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

Abstract 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) ([Gly 2 , Glu 3 ]-OXM), a glucagon analog ([Gly 2 , Glu 3 ]-glucagon), and two derivatives of Ex-4 (glucandin and [Gly 2 , Glu 3 ]-glucandin) were synthesized by substituting with Gly 2 , Glu 3 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 [Gly 2 , Glu 3 ]-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. [Gly 2 , Glu 3 ]-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 [Gly 2 , Glu 3 ]-glucandin, in comparison with Ex-4 and glucagon-like peptide-1 (GLP-1), using 4.5-mo-old Holstein steers. [Gly 2 , Glu 3 ]-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 [Gly 2 , Glu 3 ]-glucandin were not as potent as for Ex-4 and GLP-1, and the minimum effective dose of [Gly 2 , Glu 3 ]-glucandin to regulate plasma glucose concentrations was 3.2 μg/kg BW. In experiment 3, [Gly 2 , Glu 3 ]-OXM and [Gly 2 , Glu 3 ]-glucagon were injected at dose rates of 5 μg/kg BW in 5-mo-old Holstein steers. Both [Gly 2 , Glu 3 ]-OXM and [Gly 2 , Glu 3 ]-glucagon increased insulin concentration. [Gly 2 , Glu 3 ]-OXM potently lowered plasma glucose, but [Gly 2 , Glu 3 ]-glucagon did not change it. In summary, our findings clearly demonstrate that Ex-4 (1–3) fragment contributes to the regulation of glucose. [Gly 2 , Glu 3 ]-OXM and [Gly 2 , Glu 3 ]-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, [Gly 2 , Glu 3 ]-OXM seemed almost as effective as Ex-4, and [Gly 2 , Glu 3 ]-glucandin was less profound than Ex-4. These findings contributed new insights into the hormonal regulation of glucose in ruminants. The action of [Gly 2 , Glu 3 ]-OXM and [Gly 2 , Glu 3 ]-glucandin might provide an advantage in glycemic control of insulin resistance in cattle and humans.