Document Detail


Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats.
MedLine Citation:
PMID:  22127228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC) on hepatic glycogen synthesis and FoxO1 transcriptional activity in type 2 diabetic rats and the mechanism underlying these effects. Fasting blood glucose and glycogen deposition, together with expressions of two key genes related to gluconeogenesis, were studied in the liver of rats fed a normal diet (NC), high-fat diet (HFD)-induced insulin-resistant rats made type 2 diabetic by a single intraperitoneal injection of streptozotocin (DM), and a DM with intervention of PDTC (DM + PDTC) for 1 wk. The phosphorylation of Akt, GSK-3β, and FoxO1 was assessed in liver extracts of fasted rats by Western blot, whereas indirect immunofluorescence staining was performed to determine the cellular distribution of FoxO1. The DM rats exhibited obvious increases in fasting blood glucose as well as decreased hepatic glycogen content compared with the NC group. Activation of the Akt/GSK-3β pathway and inactivating phosphorylation of FoxO1 were reduced greatly in DM rat livers (P < 0.01). By contrast, PDTC treatment protected DM rats against high fasting blood glucose and hepatic glycogen deposition loss. PDTC also elicited an increase in Akt/GSK-3β signaling and subsequent inactivation and nuclear export of FoxO1 in DM rat livers, which translated into a significant reduction in the expression of two FoxO1 target genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. This study suggests that PDTC enhances hepatic glycogen synthesis, whereas it reduces FoxO1 transcriptional activity in DM rats.
Authors:
Tienian Zhu; Ruijing Zhao; Lizhong Zhang; Michel Bernier; Jiankun Liu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2011-11-29
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  302     ISSN:  1522-1555     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-03-30     Revised Date:  2013-09-19    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E409-16     Citation Subset:  IM    
Affiliation:
Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / pharmacology*
Blood Glucose / drug effects
Diabetes Mellitus, Type 2 / metabolism*
Diet, High-Fat
Fasting / blood
Forkhead Transcription Factors / metabolism*
Gluconeogenesis / drug effects
Glucose-6-Phosphatase / biosynthesis
Glycogen Synthase Kinase 3 / metabolism
Insulin Resistance
Liver / chemistry,  drug effects*,  metabolism
Liver Glycogen / biosynthesis*
Male
Nerve Tissue Proteins / metabolism*
Phosphoenolpyruvate Carboxykinase (ATP) / biosynthesis
Phosphorylation
Pyrrolidines / pharmacology*
Rats
Rats, Wistar
Thiocarbamates / pharmacology*
Transcription, Genetic / drug effects*
Grant Support
ID/Acronym/Agency:
ZIA AG000900-03/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Blood Glucose; 0/Forkhead Transcription Factors; 0/Liver Glycogen; 0/Nerve Tissue Proteins; 0/Pyrrolidines; 0/Thiocarbamates; 147604-79-3/Foxo1 protein, rat; 25769-03-3/pyrrolidine dithiocarbamic acid; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.1.3.9/Glucose-6-Phosphatase; EC 4.1.1.49/Phosphoenolpyruvate Carboxykinase (ATP)
Comments/Corrections

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