['The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors.', 'Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) recorded in isolated mouse alpha cells.', 'Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K(+), glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K(+) channels. Glucose lowered [Ca(2+)](i) of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn(2+) and gamma-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca(2+)-ATPase, which abolished the [Ca(2+)](i)-lowering effect of glucose on isolated alpha cells.'] Does glucose inhibit glucagon secretion by a direct effect on mouse pancreatic alpha cells?