Somatostatin and Neuropeptide-Y Differentially Inhibit Insulin Secretion

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Glucose homeostasis is a tightly regulated process coordinated by insulin and glucagon secretion. In β-cells, G-protein coupled receptor (GPCR) activation facilitates the optimization of insulin secretion. Somatostatin (SST) and Neuropeptide-Y (NPY) inhibit insulin secretion through Gi activation; this inhibitory effect is mediated by the SSTR2/5 and Y1 receptors, respectively. Here, we questioned the mechanism by which SST and NPY attenuate insulin secretion. Two-photon excitation microscopy was utilized to measure the combined autofluorescence of NADH and NADPH (NAD(P)H, a cellular redox state indicator) upon SST or NPY application. Treatment with SST or NPY induces a supplementary increase in NAD(P)H autofluorescence at glucose levels ranging from 5-23 mM compared to untreated control, suggesting that the inhibitory effect of SST and NPY is not mediated through metabolic inhibition. We then tested the effect of these GPCR ligands on intracellular calcium ([Ca2+]i). At glucose concentrations above ∼7 mM, pancreatic islets display synchronous oscillations in [Ca2+]i, resulting in the pulsatile release of insulin. SST treatment decreases the [Ca2+]i oscillation frequency, while NPY has no effect; the oscillation amplitude is not altered in the presence of either ligand. Insulin secretion assays were performed at low (2.8 mM) and high (16.7 mM) glucose levels to determine the effect of SST and NPY on the Gi pathway. At both glucose concentrations, mSIRK, a Gβγ-activating peptide, significantly potentiates insulin secretion; treatment with mSIRK(L9A), which serves as a negative control for mSIRK, does not affect secretion. However, combination treatment with SST and mSIRK inhibits insulin secretion at high glucose compared to mSIRK alone. Insulin secretion is not altered with NPY and mSIRK treatment compared to mSIRK only. These data suggest that SST attenuates insulin secretion through inhibition of Gβγ acting on voltage-gated Ca2+ channels and/or phospholipase-C, while NPY inhibits insulin secretion through Gα.