Apelin inhibits insulin secretion in pancreatic beta-cells by activation of PI3-kinase-phosphodiesterase 3B.
OBJECTIVE
Apelin is secreted by adipocytes acting on APJ receptor and plays an important role in control of feeding behavior, energy expenditure, and the regulation of body fluid homeostasis. The adipokine is regulated by insulin and tumor necrosis factor-alpha in adipose tissue, suggesting apelin is involved in the regulation of pancreatic function. In this study, we incubated rat insulinoma INS-1 cells producing insulin for 60 min and examined the effects of pyr(1)-apelin-13 on insulin secretion and the mechanism.


METHODS
INS-1 cells were incubated in the presence of various concentrations of glucose and/or apelin, glucagon-like peptide-1 (GLP-1), phosphoinositide 3-kinase (PI3-kinase) inhibitor, phosphodiesterase 3B (PDE3B) inhibitor, and cAMP analogues. We examined the effect of apelin on insulin secretion and the pathway of the action. Insulin concentrations were measured by radioimmunoassay.


RESULTS
We found that apelin over the concentration range of 1-10(4) nmol/L inhibited the insulin response to glucose and GLP-1 and the concentration effect was biphasic. The effect of apelin was abolished when insulin secretion was induced with cAMP analogues that cannot be hydrolyzed by cyclic nucleotide PDE3B. Selective inhibitors of PDE3B and PI3-kinase completely prevent the apelin effect on insulin secretion and cAMP accumulation.


CONCLUSIONS
These findings suggest that apelin exerts direct inhibitory actions on the pancreatic beta-cells by activating PI3-kinase-dependent PDE3B and subsequently suppressing of cAMP levels.
Guo
Lin
L
Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Li
Qiang
Q
Wang
Wei
W
Yu
Ping
P
Pan
Hongyan
H
Li
Pengjie
P
Sun
Yuqian
Y
Zhang
Jinchao
J
D000818:Animals; D000073861:Apelin; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D020105:Milrinone / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats
D000073861:Apelin; D002352:Carrier Proteins; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005947:Glucose; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020105:Milrinone; D019869:Phosphatidylinositol 3-Kinases; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C498579:Apln protein, rat; C517294:Pde3b protein, rat