P2Y purinergic potentiation of glucose-induced insulin secretion and pancreatic beta-cell metabolism.
Purine nucleotides and their analogs increase insulin secretion through activation of pancreatic beta-cell P2Y receptors. The present study aimed at determining the role of glucose metabolism in the response to P2Y agonists and whether ATP-activated K+ channels (KATP channels) are involved in this response. The experiments were performed in the rat isolated pancreas, perfused with a Krebs-bicarbonate buffer supplemented with 2 g/l bovine serum albumin under dynamic glucose conditions from 5 mmol/l baseline to 11 mmol/l. ADPbetaS (0.5 micromol/l) was selected as a stable and selective P2Y agonist. This compound, ineffective on the 5 mmol/l glucose background, induced a significant threefold increase in insulin release triggered by the glucose challenge. The effect of ADPbetaS was markedly reduced (P <0.001) in the presence of an inhibitor of glucose metabolism. In addition to glucose, the ADP analog also amplified the beta-cell insulin response to 15 mmol/l methyl pyruvate (P <0.05), but it was ineffective on the insulin response to 2.5 mmol/l methyl succinate. A nonmetabolic stimulus was applied using tolbutamide (185 micromol/l). Insulin secretion induced by the KATP channel blocker was strongly reinforced by ADPbetaS (P <0.001), which prompted us to check a possible interplay of KATP channels in the effect of ADPbetaS. In the presence of diazoxide 250 micromol/l and 21 mmol/l KCl, ADPbetaS still amplified the second phase of glucose-induced insulin secretion (P <0.001). We conclude that P2Y receptor activation is able to promote insulin secretion through a mechanism, involving beta-cell metabolism and a rise in intracellular calcium; this effect does not result from a direct inhibitory effect on KATP channels.
Farret
A
A
Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Faculté de Médecine, Institut de Biologie, 4 Boulevard Henri IV, CS89508, 34960 Montpellier Cedex 2, France.
Vignaud
M
M
Dietz
S
S
Vignon
J
J
Petit
P
P
Gross
R
R
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
D007328:Insulin; D015221:Potassium Channels; D018047:Receptors, Purinergic P1; D013873:Thionucleotides; D009599:Nitroprusside; C030812:adenosine 5'-O-(2-thiodiphosphate); D000244:Adenosine Diphosphate; D005947:Glucose; D003981:Diazoxide