Nine lean diabetic patients with secondary failure of oral hypoglycemic agents and with a poor residual insulin release under treatment with glibenclamide (15 mg/day) entered a cross-over study, in which ultralente insulin was administered alone or in combination with glibenclamide (15 mg/day). Combined therapy was accompanied by increased serum free-insulin levels and was more effective than glibenclamide alone on daily blood glucose profile, on glycosylated haemoglobin (HbA1C) and on Beta-OH butyrate; in 6 patients a near normalization of blood glucose control (daily blood glucose levels less than 180 mg/dl) occurred. C peptide release, evaluated as daily profile and as response to i.v. glucagon, did not significantly change. When patients received insulin alone, daily blood glucose profile and HbA1C worsened, and serum free-insulin levels and C peptide release decreased, while Beta-OH butyrate levels remained low. These data indicate that combined therapy is effective since it maintains insulin release and enhances free insulin levels in insulinopenic patients. Four responders continued combined therapy for 2 years: the treatment was still effective and was accompanied by an increased C peptide release, probably due to persistent euglycemia.