To test the hypothesis that short-term insulin therapy may induce long-lasting metabolic improvements in patients with type 2 diabetes resistant to oral therapy, 19 patients were studied before and four weeks after insulin therapy, and again four weeks after resumption of oral medication. The mechanisms associated with changes of glycemic control after discontinuation of insulin therapy were also evaluated. During insulin therapy, blood glucose levels (228 +/- 13 versus 123 +/- 18 mg/dl, p less than 0.001) and the basal glucose production rate (p less than 0.001) decreased, and the insulin secretory response to glucagon at a standardized glucose level, insulin action in vivo, and insulin binding and action in vitro in fat cells improved significantly. During the post-insulin oral therapy, blood glucose levels increased (194 +/- 11 mg/dl, p less than 0.001) but remained below pre-insulin treatment values (p less than 0.01). The mean daily glucose concentration after post-insulin oral therapy correlated with the initial pre-insulin therapy glucose concentration (r = 0.83, p less than 0.001). The improved rate of in vivo glucose disposal and the enhanced insulin secretory response persisted during oral therapy whereas the basal glucose production rate returned to its pre-insulin therapy value. It is concluded that patients with type 2 diabetes in whom oral therapy fails show favorable responses to insulin therapy. After discontinuation of insulin therapy, blood glucose concentrations tend to return to their individual initial values. Therefore, most of these patients require long-term insulin therapy. The mechanism behind the change of glycemic control after cessation of insulin therapy seems to be an increase in the basal glucose production rate rather than deterioration of extrahepatic insulin action or the insulin secretory response.