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.