Glucose-dependent alterations of intracellular free calcium by glucagon-like peptide-1(7-36amide) in individual ob/ob mouse beta-cells.
Depolarizing concentrations of glucose produce characteristic alterations of intracellular free Ca2+ ([Ca2+]i) in pancreatic beta-cells. The effects of the proposed incretin, glucagon-like peptide-1(7-36amide) (GLP-1a) on [Ca2+]i were determined from Fura-2 fluorescence ratio imaging of cultured ob/ob mouse pancreatic beta-cells. In control cells, [Ca2+]i is low in 3 mM glucose; increasing [glucose] to 8-12 mM results in an initial dip in [Ca2+]i followed by slow oscillating increases in [Ca2+]i. GLP-1a (0.03-10,000 pM) does not alter [Ca2+]i in 3 mM glucose, but does change the response to elevated glucose (8-12 mM). The time integral of the initial dip is reduced ([GLP-1a] 10-100 pM), and the integral of the [Ca2+]i signal is increased ([GLP-1a] > or = 1 pM). GLP-1a increases the frequency of sustained, stable plateau responses to elevated glucose, and the frequency of large, rapid spikes of increased [Ca2+]i associated with either plateaus, or oscillations. Application of a cAMP analog mimics most of the actions of GLP-1a. Activation of the GLP-1a receptor, or application of cAMP alters pancreatic beta-cell [Ca2+]i only when [glucose] is high.
Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey.
C A
CA
Cullinan
E J
EJ
Brady
R
R
Saperstein
M D
MD
Leibowitz
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015736:Felodipine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology
D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose; D015736:Felodipine; D002118:Calcium