Skip to main content
ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #331174
Title: Insulin induces a shift in lipid and primary carbon metabolites in a model of fasting-induced insulin resistance

Author
item OLMSTEAD, KEEDRIAN - University Of California
item LAFRANO, MICHAEL - University Of California
item FAHRMANN, JOHANNES - University Of California
item GRAPOV, DMITRY - University Of California
item VISCARRA, JOSE - University Of California
item Newman, John
item OLIVER, FIEHN - University Of California
item CROCKER, DANIEL - Sonoma State University
item FILIPP, FABIAN - University Of California
item ORTIZ, RUDY - University Of California

Submitted to: Metabolomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/17/2017
Publication Date: 2/20/2017
Citation: Olmstead, K.I., Lafrano, M.R., Fahrmann, J., Grapov, D., Viscarra, J.A., Newman, J.W., Oliver, F., Crocker, D.E., Filipp, F.V., Ortiz, R.M. 2017. Insulin induces a shift in lipid and primary carbon metabolites in a model of fasting-induced insulin resistance. Metabolomics. 13:60. doi: 10.1007/s11306-017-1186-y.

Interpretive Summary: The northern elephant seal (NES) provides a unique natural model of physiological energy regulation. Prolonged fasting associated with the natural lifecycle of the NES is characterized by a reliance on lipid metabolism, conservation of protein, and temporary insulin resistance. During early fasting, glucose infusion reduces plasma free fatty acids (FFA); however, during late-fasting, it induces an atypical elevation in FFA suggesting a shift in tissue response to glucose-stimulated insulin secretion. To better assess this shift in metabolism, we compared the responses of plasma amino acids (AA), FFA, endocannabinoids (EC), and primary carbon metabolites (PCM) to insulin infusion (65 mU/kg) in early- and late-fasted NES pups (n=5/group). Ketone and branched-chain AA metabolism were the most effected pathways. Insulin infusion decreased the total amount of FFA in plasma at both early and late fasting suggesting that insulin suppresses triglyceride hydrolysis. Insulin increased plasma PCM and AA area under the curve (AUC), i.e. the amount of these compounds in the blood over a period of time, in late-fasted seals suggesting an increase in insulin-induced synthesis of small molecules with fasting duration. In early fasting, 72% of metabolites return to baseline levels within 2 hours, but in late fasting they do not decline as fast indicating an increase in tissue sensitivity to insulin. In late-fasting, increases in FFA and ketone pools, coupled with decreases in AA and PCM, indicate a shift toward lipolysis, beta-oxidation, ketone metabolism, and decreased protein catabolism. Conversely, insulin increased PCM AUC in late fasting suggesting that gluconeogenic pathways are activated. Together these metabolic changes suggest that naturally adapted tolerance to prolonged fasting in these mammals is accomplished by suppressing insulin levels and activity, providing novel insight into the evolution of insulin resistance during temporary but dramatic periods of caloric restriction.

Technical Abstract: Peripheral insulin resistance shifts metabolic fuel use away from carbohydrates, and towards lipids, and is most commonly associated with Type 2 diabetes mellitus. However, regulated insulin resistance is an evolved mechanism to preserve glucose for the brain in conditions of high demand or carbohydrate restriction. After birth and post weaning northern elephant seal (NES) pups fast for ~1 month while preparing for life at sea. During this time, they live on the energy reserves delivered in mother’s milk, primarily burning fat and reduced glucose clearance, while they conserve protein for use in growth. This study was conducted to better understand the insulin-associated changes in metabolism in this unique physiological model of energy regulation. Early in the fast, glucose infusion reduced plasma free fatty acids (FFA), but during late-fasting, it induces elevated FFA demonstrating a change in tissue response to glucose-stimulated insulin secretion. To better assess this shift in metabolism, we compared the responses of fuels (i.e. FFAs; plasma amino acids; [AA]), components of central energy metabolism (i.e. primary carbon metabolites; PCM) and appetite/fuel use regulators (i.e. endocannabinoids [EC]) to insulin infusion (65 mU/kg) in early- and late-fasted NES pups (n=5/group). Insulin infusion decreased the total FFAs in plasma at both times suggesting that insulin action to suppress lipolysis is unaffected. Ketone and branched-chain AA metabolism were the most effected pathways. Insulin infusion increased plasma concentrations of PCM and AA in late- but not early-fasted seals suggesting an increase in insulin-induced synthesis of non-lipid small molecule fuels with fasting duration. In early fasting, 72% of metabolites altered by insulin infusion returned to baseline levels within 2 hours, but this recovery was delayed in late-fasting pups indicating an increase in tissue sensitivity to insulin. In late-fasting NES pups, increases in FFA and ketone pools, coupled with decreases in AA and PCM, indicate a shift toward lipolysis, beta-oxidation, ketone metabolism, and decreased protein catabolism. Conversely, their late-fasting response to insulin infusion including an increase in PCM suggesting that gluconeogenic pathways are activated. Together these metabolic changes suggest that naturally adapted tolerance to prolonged fasting in these mammals is accomplished by suppressing insulin levels and activity, providing novel insight into the evolution of insulin resistance during temporary but dramatic periods of caloric restriction.