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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
Summary
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.
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