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.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism
-
Animals
-
Cation Transport Proteins / genetics
-
Cation Transport Proteins / metabolism
-
Crosses, Genetic
-
Diazoxide / pharmacology
-
Glucagon / metabolism*
-
Glucose / metabolism
-
Hypoglycemic Agents / pharmacology*
-
Insulin-Secreting Cells / drug effects*
-
Insulin-Secreting Cells / metabolism
-
Islets of Langerhans / drug effects*
-
Islets of Langerhans / metabolism
-
KATP Channels / agonists
-
KATP Channels / antagonists & inhibitors
-
KATP Channels / metabolism*
-
Membrane Transport Modulators / pharmacology
-
Mice
-
Mice, Knockout
-
Osmolar Concentration
-
Potassium Channel Blockers / pharmacology
-
Potassium Channels, Inwardly Rectifying / genetics
-
Potassium Channels, Inwardly Rectifying / metabolism
-
Receptors, Drug / genetics
-
Receptors, Drug / metabolism
-
Somatostatin / genetics
-
Somatostatin / metabolism
-
Somatostatin-Secreting Cells / drug effects*
-
Somatostatin-Secreting Cells / metabolism
-
Sulfonylurea Receptors
-
Tissue Culture Techniques
-
Tolbutamide / pharmacology*
-
Zinc Transporter 8
Substances
-
ATP-Binding Cassette Transporters
-
Abcc8 protein, mouse
-
Cation Transport Proteins
-
Hypoglycemic Agents
-
KATP Channels
-
Membrane Transport Modulators
-
Potassium Channel Blockers
-
Potassium Channels, Inwardly Rectifying
-
Receptors, Drug
-
Slc30a8 protein, mouse
-
Sulfonylurea Receptors
-
Zinc Transporter 8
-
Somatostatin
-
Glucagon
-
Tolbutamide
-
Glucose
-
Diazoxide