Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management

Table 4 Possible pharmacological effects of the ingredients in the top 10 herbs and formulas

	Possible pharmacological effects of the ingredients	Average daily dose (g)	No. of persons-dosage	Frequency (%)	aHR1	95%CI	P value
Single Herbs: Pin-yin name/Latin name					1.00	(Ref.)
Da Huang/Rheum palmatum L	Reduces oxidative stress, inhibits β-cell apoptosis and improves β-cell function[28]; Activates AMP-Activated Protein Kinase and improves glucose tolerance[37]; Ameliorates insulin resistance via reducing FATP1-mediated skeletal muscle lipid accumulation[38]; Inhibits HCC via inhibiting STAT 3 signaling pathway[39]	1	1060286	109102 (15.25)	0.83	(0.7, 0.98)a	0.013
Dan Shen/Salvia miltiorrhiza Bunge	Reduces oxidative stress and inhibits apoptosis and inflammation via the regulation of Wnt/β-catenin, TSP-1/TGF-β1/STAT3, JNK/PI3K/Akt, TGF-β1/NF-κB, AMPK/ACC, signaling pathways in DM model[40]. Inhibits IGF-1[31,32]. Inhibits HCC via modulating PI3K/Akt, MAPK and JAK/STAT3 signaling pathways[41]	1.9	2162061	107301 (15.00)	0.87	(0.76, 1.00)a	0.0123
Huang Qi/Astragalus propinquus	Protects pancreatic β cells from apoptotic death[29]. Regulates resistin (an insulin-resistance protein)[29]. Ameliorates insulin resistance[42]. Induces apoptosis in HCC via decreasing the expression of Notch 1[43]. Inhibits HCC via repression of M2 polarization of tumor-associated macrophages[44]	2.2	2188885	94799 (13.25)	0.87	(0.75, 1.01)	0.0183
Tian Hua Fen/Trichosanthes kirilowii Maxim	Ameliorates insulin resistance via decreasing the expression of PTGS2, NF-κB, JNK, and AKT[45]. Stimulates insulin receptor kinase activity and enhances glucose clearance[46]. Inhibits HCC cell proliferation via blocking PKM2-dependent glycolysis[47]	2.2	1787396	77376 (10.81)	0.83	(0.71, 0.97)a	0.0027
Yan Hu Suo/Corydalis yanhusuo	Induces autophagy in HCC via activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascade and impairing the ERK/AKT signaling pathway[26]	1.8	925275	62808 (8.78)	0.89	(0.77, 1.03)	0.0496
Ge Gen/Pueraria montana var. lobata	Elevates insulin expression and enhances insulin sensitivity index[48]. Ameliorates insulin resistance[49]. Inhibits HCC invasion and metastasis via miR-21-mediated PTEN/AKT signaling pathway[50]	1.8	1032475	62061 (8.67)	0.86	(0.73, 1.00)	0.0128
Xuan Shen/Scrophularia ningpoensis Hemsl	Improves insulin sensitivity via AMPK-mediated NLRP3 inflammasome inhibition[51,52]	2.2	1099700	52418 (7.33)	0.79	(0.67, 0.94)b	0.002
Huang Chin/Scutellaria baicalensis Georgi	Regulates IGF-1R/AKT signaling pathway[53]. Ameliorates insulin resistance via inhibiting macrophage-mediated inflammation[54]. Elevates AMPK expression[34]. Modulates gut microbiota[34]. Inhibits HCC via affecting p53 signal pathway, MAPK signal pathway, apoptosis pathway, T cell receptor pathway, and macrophage-mediated tumor immunity[55]	1.9	852156	50546 (7.06)	0.93	(0.80, 1.09)	0.2098
Mai Men Dong/Ophiopogon japonicus (Thunb.) Ker Gawl	Ameliorates insulin resistance via InsR/IRS-1/PI3K/Akt/GSK-3/Glut-4 signalling pathway[56]. Modulates gut microbiota[35]. Inhibits HCC via downregulating PTP1B expression, thereby inactivating the PI3K/AKT pathway and activating the AMPK pathway[57]	2.3	1064080	49974 (6.98)	0.88	(0.75, 1.04)	0.0429
Hou Po/Magnolia officinalis	Decreases IGF-1 and IGFBP-5[33]. Protects pancreatic β-cells[30]. Inhibits HCC via AKT inhibition[58]	2.1	946453	49148 (6.87)	0.84	(0.70, 1.01)	0.0232
Herbal Formula: Pin-yin name/Latin name
Ji Sheng Shen Qi Wan	Ameliorates insulin resistance[59]. Inhibits HCC development[60]	6.9	6239325	87687 (15.62)	0.82	(0.71, 0.96)a	0.0026
Liu Wei Di Huang Wan	Ameliorates insulin resistance via antioxidative effect and supressing inflammation[61]. Induces apoptosis in HCC[62]	8.6	6803688	78029 (13.90)	0.83	(0.72, 0.96)a	0.0022
Shu Jing Huo Xie Tang	Ameliorates insulin resistance[63]. Inhibits HCC via regulating iron metabolism[64]	7.8	3550686	56106 (10.00)	0.86	(0.74, 1.00)a	0.0152
Xue Fu Zhu Yu Tang	Ameliorates insulin resistance, inflammation and oxidative stress[65]. Inhibits angiogenesis in HCC via blocking ERK/MAPK and NF-κB signalling pathway[66]	6.4	3466030	55091 (9.81)	0.80	(0.68, 0.94)b	0.0025
Jia Wei Xiao Yao San	Ameliorates insulin resistance[67]. Induces apoptosis in HCC[68]. Inhibits invasion and metastasis in HCC[69]	7.7	3823372	51350 (9.15)	0.92	(0.78, 1.08)	0.1529
Qi Ju Di Huang Wan	Ameliorates insulin resistance[70]. Modulates gut microbiota[71]. Inhibits HCC via inducing p53-mediated apoptosis and inhibiting proliferation[62]	7.7	4309801	50271 (8.96)	0.83	(0.68, 1.00)a	0.0219
Ma Zi Ren Wan	Reduces oxidative stress, inhibits β-cell apoptosis and improves β-cell function[28]. Inhibits HCC via AKT inhibition[58]	5	2609093	50100 (8.93)	0.87	(0.70, 1.08)	0.1288
Zhi Bai Di Huang Wan	Ameliorates insulin resistance via IRS-1/PI3K/AKT pathway[72]. Modulates gut microbiota[36]. Induces autophagy and apoptosis in HCC[27]	7.1	3557458	46284 (8.25)	1.05	(0.89, 1.23)	0.9271
Bai Hu Jia Ren Shen Tang	Inhibits IGF-1R/Akt pathway[73]. Ameliorates insulin resistance[74,75]. Induces apoptosis in HCC[76]	8.4	4051247	43451 (7.74)	0.79	(0.65, 0.96)a	0.0043
Zhi Gan Cao Tang	Decreases blood glucose[77]; Ameliorates insulin resistance[77]; Induces apoptosis and inhibits proliferation in HCC via blocking PI3K/AKT signal pathway[78]	5.9	2423303	42951 (7.65)	0.77	(0.63, 0.93)b	0.0042

