Role of Glucagon in Enhancing Ketone Body Production in Ketotic Diabetic Man

To assess the role of endogenous glucagon in regulating hepatic ketone body production in ketotic insulinwithdrawn diabetic subjects, ketone body kinetics were determined in two groups of C-peptide-negative diabetics 6 h after interruption of a s.c. insulin infusion. In group 1 (N = 5), glucagon levels were suppressed by infusion of somatostatin (SRIF), whereas in group 2 (N = 6) glucagon was replaced during SRIF by infusing glucagon at 2 ng/kg/min. Ketone body production rates as determined by primed-continuous infusion of [3-¹⁴C]acetoacetate declined from 19.5 ± 0.8 to 16.4 ± 0.4 fimol/kg/min (P < 0.01) during 105 min of SRIF-induced glucagon suppression, whereas they remained unchanged (+ 0.2 ± 0.4 μmol/kg/min, P < 0.01 compared with SRIF) during glucagon replacement. Total ketone body concentrations remained unchanged during SRIF infusion but increased from 2.2 ± 0.3 to 2.9 ± 0.2 mmol/L (P < 0.01) during glucagon replacement. The metabolic clearance rate of total ketone bodies declined significantly (P < 0.01) by 27% and 21% in the two groups. Plasma free fatty acid and glycerol concentrations remained unchanged in both groups whereas plasma glucose decreased by 3.2 ± 0.5 mmol/L during SRIF (P < 0.01). Thus, endogenous glucagon contributed significantly to the maintenance of ketone body production rates in ketotic insulin-deficient diabetics. Since ketogenesis was altered in the absence of changes in free fatty acid levels, the results suggested that glucagon enhanced ketogenesis by an intrahepatic effect.