway may offer a novel therapeutic strategy for T2D.
Keywords:
G protein–coupled receptorGPCRdiabeteshormoneinsulin secretionisletpancreaspurinepurinoceptor

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