(A) Responses of insulin and glucagon to minor changes in glucose perfused into isolated pancreata of normal dogs. The perfusate glucose concentration varied from 60 to 90 mg/dl. Modest changes in the perfusing glucose concentration led to major reciprocal responses of both insulin and glucagon. Figure adapted with permission from Diabetologia (38). (B) Demonstration that a rise in glucose “paradoxically” stimulates glucagon secretion when it is not accompanied by the rise in insulin that normally accompanies elevations in glucose concentration. Figure adapted from Journal of Clinical Investigation (43). (C) Topographic scheme of a normal human islet showing the extensive juxtaposition of β cells (red) to α cells (green) that facilitates instantaneous insulin control of glucagon secretion via the interstitial space separating the two cells. Scale bar: 50 μm. Figure reproduced with permission from Diabetes (48). (D) Direct physiologic evidence of the paracrine role of insulin on α cell function in rodents. The isolated pancreata of normal rats are perfused with either nonimmune serum, as control, or a potent anti-insulin serum. The sudden rise in glucagon upon infusion of the anti-insulin serum indicates an ongoing paracrine inhibition of glucagon secretion by the insulin in the islets. Figure adapted from Journal of Clinical Investigation (53).