GLP‐1 Induces a Shift in Primary Carbon Metabolites in Late‐fasted Northern Elephant Seals

• Published in: The FASEB Journal
• Main Authors: Dhillon, Jaapna, Viscarra, Jose A., Fiehn, Oliver, Ortiz, Rudy M.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2020
• Subjects: Elephant Seals
• Online Access: http://dx.doi.org/10.1096/fasebj.2020.34.s1.09499; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1096%2Ffasebj.2020.34.s1.09499; http://onlinelibrary.wiley.com/wol1/doi/10.1096/fasebj.2020.34.s1.09499/fullpdf

Insulin resistance has been suggested to be an adaptive response to food deprivation since it promotes the preservation of glucose and oxidation of fat. However, the insulin resistance‐like conditions that fasting mammals experience may result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. Glucagon‐like peptide 1 (GLP‐1) is a gastrointestinal hormone that enhances postprandial glucose‐stimulated insulin secretion. To better assess the effects of GLP‐1 on the metabolism of primary carbon metabolites associated with late‐fasting induced insulin resistance, we dose‐dependently infused late‐fasted seals (naturally adapted to prolonged fasting) with low (10 pM/kg; n=3) or high (100 pM/kg; n=4) GLP‐1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP‐1 as control (n=5). The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions and areas under the curve (AUC) were calculated. The median AUC fold changes between the GLP‐1‐treated (low and high doses combined) and control group were analyzed using ChemRICH which is a chemical similarity enrichment analysis software for metabolomics datasets that uses medical subject headings and Tanimoto substructure chemical similarity coefficients to cluster metabolites into non‐overlapping chemical groups. Statistically significant p‐values for clusters were obtained by self‐contained Kolmogorov–Smirnov tests. ChemRich mapped 149 of the identified metabolites to 23 nonoverlapping chemical classes, of which 2 were found to be significantly different between the GLP‐1‐treated and control group (false discovery rate adjusted P value < 0.05). Treatment with GLP‐1 infusions was associated with altered Kreb Cycle activity represented by increased levels of tricarboxylic acids, and reduced levels of carbocyclic acids (benzoic acid being a key compound). Hence, GLP‐1 infusion induced a shift in primary carbon metabolites in a model of fasting‐induced insulin resistance. Support or ...