Type 2 diabetes is a heterogeneous metabolic disorder characterized by the impairment of insulin secretion from pancreatic b-cells and insulin resistance in peripheral tissues such as the liver, skeletal muscle and adipose tissue.1) In most cases, insulin resistance mostly precedes the impairment of insulin secretion in humans. For example, obesity induces hepatic, skeletal muscle and adipocyte insulin resistance, and hypersecretion of insulin maintains normoglycemia by compensating for insulin resistance. As long as insulin secretion compensates for peripheral insulin resistance, diabetes is not developed and exacerbated. Thus, herbs or drugs for type 2 diabetes mellitus should have an insulin sensitizing action to relieve insulin resistance and an insulinotropic action to improve glucose-stimulated insulin secretion and pancreatic b-cell survival.Extracts from Coptidis Rhizoma (CR) and Cortex Phellodendri, a Southeast Asian herb, have been used to treat diabetes mellitus for more than one thousand years in the history of Chinese medicinal remedies. , one of the main constituents of CR and Cortex Phellodendri, is a type of isoquinoline alkaloid, suggesting that it is a candidate of the principal anti-diabetic constituents of CR. According to reports, 2-4) berberine acts as an a-adrenoceptor antagonist. In addition, some aadrenoceptor antagonists, such as phentolamine, stimulate insulin release by inhibiting pancreatic b-cell ATP-sensitive potassium channels. 5,6) Berberine is a candidate for insulin secretagogues, but it's effect was not sufficient to recommend CR or berberine to treat type 2 diabetes. Post-prandial hyperglycemia is a prominent early defect in type 2 diabetes, predominantly due to loss of acute phase insulin secretion after eating. 7,8) Thus, insulin secretagogues have long been used as a diabetic drug to reduce post-prandial hyperglycemia to normal levels. Insulin secretagogues such as sulfonylurea make normoglycemia in the early stage of diabetes. However, most of them stimulate insulin secretion with and without glucose challenge by closing ATP-sensitive potassium channels in b-cells. 7,8) As a result, they increase insulin secretion without glucose loading, resulting in exhausting and damaging b-cells and frequent hypoglycemia. Eventually, they exacerbate the symptoms of diabetes. The ideal agent to treat post-prandial hyperglycemia should restore the acute-phase insulin secretion without hypoglycemia and enhance pancreatic b-cell survival. Thus, an insulinotropic agent is a better anti-diabetic agent than a simple insulin secretagogue. Insulinotropic agents, such as glucagon like peptide-1 receptor agonist (exendin-4), improve glucose-stimulated acute insulin secretion with the expansion of b-cell mass through improving insulin like growth factors (IGF)-1 and/or insulin. [9][10][11] In the present study, the fractions of CR were investigated for their effects as an insulin sensitizer through insulin-mediated glucose uptake in 3T3-L1 adipocytes and as an insulinotropic agent in Min6 cells. ...