Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype

beta-Cells from rodents and humans express different receptors recognizing hormones of the secretin-glucagon family, which-when activated-synergize wi th glucose in the control of insulin release. We have recently reported tha t isolated islets from mice homozygous for a GLP-1 receptor null mutation ( GLP-1R-/-) exhibit a well-preserved insulin-secretory response to glucose. This observation can be interpreted in two different ways: 1) the presence of GLP-1R is not essential for the secretory response of isolated islets to glucose alone; 2) beta-cells in GLP-1R-/- pancreases underwent compensator y changes in response to the null mutation. To explore these possibilities, we studied islets horn control GLP-1R+/+ mice in the absence or presence o f 1 mu mol/l exendin (9-39)amide, a specific and potent GLP-1R antagonist. Exendin (9-39)amide (15-min exposure) reduced glucose-induced insulin secre tion from both perifused and statically incubated GLP-1R+/+ islets by 50% ( P < 0.05), and reduced islet cAMP production in parallel (P < 0.001), Furth ermore, GLP-1R-/- islets exhibited: 1) reduced cAMP accumulation in the pre sence of 20 mmol/l glucose (knockout islets versus control islets, 12 +/- 1 vs. 27 +/- 3 fmol.islet(-1).15 min(-1) P < 0.001) and exaggerated accelera tion of cAMP production by 10 nmol/l glucose-dependent insulinotropic pepti de (GIP) (increase over 20 mmol/l glucose by GIP in knockout islets versus control islets: 66 +/- 5 vs, 14 +/- 3 fmol.islet(-1).15 min(-1) P < 0.001); 2) increased mean cytosolic [Ca2+] ([Ca2+](c)) at 7, 10, and 15 mmol/l glu cose in knockout islets versus control islets; and 3) signs of asynchrony o f [Ca2+], oscillations between different islet subregions. In conclusion, d isruption of GLP-1R signaling is associated with reduced basal but enhanced GIP-stimulated cAMP production and abnormalities in basal and glucose-stim ulated [Ca2+](c). These abnormalities suggest that GLP-1R signaling is an e ssential upstream component of multiple beta-cell signaling pathways.