title: Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.
abstract: Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
authors.affiliation: Department of Metabolic Disease Research, Abbott Laboratories, R47M, AP10-111, 100 Abbott Park Rd., Abbott Park, IL 60064, USA. peer.b.jacobson@abbott.com
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: Lars
authors.initials: L
authors.lastname: Ohman
authors.forename: Marie
authors.initials: M
authors.lastname: Osterland
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Bradley
authors.initials: B
authors.lastname: Zinker
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.forename: Phong T
authors.initials: PT
authors.lastname: Nguyen
authors.forename: Amanda
authors.initials: A
authors.lastname: Mika
authors.forename: Steven
authors.initials: S
authors.lastname: Fung
authors.forename: Thomas
authors.initials: T
authors.lastname: Fey
authors.forename: Annika
authors.initials: A
authors.lastname: Goos-Nilsson
authors.forename: Marlena
authors.initials: M
authors.lastname: Grynfarb
authors.forename: Tomas
authors.initials: T
authors.lastname: Barkhem
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Bach
authors.initials: B
authors.lastname: Nga-Nguyen
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: James T
authors.initials: JT
authors.lastname: Link
authors.forename: Noah
authors.initials: N
authors.lastname: Tu
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.forename: Alan
authors.initials: A
authors.lastname: Cherrington
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lane
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002793:Cholic Acids / Q000378:metabolism / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D004285:Dogs; D004357:Drug Synergism; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014444:Tyrosine Transaminase / Q000378:metabolism
chemical_list: C503101:(3b,5b,7a,12a)-7,12-dihydroxy-3-(2-((4-((11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl) phenyl)(methyl)amino)ethoxy)cholan-24-oic acid; D001786:Blood Glucose; D002793:Cholic Acids; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004970:Estrone; D011239:Prednisolone; D014444:Tyrosine Transaminase; D005974:Glutamate-Ammonia Ligase; D005947:Glucose