This study was designed to evaluate whether chronic deficiency of pancreatic glucagon in patients with diabetes secondary to total pancreatectomy (PX) is responsible for the commonly observed increase in blood concentrations of gluconeogenic precursors (alanine, lactate, and pyruvate). Seven PX patients were studied on two different occasions: 1) after an overnight insulin infusion (0.15 mU/kg.min) and 2) after an overnight insulin/glucagon infusion (2 ng/kg.min). Five type 1 diabetic individuals were also studied after a similar overnight insulin infusion. In the morning of each study day, [6-3H]glucose and [1-14C]glucose were rapidly injected for determination of total glucose turnover rate [( 6-3H]glucose) and glucose recycling (difference between [6-3H]glucose and [1-14C]glucose turnover rate). Basal concentrations of hormones, glucose, and intermediary metabolites were measured. After overnight insulin infusion, plasma glucose concentration (3.8 +/- 0.4 vs. 6.8 +/- 1.4 mmol/L), turnover rate (8.4 +/- 1.0 vs. 13.7 +/- 1.9 mumol/kg.min), and percent glucose recycling (5.6 +/- 3.9% vs. 19.0 +/- 3.8%) were significantly lower in PX patients than in type 1 diabetic individuals (P less than 0.05-0.01). On the contrary, blood alanine (459 +/- 93 vs. 263 +/- 28 mumol/L), lactate (1157 +/- 109 vs. 818 +/- 116 mumol/L), and pyruvate (71 +/- 8 vs. 42 +/- 3 mumol/L) were significantly higher than those values in type 1 diabetic patients (P less than 0.05-0.01). Insulin/glucagon infusion increased plasma glucose concentration (8.7 +/- 1.5 mmol/L), total turnover (18.1 +/- 1.7 mumol/kg.min), and percent recycling (20.4 +/- 6.6%) to values similar to those in type 1 diabetic subjects. The change in glucose metabolism was associated with a significant drop in blood concentrations of alanine (179 +/- 24 mumol/L), lactate (611 +/- 25 mumol/L), and pyruvate (30 +/- 3 mumol/L; all P less than 0.05-0.01 vs. insulin infusion alone). In PX patients, the glucose turnover rate was inversely correlated with blood concentrations of both alanine (r = 0.67) and lactate (r = 0.71; P less than 0.01). In conclusion, chronic deficiency of pancreatic glucagon in PX patients 1) is associated with a decreased rate of glucose turnover, 2) causes a marked impairment in glucose recycling (an index of the activity of hepatic gluconeogenesis), and 3) increases blood concentrations of alanine, lactate, and pyruvate. All abnormalities are reversed by glucagon.