In early 1988, a colony of GK rats was started in Paris with progenitors issued from F35 of the original colony reported by Goto and Kakisaki. When studied longitudinally up to 8 mo, GK rats showed as early as 1 mo (weaning) significantly higher basal plasma glucose (9 mM) and insulin levels (doubled), altered glucose tolerance (intravenous glucose), and a very poor insulin secretory response to glucose in vivo compared with Wistar controls. Males and females were similarly affected. Studies of in vitro pancreatic function were carried out with the isolated perfused pancreas preparation. Compared with nondiabetic Wistar rats, GK rats at 2 mo showed a significantly increased basal insulin release, no insulin response to 16 mM glucose, and hyperresponse to 19 mM arginine. Pancreatic insulin stores were only 50% of that in Wistar rats. Perfusion of GK pancreases for 50 or 90 min with buffer containing no glucose partially improved the insulin response to 16 mM glucose and markedly diminished the response to 19 mM arginine, whereas the responses by Wistar pancreases were unchanged. These findings are similar to those reported in rats with non-insulin-dependent diabetes induced by neonatal streptozocin administration and support the concept that chronic elevation in plasma glucose may be responsible, at least in part, for the β-cell desensitization to glucose in this model. The GK rat seems to be a valuable model for identifying the etiology of β-cell desensitization to glucose.