To determine the effect of isolated beta-cell impairment on glucose turnover, we administered a 46-h infusion of somatostatin (200 micrograms/h) with glucagon replacement (0.75 ng/kg X min) to eight normal men. Fasting plasma insulin levels fell slightly, but significantly, from 8 +/- 2 (+/- SEM; control) to 6 +/- 2 microU/ml 46 h after beginning the infusion (P less than 0.001). Over the same period, fasting plasma glucose rose from 89 +/- 2 to 114 +/- 2 mg/dl (P less than 0.001), and plasma glucagon levels remained unchanged (79 +/- 5 vs. 82 +/- 8 pg/ml P = NS). Glucose turnover was measured by isotope dilution using [3-3H]glucose. The glucose production rate rose consistently from a baseline value of 2.08 +/- 0.04 to 2.45 +/- 0.06 mg/kg X min (P less than 0.01). The glucose disposal rate also rose consistently from 2.11 +/- 0.04 to 2.53 +/- 0.09 mg/kg X min (P less than 0.01). We conclude that prolonged mild selective insulin deficiency produced by infusion of somatostatin with glucagon replacement in normal men causes an elevation of the fasting plasma glucose level, which is maintained by glucose overproduction rather than by glucose underutilization. Overproduction of glucose may also be important in maintaining basal hyperglycemia in patients with noninsulin-dependent diabetes mellitus who have a similar impairment of insulin secretion.