title: 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) ([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, Glu3at 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.
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: S
authors.initials: S
authors.lastname: ThanThan
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Asada
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ochiiwa
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
authors.forename: S W
authors.initials: SW
authors.lastname: Naing
authors.affiliation: Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan. Electronic address: fujino@obihiro.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Kuwayama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D002417:Cattle / Q000097:blood*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000097:blood; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D053772:Oxyntomodulin / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D014688:Venoms / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D009842:Oligopeptides; D053772:Oxyntomodulin; D010455:Peptides; D014688:Venoms; C000625524:histidyl-glycyl-glutamic acid; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Exendin-4; Glucagon; Glucandin; Glucose; Insulin; Oxyntomodulin