The quantitative insulin response to glucose stimulus can be drastically reduced by subtotal pancreatectomy. An 80% pancreatectomy was performed preserving the pancreatic duct in seven dogs. The insulin output into the portal vein and cephalic vein insulin after intravenous glucose challenge were measured. Output was recorded in 25 controls, and before and 2 wk after subtotal pancreatectomy in the seven animals. Histologic sections of the original resection were compared with the remnant of pancreas taken at the end of the study. In this model, which approaches islet cell failure in terms of glucose homeostasis, the tactics that permit enhancement of islet function can be discerned and to some degree quantitated. The pancreatic remnant does not oversecrete to approximate normal function, although glucose sensitivity is somewhat enhanced. No beta-cell hyperplasia was seen. Despite low insulin output into the portal vein, systemic insulin levels are conserved. This decrease in the plasma clearance of insulin supports glucose homeostasis. Accommodation to severe islet reduction occurs via both intrapancreatic and, more importantly, extrapancreatic mechanisms.