Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose: Involvement of KATP Channels From Both-Cells and-Cells
(2013) Diabetes — Vol. 62, n° 5, p. 1612-1622 (2013)
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- 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.
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Cheng-Xue, R., Gomez-Ruiz, A., Antoine, N., Noel, L. A., Chae, H.-Y., Ravier, M. A., Chimienti, F., Schuit, F. C., & Gilon, P. (2013). Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose: Involvement of KATP Channels From Both-Cells and-Cells. Diabetes, 62(5), 1612-1622. https://doi.org/10.2337/db12-0347 (Original work published 2013)