Phytomedicine 19 (2012) 719–724 Contents lists available at SciVerse ScienceDirect Phytomedicine j ourna l ho mepage: www.elsevier.de/phymed Borapetoside C from Tinospora crispa improves insulin sensitivity in diabetic mice Chi-Tun Ruan a , Sio-Hong Lam b , Tzong-Cherng Chi c , Shoei-Sheng Lee b , Ming-Jai Su a,∗ a Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan b School of Pharmacy, National Taiwan University, Taipei, Taiwan c Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan County, Taiwan a r t i c l e i n f o Keywords: Tinospora crispa Borapetoside C Antihyperglycemia Diabetic mice Glucose transporter-2 (GLUT2) a b s t r a c t Diabetes mellitus (DM) often leads to disability from vascular complications and neurological complica- tions. Tinospora crispa has been widely used in Asia and Africa as a remedy for diabetes and other diseases. In this study, we investigated the hypoglycemic actions of borapetoside C isolated from T. crispa, and the mechanisms underlying its actions. Acute treatment with borapetoside C (5 mg/kg, i.p.) attenuated the elevated plasma glucose induced by oral glucose in normal and type 2 DM (T2DM) mice. Compared to the effect of injected insulin (0.5 IU/kg), borapetoside C caused a more prominent increase of glycogen content in skeletal muscle of T2DM mice, but a less increase in type 1 DM (T1DM) mice. Combined treat- ment of a low dose borapetoside C (0.1 mg/kg, i.p.) plus insulin enhanced insulin-induced lowering of the plasma glucose level and insulin-induced increase of muscle glycogen content. Continuous treatment with 5 mg/kg borapetoside C (twice daily) for 7 days increased phosphorylation of insulin receptor (IR) and protein kinase B (Akt) as well as the expression of glucose transporter-2 (GLUT2) in T1DM mice. Com- bined treatment of a low dose borapetoside C (0.1 mg/kg, twice daily) plus insulin for 7 days enhanced insulin-induced IR and Akt phosphorylation and GLUT2 expression in the liver of T1DM mice. This study proved that borapetoside C can increase glucose utilization, delayed the development of insulin resis- tance and enhanced insulin sensitivity. The activation of IR-Akt-GLUT2 expression and the enhancement of insulin sensitivity may contribute to the hypoglycemic action of borapetoside C in diabetic mice. © 2012 Elsevier GmbH. All rights reserved. Introduction Diabetes mellitus (DM) is associated with the pathological pro- gression in various organs such as the liver and skeletal muscle. The epidemiological studies characterize obesity to be highly asso- ciated with DM. About 80% of individuals with type 2 DM (T2DM) are overweight (Bays et al. 2007). Since the onset of metabolic dis- ease starts to develop earlier in obese people, studies have focused on the development of pharmaceuticals that can be used in patients with obesity and DM (Bays 2009). There are several studies showing that diabetes is associated with abnormal insulin secretion and insulin sensitivity. Since insulin is the most important substance in regulating glucose metabolism, impaired insulin secretion results in an increase in hepatic glucose production and reduction of glucose uptake in muscle (Kahn et al. 2006). On the other hand, increased insulin resistance is a key feature in T2DM. It is characterized with a ∗ Corresponding author at: Institute of Pharmacology, College of Medicine, National Taiwan University. Room 1150, No. 1, Sec. 1, Jen-Ai Rd., Taipei, Taiwan. Tel.: +886 2 23123456x88317; fax: +886 2 23971403. E-mail address: mingja@ntu.edu.tw (M.-J. Su). remarkable decrease in tissue glucose utilization in response to insulin (Granberry et al. 2007). Tinospora crispa (family Menispermaceae) has been widely used in Asia and Africa as a herbal remedy for a long time. In traditional medicine, a decoction from the stems of T. crispa has been used for anti-inflammation, reducing thirst, increasing appetite, antipyret- ics, and maintaining good health (Messmer 1961; Zafinindra et al. 2003). The chemical constituents of T. crispa extracts have been extensively studied since the 1980s. The major active ingredients of T. crispa are identified as terpenoids and terpenoid glycosides. The terpenoid glycosides are mainly composed of borapetosides A, B, C, D, E and F (Cavin et al. 1998; Choudhary et al. 2010a,b; Kongkathip et al. 2002; Martin et al. 1996; Pachaly et al. 1992; Pathak et al. 1995; Ragasa et al. 2000; Yonemitsu et al. 1993). Most of these substances are yet to be investigated for their pharmacological activities. Our previous study showed that borapetoside C from T. crispa could decrease serum glucose via enhancing insulin secretion in both normal and T2DM mice, whereas it reduced glucose level without changing the insulin level in type 1 DM (T1DM) mice (Lam et al. 2012). The molecular mechanism for the increase of glucose utilization, inhibition of hepatic gluconeogenesis, and asso- ciated lowering of plasma glucose by borapetoside C in diabetic mice remain to be investigated. In this study, we demonstrated that borapetoside C attenuated the elevation of plasma glucose 0944-7113/$ – see front matter © 2012 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2012.03.009