title: Oleanolic acid reduces hyperglycemia beyond treatment period with Akt/FoxO1-induced suppression of hepatic gluconeogenesis in type-2 diabetic mice.
abstract: The present study investigated the chronic efficacy of oleanolic acid (OA), a triterpenoid selected from our recent screening, on hyperglycemia in type-2 diabetic mice. C57BL/6J mice were fed a high-fat diet followed by low doses of streptozotocin to generate a type-2 diabetic model. OA (100 mg/kg/day) was administered orally for 2 weeks with its effects monitored for 6 weeks. High-fat feeding and streptozotocin generated a steady hyperglycemia (21.2 ± 1.1 mM) but OA administration reversed the hyperglycemia by ~60%. Interestingly, after the cessation of OA administration, the reversed hyperglycemia was sustained for the entire post-treatment period of the study (4 weeks) despite the reoccurrence of dyslipidemia. Examination of insulin secretion and pancreas morphology did not indicate improved β-cell function as a likely mechanism. Urine glucose loss was decreased with substantial improvement of diabetic nephropathy after the OA treatment. Pair-feeding the OA-treated mice to an untreated group ruled out food intake as a main factor attributable for this sustained reduction in hyperglycemia. Studies with the use of glucose tracers revealed no increase in glucose influx into muscle, adipose tissue or liver in the OA-treated mice. Finally, we analyzed key regulators of gluconeogenesis in the liver and found significant increases in the phosphorylation of both Akt and FoxO1 after treatment with OA. Importantly, these increases were significantly correlated with a down-regulation of glucose-6-phosphatase expression. Our findings suggest triterpenoids are a potential source of new efficacious drugs for sustained control of hyperglycemia. The liver appears to be a major site of action, possibly by the suppression of hepatic glucose production via the Akt/FoxO1 axis.
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Cantley
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Iseli
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Molero
authors.forename: Bronwyn D
authors.initials: BD
authors.lastname: Hegarty
authors.forename: Edward W
authors.initials: EW
authors.lastname: Kraegen
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D014280:Triglycerides; D009828:Oleanolic Acid; D051057:Proto-Oncogene Proteins c-akt