1332-P: Increased and Decreased Glucagon Receptor Signaling Respectively Enhances and Impairs Triglyceride Metabolism Acutely and Chronically

Abstract

Listen

Translate article

Glucagon receptor antagonists (GRAs) reduce blood glucose in subjects with type 2 diabetes (T2D) but may cause dyslipidemia. Increased plasma triglyceride (TG) levels in patients with T2D are thought to be caused partly by insulin resistance but it is unknown if altered glucagon receptor (GCGR) signaling contributes. We investigated the effects of chronic GCGR inhibition and activation on plasma TG and cholesterol levels during an 180 min oral lipid tolerance test (µL/g body weight olive oil; OLTT) in GCGR knockout (Gcgr-/-) mice, and in C57Bl/6JRj mice treated with a GCGR antibody (GCGR Ab, REGN1193, Regeneron) or a long-acting glucagon analogue (GCGA, NNC9204-0043, Novo Nordisk A/S) . Plasma TG levels increased 3-fold in Gcgr-/- mice compared to wild-type littermates (Gcgr+/+) during the OLTT. Eight weeks treatment with GCGR Ab increased plasma TG levels during OLTTs by 39% whereas GCGA reduced levels by 39%. Low-density lipoprotein levels, estimated using fast protein liquid chromatography, were increased in Gcgr-/- mice and GCGR Ab treated mice, whereas GCGA treatment lowered very-low density lipoprotein levels. We next investigated the effects of acute GCGR inhibition and activation; a single treatment with GRA (25-2648, Novo Nordisk A/S) and GCGA respectively increased and decreased TG levels by 55% and 32% during OLTTs. Our study suggests that impaired and increased GCGR signaling respectively impairs and accelerates TG metabolism, chronically and acutely, in female mice. We were unable to identify GCGR in adipocytes using autoradiography and immunohistochemistry and our data thus implicate that glucagon has acute and chronic effects on intestinal lipid uptake and/or acts to enhance hepatic lipid metabolism in mice. Thus, impaired actions of glucagon may cause hypertriglyceridemia, while enhancing GCGR signaling may benefit subjects with dyslipidemia. Disclosure K.D.Galsgaard: None. E.E.Christensen: None. A.B.Bomholt: None. J.Hunt: None. T.Kruse: Employee; Novo Nordisk. J.F.Lau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Christoffersen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Merck & Co., Inc., Mercodia AB. Funding This work was supported by the Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research University of Copenhagen, (NNF Application Number: 13563) ; The A.P. Møller Foundation; NNF Tandem Programme (NNF Application Number: 31526) ; NNF Project Support in Endocrinology and Metabolism–Nordic Region (NNF Application Number: 34250) . Nicolai J. Wewer Albrechtsen were financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude. Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (grant agreement NNF14CC0001) .