Oxyntomodulin attenuates exendin-4-induced hypoglycemia in cattle.

Oxyntomodulin (OXM), glucagon, glucagon-like peptide-1 (GLP-1), and exendin-4 (Ex-4) are peptide hormones that regulate glucose homeostasis in monogastric and ruminant animals. Recently, we reported that the insulin-releasing effects of OXM and glucagon in cattle are mediated through both GLP-1 and glucagon receptors. The purpose of this study was to examine the mechanisms of the glucoregulatory actions induced by Ex-4, GLP-1, OXM, and glucagon and the interrelationships among these hormones in cattle. Two experiments were performed in Holstein cattle. In Experiment 1, we initially assessed the effects of intravenous (iv) bolus injection of 0, 0.25, 1, and 2 μg/kg body weight (BW) of Ex-4, GLP-1, and OXM on insulin and glucose concentrations in 3-mo-old intact male Holstein calves. In Experiment 2, we studied insulin and glucose responses to iv coinjection of 0.25 μg of Ex-4 or GLP-1/kg BW with 2 μg of OXM or glucagon/kg BW in 4-mo-old Holstein steers. Administration of peptides and blood sampling were done via a jugular catheter. Plasma was separated and the concentrations of peptides and glucose in plasma were analyzed using radioimmunoassay and enzymatic methods, respectively. Results showed that the potent glucoregulatory action of Ex-4 in 4-mo-old steers was delayed and attenuated when Ex-4 was coinjected with OXM. The decline in plasma glucose concentrations began at 5 min in the Ex-4-injected group (P < 0.05) vs 15 min in the Ex-4 + OXM-injected group (P < 0.05). Plasma concentrations of glucose at 30 min were reduced 26% from basal concentrations in the Ex-4-injected group and 13% in the Ex-4 + OXM-injected group (P < 0.001). Results also showed that the glucose concentrations initially increased in the Ex-4 + glucagon-treated group, but declined to a relatively hypoglycemic condition by 90 to 120 min. In contrast, the glucose concentrations at specific time points between the GLP-1 + OXM-injected group and the OXM-injected group did not differ. Similarly, the glucose concentrations in the GLP-1 + glucagon-injected group did not differ from those in the glucagon-injected group. Because OXM and glucagon mediate glucose concentrations via the glucagon receptor, it is suggested that the potent glucose-lowering action of Ex-4 might include the glucagon receptor antagonistic action of Ex-4.