There has been much debate about whether glucagon secretion is controlled by intrinsic properties of alpha cells or by paracrine suppression by beta and delta cells because it has been difficult to observe appropriate reduction of secretion in isolated alpha cells. We have previously published a model for the intrinsic response (Biophys. J. 2014 106:741) and confirmed the hypothesis of Rorsman and colleagues that glucose sensing can occur by closure of KATP channels, which inactivates Na+ and Ca2+ channels.  However, the response to glucose is bell-shaped, so either suppression or stimulation can be exhibited depending on KATP expression levels in each cell.  We show now with a tri-hormone islet model that this problem can be solved by paracrine interactions: glucose stimulates insulin and somatostatin secretion, which suppress those alpha cells that would otherwise be active at high glucose.  The model suggests that somatostatin plays the more critical role as it always suppresses secretion, whereas insulin may suppress or stimulate, depending on the state of the individual cell.  The model thus accounts for both the heterogeneity observed in isolated alpha cells and the appropriate stereotypical behavior of the intact islet. * Joint work with Margaret Watts