Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose

Abstract

We evaluated the role of ATP-sensitive K+ (KATP) 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 KATP 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 KATP 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+, KATP channels, and somatostatin. Closure of KATP 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.

Zinc, insulin, and the liver: a ménage à trois

“…However, Tamaki et al did not observe any difference in glucagon secretion in the Slc30a8-KO mice. Together with prior studies (8), these data suggest that the Zn 2+ cosecreted with insulin is not responsible for the suppressive effect of insulin secretion on glucagon secretion.…”

“…Slc30a8 deletion in mice decreases DCV Zn 2+ content (4,(7)(8)(9). A role for decreased Zn 2+ in DCV functional defects is not obvious, because some species (e.g., guinea pig) produce insulin molecules that do not bind to Zn 2+ but still maintain normal insulin secretion.…”

Paracrine control of glucagon release by somatostatin (Review)

“…In two articles recently published in Diabetes, emphasis was placed on the modulation of glucagon secretion attributable to a paracrine effect of somatostatin under selected experimental conditions (1,2). In the present review, attention is drawn to prior publications compatible with such a view, but not cited in the two recent articles.…”

ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

“…The findings that glucose remains capable of inhibiting glucagon secretion in somatostatin-deficient islets [19] and in the presence of somatostatin receptor antagonists [20] also suggest that somatostatin released by the delta cells does not function as a 'switch-off' signal for glucagon release. Collectively, these data provide little evidence of a paracrine regulation of glucagon secretion by insulin at glucose concentrations at or below the threshold for stimulation of insulin or somatostatin release (6 mmol/l).…”