Rhizoma coptidis plays a therapeutic role in insulin resistance partly by regulating the TLR4/JNK/NF-κB pathways and Akt/AMPK/GLP-1/ERS pathways. In the insulin resistance models, Rhizoma coptidis acts on the TLR4/JNK/NF-κB inflammatory pathways and inhibits the activities of MCP-1, IL-6, TNF-α, JNK and NF-κB [
9,
90‐
93]. AMPK also plays an important role in Rhizoma coptidis’s treatments on diabetes [
94]. Rhizoma coptidis up-regulates the expression of LKB1, AMPK and inhibits the translocation of TOCR2 into the nucleus in the liver of diabetic rats [
46]. Berberine regulates the expression of GLUT4 in insulin-resistant cells with AMPK dependent and Akt independent ways. Akt is an important kinase that mediates glucose metabolism stimulated by insulin, and the deficiency of Akt can lead to glucose metabolism disorder. Rhizoma coptidis acts on Akt pathways by modifying IRS, phosphorylation of downstream Akt and activating PKC to improve insulin signaling cascade [
66,
95,
96]. Protein kinase C (PKC) is expressed by the insulin receptor. Berberine can decrease insulin resistance by activating PKC, and inhibitor of PKC can eliminates InsR activation and InsR mRNA transcription induced by berberine [
97]. IRS-1 is the principal link between inflammation and insulin resistance [
95]. Berberine can improve the IRS-1 level in the brain and restore the expressions of GLUT1 and GLUT3 in the treatment of diabetic animals [
98]. Berberine also improves insulin resistance in nonalcoholic fatty liver disease by regulating the expression levels of IRS-2 [
95]. Akt induces GLUT translocation to the plasma membrane and regulates downstream targets involved in glycogen synthesis including GSK-3β and glucokinase [
99]. Berberine activates Akt and GCK in liver and adipose tissue. The activity of GSK-3β in the liver was also inhibited by berberine [
90,
96,
99]. Recent studies have shown that ERS play important roles in obesity, insulin resistance and T2DM. Rhizoma coptidis treats on insulin resistance partly by acting on the ERS pathways, including JNK, PERK, eIF2α and ORP150 to protect cells from ER stress injury [
66].
Rhizoma coptidis also treats insulin resistance by activation of GLP-1. Berberine may regulate the secretion of GLP-1 by regulating AMPK [
100]. GLP-1 plays an important role in stimulating glucose dependent insulin secretion, inhibiting glucagon release, promoting β cell proliferation, and gastric emptying and food intake [
100]. Rhizoma coptidis can increase the expression of GLP in type 2 diabetic rats to stimulate glucose consumption and lower the levels of blood glucose [
101]. Berberine also promotes the secretion of GLP-1 by activating TGR5 and bitterer receptor subtype TAS2R38. TGR5 plays an important role in regulating glycolipid metabolism, inhibiting inflammation, and improving kidney disease [
101,
102].
Glucose transportation is the speed limiting step of glucose metabolism and can be activated in the peripheral tissue by two different ways: (1) IRS-1/PI3K signal transduction stimulated by insulin; (2) activation of muscle contraction through AMPK [
103]. Berberine can improve glucose metabolism by insulin independent way in insulin sensitive cells including HepG2, C2C12, L6, 3T3-L1 cells [
91,
104]. Berberine can increase the ratio of AMP/ATP and activate AMPK and Akt pathways to promote acute insulin mediated glucose transportation [
101,
103].