title: Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms.
abstract: Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through G(i) activation of Y(1) and SSTR(1&5) receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca(2+)](i)) activity upon glucose stimulation, whereas SST alters this response. G(βγ)-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca(2+)](i). mSIRK-induced G(βγ) activation does not modulate glucose metabolism but increases [Ca(2+)](i) activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through G(βγ) inhibition of Ca(2+) activity, while NPY activates a Ca(2+)-independent pathway mediated by G(α). GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Schwetz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ustione
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000494:pharmacology*; D055571:Secretory Pathway / Q000187:drug effects; D013004:Somatostatin / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007328:Insulin; D009478:Neuropeptide Y; D013004:Somatostatin; D005947:Glucose