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.
Highlights
The incidence of diabetes is estimated at 220 million worldwide [1] and prolonged hyperglycemia is a major cause of various diabetic complications including nephropathy [2]
The present study investigated the chronic effect of oleanolic acid (OA), a triterpenoid selected from our recent screens [14], on hyperglycemia in diabetic mice and the contributing mechanisms involved
Our results show that OA did not affect hyperglycemia in T1D mice, but was able to reverse hyperglycemia in T2D mice, as predicted
Summary
The incidence of diabetes is estimated at 220 million worldwide [1] and prolonged hyperglycemia is a major cause of various diabetic complications including nephropathy [2]. While TZDs are effective in lowering hyperglycemia, largely by an insulin sensitizing action [7,8], concerns over the adverse effects of TZDs on an increased risk of heart failure [9] and bladder cancer [10] have restricted their long-term use. Other new drugs such as GLP analogues and inhibitors of the sodium glucose cotransporter (SGLT) appear promising [11,12,13], their long term effectiveness is not clear. There remains an urgent need for the development of new anti-diabetic drugs with sustained efficacy
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