Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors.
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.
Sloop
Kyle W
KW
Endocrine Discovery, Eli Lilly and Company, Indianapolis, Indiana, USA. sloop_kyle_w@lilly.com
Cao
Julia Xiao-Chun
JX
Siesky
Angela M
AM
Zhang
Hong Yan
HY
Bodenmiller
Diane M
DM
Cox
Amy L
AL
Jacobs
Steven J
SJ
Moyers
Julie S
JS
Owens
Rebecca A
RA
Showalter
Aaron D
AD
Brenner
Martin B
MB
Raap
Achim
A
Gromada
Jesper
J
Berridge
Brian R
BR
Monteith
David K B
DK
Porksen
Niels
N
McKay
Robert A
RA
Monia
Brett P
BP
Bhanot
Sanjay
S
Watts
Lynnetta M
LM
Michael
M Dodson
MD
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*
D001786:Blood Glucose; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1