title: Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both α-cells and δ-cells.
abstract: We evaluated the role of ATP-sensitive K⁺ (K(ATP)) channels, somatostatin, and Zn²⁺ in the control of glucagon secretion from mouse islets. Switching from 1 to 7 mmol/L glucose inhibited glucagon release. Diazoxide did not reverse the glucagonostatic effect of glucose. Tolbutamide decreased glucagon secretion at 1 mmol/L glucose (G1) but stimulated it at 7 mmol/L glucose (G7). The reduced glucagon secretion produced by high concentrations of tolbutamide or diazoxide, or disruption of K(ATP) channels (Sur1(-/-) mice) at G1 could be inhibited further by G7. Removal of the somatostatin paracrine influence (Sst(-/-) mice or pretreatement with pertussis toxin) strongly increased glucagon release, did not prevent the glucagonostatic effect of G7, and unmasked a marked glucagonotropic effect of tolbutamide. Glucose inhibited glucagon release in the absence of functional K(ATP) channels and somatostatin signaling. Knockout of the Zn²⁺ transporter ZnT8 (ZnT8(-/-) mice) did not prevent the glucagonostatic effect of glucose. In conclusion, glucose can inhibit glucagon release independently of Zn²⁺, K(ATP) channels, and somatostatin. Closure of K(ATP) channels controls glucagon secretion by two mechanisms, a direct stimulation of α-cells and an indirect inhibition via somatostatin released from δ-cells. The net effect on glucagon release results from a balance between both effects.
authors: Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors: Rui
authors: R
authors: Cheng-Xue
authors: Ana
authors: A
authors: Gómez-Ruiz
authors: Nancy
authors: N
authors: Antoine
authors: Laura A
authors: LA
authors: Noël
authors: Hee-Young
authors: HY
authors: Chae
authors: Magalie A
authors: MA
authors: Ravier
authors: Fabrice
authors: F
authors: Chimienti
authors: Frans C
authors: FC
authors: Schuit
authors: Patrick
authors: P
authors: Gilon
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D003981:Diazoxide / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009994:Osmolar Concentration; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D064233:Sulfonylurea Receptors; D046509:Tissue Culture Techniques; D014044:Tolbutamide / Q000494:pharmacology*; D000075703:Zinc Transporter 8
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D027682:Cation Transport Proteins; D007004:Hypoglycemic Agents; D054086:KATP Channels; D049990:Membrane Transport Modulators; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C516348:Slc30a8 protein, mouse; D064233:Sulfonylurea Receptors; D000075703:Zinc Transporter 8; D013004:Somatostatin; D005934:Glucagon; D014044:Tolbutamide; D005947:Glucose; D003981:Diazoxide
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