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.

Glucagon-like peptide-1 inhibits insulinotropic effects of oxyntomodulin and glucagon in cattle.

Oxyntomodulin (OXM), glucagon, and glucagon-like peptide-1 (GLP-1), peptide hormones derived from the glucagon gene, play an important role in glucose homeostasis. The insulinotropic action of these three homologous peptides has been well documented in monogastric animals. However, information on the relationships among these peptides in insulin-releasing action, specifically in ruminants, is still insufficient. In this regard, we carried out two experiments in cattle. In experiment 1, effects of glucagon and GLP-1 on plasma insulin and glucose were investigated in 10-mo-old Holstein steers (347 ± 8 kg, n = 8) under normoglycemic conditions. Peptides were administered intravenously at dose rates of 0.12, 0.25, 0.50, and 1.25 nmol/kg body weight (BW). In experiment 2, the relationships among OXM, glucagon, and GLP-1 in the insulinotropic and glucoregulatory actions were elucidated in 3-mo-old Holstein steers (94 ± 2 kg, n = 8) using agonist-antagonist strategy. In agonist strategy, these three peptides were administered alone or coadministered at dose rates of 10 µg of OXM/kg BW, 4 µg of glucagon/kg BW, and 2 µg of GLP-1/kg BW. In antagonist strategy, 2 µg of each peptide was administered alone or in combination with 10 µg of [des His1, des Phe6, Glu9] glucagon amide (a glucagon receptor antagonist) or exendin-4 (5-39) amide (a GLP-1 receptor antagonist). Our results showed that OXM, glucagon, and GLP-1 had insulinotropic actions in ruminants under normoglycemic conditions. Our results also showed that the insulin-releasing effects of OXM and glucagon were mediated through both GLP-1 receptors (GLP-1R) and glucagon receptors. These insulinotropic effects of OXM and glucagon through GLP-1R were inhibited by GLP-1. Our findings expand the relationships among OXM, glucagon, and GLP-1 in the insulinotropic and glucoregulatory actions.