Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism.

The metabolism of exogenously infused porcine insulin and glucagon was assessed concurrently in normal fasted dogs under anaesthesia. Hepatic and renal extraction of glucagon were 25.6 +/- 2.3 and 43.7 +/- 3.9%, respectively, and its metabolic clearance 16.5 +/- 0.8 ml/kg/min. Hepatic and renal extraction accounted for 28.5 +/- 4.2 and 28.7 +/- 3.7% of total glucagon clearance, respectively. Insulin MCR was 18.3 +/- 1.5 ml/kg/min and its hepatic and renal extraction were 49.6 +/- 3.4 and 41.7 +/- 4.4% accounting for 51.9 +/- 4.4 and 27.3 +/- 3.9% of total insulin clearance, respectively. Neither total glucagon metabolic clearance nor its hepatic or renal components saturated even in the face of circulating glucagon levels extending into the pharmacologic range up to 14 ng/ml. In contrast however, with increasing arterial concentrations of insulin, saturability of metabolism was apparent as evidenced by significant reductions in MCR as well as hepatic and renal extraction. This demonstration of saturability of hepatic insulin metabolism occurred at levels encountered in the portal vein after meals and is compatible with the concept that the hepatic capacity for extraction of this hormone may be an important site of control of the proportion of secreted insulin reaching the periphery. The metabolic handling of each hormone was shown to be independent of the other. Despite similarities in the interaction of insulin and glucagon with the target cell, there are important differences in the mechanisms of metabolism of these peptides as the major degradative sites.