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 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.
Highlights
Glucose-stimulated insulin secretion (GSIS) can be modulated by different metabolic, nervous, or hormonal factors [1]
Expression and cellular localization of P2Y14 was studied in rat insulinoma INS-1 832/13 cells which was in line with our observation of b-cells in human and mouse islets (Fig. 2)
Our functional data showed that the inhibitory effect of UDP-G, a selective agonist of P2Y14 [16], on GSIS is exerted via suppression of cellular cAMP generation
Summary
Glucose-stimulated insulin secretion (GSIS) can be modulated by different metabolic, nervous, or hormonal factors [1]. Expression and cellular localization of P2Y14 was studied in rat insulinoma INS-1 832/13 cells which was in line with our observation of b-cells in human and mouse islets (Fig. 2). Whereas the UDP-G did not affect basal (1 mM glucose) insulin release, it dosedependently inhibited glucose-stimulated (16.7 mM glucose) insulin secretion in scrambled control INS-1 832/13 cells (with normal P2Y14 expression), incubated for 60 min (Fig. 2F).
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