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Crateva unilocularis Buch-Ham has traditionally been used in Nepal for the treatment and prevention of diabetes. However, scientific verification through studies on the preventive effect of C. unilocularis on diabetes has not been done properly. In this study we investigated the effect of C. unilocularis leaf extract (CULE) on glucose uptake and insulin resistance. The effect of CULE on glucose uptake in an in vivo system was measured using zebrafish. In the cell-free system, enzymes activities related to diabetes were measured. Moreover, in the cell-cultured system, RIN-m5F pancreatic beta cells, 3T3-L1 adipocytes, and L6 myotubes were used to measure the effect of CULE on insulin secretion and glucose metabolism. CULE effectively enhanced glucose uptake in zebrafish larvae, and inhibited the activity of dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase-1B (PTP-1B) enzymes related to insulin secretion and insulin signaling activation. Also, CULE significantly increased insulin secretion with suppression of NO production in RIN-m5F pancreatic beta cells. In L6 myotubes and TNF-α-induced insulin resistance model of 3T3-L1 adipocytes, CULE significantly increased glucose uptake and immunofluorescence staining of glucose transporter (GLUT)4 protein. Furthermore, the regulatory response of glucose metabolism by CULE was a close correlation with the activation of insulin signaling (IRβ, PI3K, AKT) and 5′-AMP-activated protein kinase (AMPK)α and the reduction of p38 mitogen-activated protein kinase (MAPK) in TNF-α-induced insulin resistance model of 3T3-L1 adipocytes. Thus, our results suggest that CULE may act as a potential agent for the prevention and treatment of metabolic syndrome associated with type 2 diabetes. [ABSTRACT FROM AUTHOR]