title: Sodium meta-arsenite ameliorates hyperglycemia in obese diabetic db/db mice by inhibition of hepatic gluconeogenesis.
abstract: Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Young-Sun
authors.identifier: 0000-0002-2342-6093
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Eun-Kyu
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Oh
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea ; Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Namdong-gu, Guwol-dong 1198, Incheon 405-760, Republic of Korea ; Gachon Medical Research Institute, Gil Hospital, Incheon 405-760, Republic of Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Komipharm International Co. Ltd., 3188 Seongnam-dong, Jungwon-gu, Seongnam-si, Gyeonggi-do 462-827, Republic of Korea.
authors.forename: Sujong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea ; Gachon Medical Research Institute, Gil Hospital, Incheon 405-760, Republic of Korea ; College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000107:Acetylation; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D018053:Arsenites; D015415:Biomarkers; D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005952:Glucose-6-Phosphatase; D006442:Glycated Hemoglobin; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D056564:Sirtuin 1; D017670:Sodium Compounds; C467200:Foxo1 protein, mouse; C558406:HbA(1c) protein, mouse; C496593:Hnf4a protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C017947:sodium arsenite; C470545:Sirt1 protein, mouse