Abstract

Hyperglucagonemia plays an important role in pathogenesis of T2DM. The effect of glucagon on the plasma lipidome has not been studied in humans. We examined the effect of prolonged glucagon infusion on plasma lipid metabolites in healthy subjects. 8 NGT subjects (5M/3F, age=35±5, BMI=24±1, A1c=5.3±0.3%) received 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min). On a different day the subjects returned for a repeat study with infusion (6PM to 6AM) of normal saline. Top-ranking plasma lipidomes were measured by shotgun lipidomics including Phosphatidylethanolamine (PE), Lysophosphatidylethanolamine (LPE), Phosphatidylcholine (PC), Lysophosphatidylcholine (LPC), Ceramide (CER), Sphingomyelin (SM), Acylcarnitine (AC), Phosphatidylglycerol (PG), Phosphatidylinositol (PI), Phosphatidylserine (PS), Triacylglycerol (TAG), Fatty Acyl Chains in TAG (FA). Plasma glucagon increased from 57±3 to 219±21 pg/ml. Plasma insulin increased significantly following glucagon compared to saline (20±7 vs. 8±3 mU/L, p<0.05) and remained elevated. Plasma LPE, PC, LPC, CER, SM, FFA, AC increased, plasma PE, PS declined, and PG, PI, FA did not change following 12-hour glucagon infusion. The greatest increase occurred with Lysophosphatidylcholine (LPC, 18:2) which rose ∼2.5 fold (126±11 vs. 51±7 nmol/ml, p<0.005) following glucagon infusion. LPCs and LPEs are generated after activation of phospholipase A2, along with the release of fatty acids, and have been reported to induce inflammation and the effector of fatty acid induced insulin resistance. On the other hand, reduced PE is observed in animal models of obesity, supporting its role as a substrate of phospholipase A2 activation. Increased ceramide levels also have been shown to incite inflammation. In conclusion, prolonged glucagon infusion modulates novel lipid metabolites involved in inflammation and represents a fundamental mechanism by which glucagon activates inflammation pathways, contributing to insulin resistance. Disclosure X. Chen: None. X. Han: None. J. Trejo: None. E. Case: None. R.A. DeFronzo: None. D. Tripathy: None. Funding Foundation for Advancement of Veteran’s Health and Research

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call