Oxyntomodulin analog and exendin-4 derivative lower plasma glucose in cattle.

The present study was undertaken with the aim of examining whether and how exendin-4 (1-3) fragment, ie, Ex-4 (1-3) fragment, contributes to the regulation of glucose. An analog of oxyntomodulin (OXM) ([Gly2, Glu3]-OXM), a glucagon analog ([Gly2, Glu3]-glucagon), and two derivatives of Ex-4 (glucandin and [Gly2, Glu3]-glucandin) were synthesized by substituting with Gly2, Glu3 at the N-terminuses of OXM and glucagon and/or by attaching Ex-4 (30-39) amide at the C-terminus of glucagon. Effects of these peptides on plasma insulin and glucose concentrations were investigated in cattle by conducting 3 in vivo experiments. In all 3 experiments, 0.1% BSA saline was injected as a control. In experiment 1, glucandin (amino acid sequence was glucagon [1-29]-Ex-4 [30-39] amide) and [Gly2, Glu3]-glucandin were injected at the dose rates of 5 µg/kg BW in 4-mo-old Holstein steers. Results showed that glucoregulatory effects of glucandin were similar to those of glucagon. [Gly2, Glu3]-glucandin stimulated insulin secretion at 2 to 10 min and lowered glucose concentrations at 15 to 75 min. Experiment 2 was carried out to better understand the glucose-lowering potency of [Gly2, Glu3]-glucandin, in comparison with Ex-4 and glucagon-like peptide-1 (GLP-1), using 4.5-mo-old Holstein steers. [Gly2, Glu3]-glucandin was injected at dose rates of 0.3 µg/kg BW, 1.0 µg/kg BW, 3.2 µg/kg BW, and 6.4 µg/kg BW. Ex-4 and GLP-1 were injected at dose rates of 0.3 µg/kg BW. Results showed that the insulinotropic and glucose-lowering effects of [Gly2, Glu3]-glucandin were not as potent as for Ex-4 and GLP-1, and the minimum effective dose of [Gly2, Glu3]-glucandin to regulate plasma glucose concentrations was 3.2 µg/kg BW. In experiment 3, [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucagon were injected at dose rates of 5 µg/kg BW in 5-mo-old Holstein steers. Both [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucagon increased insulin concentration. [Gly2, Glu3]-OXM potently lowered plasma glucose, but [Gly2, Glu3]-glucagon did not change it. In summary, our findings clearly demonstrate that Ex-4 (1-3) fragment contributes to the regulation of glucose. [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucandin are insulinotropic and glucose-lowering peptides. It was of interest that the substitution of the first 3 amino acids of OXM with Ex-4 (1-3) could reverse the upregulation of glucose by OXM into downregulation of glucose. In lowering glycemia, [Gly2, Glu3]-OXM seemed almost as effective as Ex-4, and [Gly2, Glu3]-glucandin was less profound than Ex-4. These findings contributed new insights into the hormonal regulation of glucose in ruminants. The action of [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucandin might provide an advantage in glycemic control of insulin resistance in cattle and humans.

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.