title: Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors.
abstract: Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2'-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic beta cell function.
authors.affiliation: Endocrine Discovery, Eli Lilly and Company, Indianapolis, Indiana, USA. sloop_kyle_w@lilly.com
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
authors.forename: Julia Xiao-Chun
authors.initials: JX
authors.lastname: Cao
authors.forename: Angela M
authors.initials: AM
authors.lastname: Siesky
authors.forename: Hong Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Diane M
authors.initials: DM
authors.lastname: Bodenmiller
authors.forename: Amy L
authors.initials: AL
authors.lastname: Cox
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jacobs
authors.forename: Julie S
authors.initials: JS
authors.lastname: Moyers
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Owens
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Showalter
authors.forename: Martin B
authors.initials: MB
authors.lastname: Brenner
authors.forename: Achim
authors.initials: A
authors.lastname: Raap
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Brian R
authors.initials: BR
authors.lastname: Berridge
authors.forename: David K B
authors.initials: DK
authors.lastname: Monteith
authors.forename: Niels
authors.initials: N
authors.lastname: Porksen
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKay
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Lynnetta M
authors.initials: LM
authors.lastname: Watts
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D008099:Liver / Q000378:metabolism*; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1