Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.
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.
Jacobson
Peer B
PB
Department of Metabolic Disease Research, Abbott Laboratories, R47M, AP10-111, 100 Abbott Park Rd., Abbott Park, IL 60064, USA. peer.b.jacobson@abbott.com
von Geldern
Thomas W
TW
Ohman
Lars
L
Osterland
Marie
M
Wang
Jiahong
J
Zinker
Bradley
B
Wilcox
Denise
D
Nguyen
Phong T
PT
Mika
Amanda
A
Fung
Steven
S
Fey
Thomas
T
Goos-Nilsson
Annika
A
Grynfarb
Marlena
M
Barkhem
Tomas
T
Marsh
Kennan
K
Beno
David W A
DW
Nga-Nguyen
Bach
B
Kym
Philip R
PR
Link
James T
JT
Tu
Noah
N
Edgerton
Dale S
DS
Cherrington
Alan
A
Efendic
Suad
S
Lane
Benjamin C
BC
Opgenorth
Terry J
TJ
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
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