SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.
Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states in type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic gluconeogenesis during fasting through the induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease fasting hyperglycemia in a rat model of T2DM. SirT1 ASO lowered both fasting glucose concentration and hepatic glucose production in the T2DM rat model. Whole body insulin sensitivity was also increased in the SirT1 ASO treated rats as reflected by a 25% increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp and could entirely be attributed to increased suppression of hepatic glucose production by insulin. The reduction in basal and clamped rates of glucose production could in turn be attributed to decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer and activator of transcription 3 (STAT3), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), known substrates of SirT1. In addition to the effects on glucose metabolism, SirT1 ASO decreased plasma total cholesterol, which was attributed to increased cholesterol uptake and export from the liver. These results indicate that inhibition of hepatic SirT1 may be an attractive approach for treatment of T2DM.
Erion
Derek M
DM
Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06510, USA.
Yonemitsu
Shin
S
Nie
Yongzhan
Y
Nagai
Yoshio
Y
Gillum
Matthew P
MP
Hsiao
Jennifer J
JJ
Iwasaki
Takanori
T
Stark
Romana
R
Weismann
Dirk
D
Yu
Xing Xian
XX
Murray
Susan F
SF
Bhanot
Sanjay
S
Monia
Brett P
BP
Horvath
Tamas L
TL
Gao
Qian
Q
Samuel
Varman T
VT
Shulman
Gerald I
GI
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis*; D006946:Hyperinsulinism / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1; D037761:Sirtuins / Q000172:deficiency* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D007328:Insulin; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D002784:Cholesterol; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose