title: Glucagon receptor antagonism induces increased cholesterol absorption.
abstract: Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Guan
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Ku
authors.initials: K
authors.lastname: Lu
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Castro-Perez
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Stephen
authors.initials: S
authors.lastname: Previs
authors.affiliation: Late Stage In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Vinit
authors.initials: V
authors.lastname: Shah
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Late Stage In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.affiliation: Late Stage In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Jing Chen
authors.initials: JC
authors.lastname: Xiao
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Sun
authors.affiliation: Clinical Research Department, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Andryuk
authors.affiliation: Clinical Research Department, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Engel
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: David E
authors.initials: DE
authors.lastname: Kelley
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Davis
authors.affiliation: Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D015091:beta-Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D009281:Naphthalenes
chemical_list: D002784:Cholesterol; D011720:Pyrazoles; D018027:Receptors, Glucagon; D015091:beta-Alanine; C575263:N-((4-(1-(3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl)ethyl)phenyl)carbonyl)-beta-alanine; D009281:Naphthalenes
keywords: bile acids; cholesterol/absorption; diabetes; glucagon receptor antagonist; glucagon-like peptide 2; hypercholesterolemia