Metabolic clearance rates of oxyntomodulin and glucagon in the rat: contribution of the kidney

Abstract

The half-life ( t 1 2 ) and metabolic clearance rate (MCR) of exogenous natural porcine oxyntomodulin (porcine OXM) and the synthetic analog of rat oxyntomodulin, [Nle 27]-OXM (rat OXM), were compared with that of glucagon in control, sham-operated and acutely nephrectomized rats using the primed-continuous infusion technique. The half-disappearance times for porcine OXM ( 8.2 ± 0.5 min ) and rat OXM ( 6.4 ± 0.5 min ) were 3-fold slower than that of glucagon ( 1.9 ± 0.1 min ). Acute bilateral nephrectomy significantly prolonged the half-disappearance time of rat OXM ( 8.2 ± 0.7 min ) and glucagon ( 3.6 ± 0.4 min ) compared with that of sham-operated animals ( 6.5 ± 0.8 min and 2.5 ± 0.2 min , respectively). The mean MCRs were similar for porcine and rat OXM ( 11.3 ± 0.7 and 11.9 ± 0.5 ml · kg −1 · min −1 ) but were 3 times lower than that measured with glucagon ( 36 ± 5 ml · kg −1 · min −1 ). Bilateral nephrectomy reduced the MCR of OXM and glucagon by 38% and 34%, respectively. No significant increase in C-terminal glucagon immunoreactivity was noticed during infusion of either porcine or rat OXM, measured directly in plasma, with a specific C-terminal glucagon antiserum or after HPLC. In the course of the glucagon infusion, blood glucose was increased 2-fold, while the same dose of porcine OXM or of rat OXM induced only a small increase over the values in phosphate buffer-infused rats. 10 times higher doses of rat OXM were necessary to obtain a similar hyperglycemic effect. These results indicate that: (1) the metabolism of OXM is 3-fold slower than that of glucagon, (2) renal clearance contributed close to 35% of the overall metabolic plasma extraction for OXM and glucagon and (3) OXM, although effective at a higher dose, when compared with glucagon, displays a hyperglycemic effect probably through the glucagon receptors.