^aP < 0.05.

^bP < 0.01.

¹adjusted by variables in Table 1.

ACC: Acetyl-CoA carboxylase; aHR: Adjusted hazard ratio; AMP: Adenosine monophosphate; AMPK: Adenosine monophosphate-activated protein kinase; ERK: Extracellular signal-regulated kinase; FATP1: Fatty acid transport protein 1; GLUT-4: Glucose transporter type 4; IGF-1: Insulin-like growth factor 1; IGFBP-5: Insulin-like growth factor binding protein-5; IRS-1: Insulin receptor substrate 1; JAK: Janus-activated kinase; JNK: C-Jun N-terminal kinases; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; Notch 1: Neurogenic locus notch homolog protein 1; PI3K: Phosphatidylinositol-3-kinase; PKM2: Pyruvate kinase M2; PTEN: Phosphatase and tensin homolog; PTGS2: Prostaglandin-endoperoxide synthase 2; PTP1B: Protein-tyrosine phosphatase 1B; ROS: Reactive oxygen species; STAT3: Signal transducer and activator of transcription 3 ; TGF-β1: Transforming growth factor beta-1; TSP1: Thrombospondin-1; ULK1: Unc-51-like kinase 1; HCC: Hepatocellular carcinoma; DM: Diabetes mellitus.