Models of the mechanisms by which sulfonylureas and glucose control glucagon release. Models of the mechanisms by which sulfonylureas and glucose control glucagon release. A: Sulfonylureas control glucagon release by two mechanisms. Left: They directly stimulate glucagon secretion by inhibiting KATP channels of the α-cells. This is well illustrated by the glucagonotropic effect that the sulfonylureas exert in the absence of the paracrine influence of SST (PTx pretreatment or Sst−/− mice). Right: They indirectly inhibit glucagon release by stimulating the release of SST from δ-cells, which will bind to SSTR2 and SSTR3 in α-cells. This is illustrated by the glucagonostatic effect that they produce in control islets or the perfused pancreas in the presence of a low glucose concentration. The net effect of glucagon release results from a balance between these direct stimulatory and indirect inhibitory effects. B: Glucose inhibits glucagon secretion by two mechanisms that are differently recruited depending on the concentration of the sugar. Left: Glucose inhibits, already at low concentrations, glucagon release by activating an unknown mechanism that is maybe intrinsic to α-cells and that is independent of KATP channels. This is illustrated by the glucagonostatic effect that the sugar produces in the absence of the paracrine influence of SST (PTx pretreatment or Sst−/− mice). Right: Glucose also stimulates the release of SST that, by binding to SSTR2 and SSTR3 in α-cells, inhibits glucagon secretion. This is illustrated by the dose-dependent glucagonostatic effect produced by glucose in control islets. This diagram does not illustrate the mechanisms by which high glucose concentrations (>10 mmol/L) stimulate glucagon release in the absence of the paracrine influence of SST. Since this effect is not observed in KATP channel knockout mice, it might result from an inhibition of these channels. Bao-Khanh Lai et al. Diabetes 2018;67:2239-2253 ©2018 by American Diabetes Association