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), fructos...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 27; p. 11288
Main Authors: Erion, Derek M, Yonemitsu, Shin, Nie, Yongzhan, Nagai, Yoshio, Gillum, Matthew P, Hsiao, Jennifer J, Iwasaki, Takanori, Stark, Romana, Weismann, Dirk, Yu, Xing Xian, Murray, Susan F, Bhanot, Sanjay, Monia, Brett P, Horvath, Tamas L, Gao, Qian, Samuel, Varman T, Shulman, Gerald I
Format: Journal Article
Language:English
Published: United States 07.07.2009
Subjects:
Acetylation - drug effects
Animals
Cholesterol - blood
Diabetes Mellitus, Experimental - blood
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - metabolism
Gene Knockdown Techniques
Gluconeogenesis - drug effects
Gluconeogenesis - genetics
Glucose - biosynthesis
Hyperinsulinism - blood
Hyperinsulinism - metabolism
Insulin - metabolism
Liver - drug effects
Liver - enzymology
Liver - metabolism
Oligonucleotides, Antisense - pharmacology
Rats
Rats, Sprague-Dawley
Sirtuin 1
Sirtuins - deficiency
Sirtuins - metabolism
Transcription Factors - metabolism
Transcription, Genetic - drug effects
ISSN:1091-6490, 1091-6490
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.0812931106