Specific reduction of hepatic glucose 6-phosphate transporter-1 ameliorates diabetes while avoiding complications of glycogen storage disease.
D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2'-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASO-treated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.
Sloop
Kyle W
KW
Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. sloop_kyle_w@lilly.com
Showalter
Aaron D
AD
Cox
Amy L
AL
Cao
Julia X C
JX
Siesky
Angela M
AM
Zhang
Hong Yan
HY
Irizarry
Armando R
AR
Murray
Susan F
SF
Booten
Sheri L
SL
Finger
Eleftheria A
EA
McKay
Robert A
RA
Monia
Brett P
BP
Bhanot
Sanjay
S
Michael
M Dodson
MD
D000140:Acidosis, Lactic / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D001786:Blood Glucose / Q000096:biosynthesis / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000628:therapy*; D005934:Glucagon / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000378:metabolism / Q000517:prevention & control*; D006949:Hyperlipidemias / Q000378:metabolism / Q000517:prevention & control; D033461:Hyperuricemia / Q000378:metabolism / Q000517:prevention & control; D007003:Hypoglycemia / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
D017920:Antiporters; D001786:Blood Glucose; D009004:Monosaccharide Transport Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; C111261:glucose 6-phosphate(transporter); D006003:Glycogen; D005934:Glucagon; D005952:Glucose-6-Phosphatase