title: Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats.
abstract: 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: Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, China.
authors: Tienian
authors: T
authors: Zhu
authors: Ruijing
authors: R
authors: Zhao
authors: Lizhong
authors: L
authors: Zhang
authors: Michel
authors: M
authors: Bernier
authors: Jiankun
authors: J
authors: Liu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D005215:Fasting / Q000097:blood; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007333:Insulin Resistance; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis; D010766:Phosphorylation; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D000071161:Forkhead Box Protein O1
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D051858:Forkhead Transcription Factors; D005952:Glucose-6-Phosphatase; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008112:Liver Glycogen; D009419:Nerve Tissue Proteins; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D011759:Pyrrolidines; D013859:Thiocarbamates; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C020972:pyrrolidine dithiocarbamic acid; C000605508:Gsk3b protein, rat