Insulin-independent actions of glucagon-like peptide-1 (GLP-1) are not yet clear in ruminants. Four Suffolk mature wethers (60.0 ± 6.7 kg body weight (BW)) were intravenously infused with insulin (0.5 mU/kg BW/min; from 0 to 90 min) and GLP-1 (0.5 μg/kg BW/min; from 60 to 150 min) with both hormones co-administered from 60 to 90 min, in a repeated-measure design under euglycemic clamp for 150 min, to investigate whether GLP-1 has insulin-independent actions. Jugular blood samples were taken at 15-min intervals for plasma hormones and metabolites analysis. Compared to baseline concentrations (at 0 min), insulin infusion decreased (P < 0.05) plasma concentrations of glucagon, non-esterified fatty acids (NEFA), lactate, nonessential amino acids (NEAA), branched-chain amino acids (BCAA), total amino acids (TAA) and urea nitrogen (UN). Insulin plus GLP-1 infusion induced a greater increase (P < 0.05) in plasma concentrations of insulin and triglyceride (TG), but decreased (P < 0.05) glucagon, total cholesterol (T-Cho), NEAA and UN plasma concentrations. GLP-1 infusion increased (P < 0.05) NEFA, β-hydroxybutyrate and TG, but decreased (P < 0.05) glucagon, T-Cho, NEAA, BCAA and UN plasma concentrations. In conclusion, GLP-1 exerts extrapancreatic roles in ruminants not only insulin-independent but probably, in contrast to non-ruminants, antagonistic to insulin effects.

Glucagon-like peptide 1 (GLP-1) and ghrelin have opposite regulatory effects on glucose metabolism in non-ruminants. However, mechanisms by which GLP-1 and ghrelin regulate nutrient partitioning, particularly in the liver, have been much less demonstrated in ruminants. A novel metabolomic method based on capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) combined with multivariate statistical analysis was applied to address the GLP-1 and ghrelin-induced metabolic changes in the liver of steers. Three Holstein steers (400 ± 5.0 kg LW) fed a maintenance diet according to Japanese feeding standards were randomly assigned to three treatments (GLP-1, ghrelin and saline) in a 3 × 3 Latin square design with one week apart. Liver biopsies were taken 30 min after a single injection (1.0 μg/kg LW) of GLP-1 or ghrelin, and analysed for metabolites by Agilent CE-TOFMS system. Also, blood samples were collected for plasma hormones analysis. Results indicated that 20 and 10 liver metabolites were altered (P < 0.05) by GLP-1 and ghrelin, respectively. Pathway analysis showed that GLP-1 is involved in biochemical pathways related to glycolysis/gluconeogenesis, lipogenesis and lipid export from the liver, oxidative stress defence and protein turnover. Ghrelin was shown to be involved in pathways related to glycolysis, protein anabolism and phospholipid biosynthesis. However, plasma concentrations of insulin, growth hormone and glucagon did not differ between treatments. These results imply that GLP-1 and ghrelin are involved in multibiochemical pathways that go beyond simply regulating glucose metabolism. In addition, the effects of GLP-1 and ghrelin may potentially be independent of insulin and growth hormone, respectively.

This study was conducted to identify the insulin-independent actions of glucagon-like peptide-1 (GLP-1 (7-36 amide)) in partitioning nutrient metabolism in ovine liver. Four Suffolk wethers (60.0 ± 6.7 kg body weight (BW)) were used in a repeated-measure design under euglycemic--hyperinsulinemic and hyper -GLP-1 clamps for 150 min with intravenous infusion of insulin (0.5 mU/kg BW/min; from 0 to 90 min), GLP-1 (0.5 µg/kg BW/min; from 60 to 150 min) and both hormones co-administered from 60 to 90 min. Liver biopsies were collected at 0, 60, 90 and 150 min to represent the metabolomic profiling of baseline, insulin, insulin plus GLP-1, and GLP-1, respectively, and were analyzed for metabolites using Capillary Electrophoresis Time-of-Flight Mass Spectrometer. Metabolomics analysis reveals 51 metabolites as being significantly altered (P < 0.05) by insulin and GLP-1 infusion compared to baseline values. Insulin infusion enhanced glycolysis, lipogenesis, oxidative stress defense and cell proliferation pathways, but reduced protein breakdown, gluconeogenesis and ketogenesis pathways. Conversely, GLP-1 infusion promoted lipolytic and ketogenic pathways accompanied by a lowered lipid clearance from the liver as well as elevated oxidative stress defense and nucleotide degradation. Despite further research still being warranted, our data suggest that GLP-1 may exert insulin-antagonistic effects on hepatic lipid and nucleotide metabolism in ruminants.