The Antihyperglycemic Effects of Rhizoma Coptidis and Mechanism of Actions: A Review of Systematic Reviews and Pharmacological Research

Table 2

Summary of berberine’s effects on insulin and glucose metabolism and the mechanism of action [15–61].

Experimental model	Mechanism of action
T2DM Chinese hamsters	Changed the expression of hepatic peroxisome proliferator-activated receptors and its target genes [15]
3T3-L1 cells	Increased glucose uptake in fat cells and inhibited the differentiation of preadipocytes [16]
Sprague Dawley rats	Reduced plasma FFA and triglyceride levels and inhibited the expression of liver TNF-α [17]
Sprague Dawley rats	Increased HNF-4α expression [18]
Wistar rats	Regulated the expression of endoplasmic reticulum chaperone ORP150 and reduced ER stress [19]
HepG2 cells	Regulated AMPK activity to decrease its downstream gluconeogenesis protein expression [20]
Wistar rats	Inhibited pancreatic β-cell apoptosis by inhibiting ASK1 protein expression [21]
Wistar rats	Increased PI-3K p85 and GLUT4 protein expression in skeletal muscles of T2DM rats [22]
Insulin resistant rat models	Inhibited TNF-α secretion and reduced serum free fatty acid level [23]
Wistar rats	Increased mRNA expression of adiponectin gene and decreased IRI in T2DM rats [24]
T2DM Chinese hamsters	Inhibited the expression of PEPCK, 6Pase, and PGC-1α by enhancing CYP7A1 and Gck expression induced by the upregulation of LXRα expression [25]
L6 myotubes	Inhibited fatty acid uptake at least in part by reducing PPAR gamma and FAT/CD36 expression [26]
L6 rat skeletal muscle cells	Induced InsR gene expression through a protein kinase C (PKC) dependent activation of its promoter. Inhibited PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription [27]
Nonalcoholic fatty liver; disease rat liver	Upregulated the mRNA and protein levels of IRS-2 [28]
3T3-L1 adipocytes	Reversed free fatty acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ [29]
Cultured HepG2 cells	Attenuated ER stress and improved insulin signal transduction [30]
Rat skeletal muscle cells	Modulated key molecules in the insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells [31]
Insulin resistant rat models	Stimulated AMPK activity [32]
T2DM hamsters	Altered the transcriptional programs of the visceral white adipose tissue LXRs, PPARs, and SREBPs [33]
Diabetic hamsters	Altered the transcriptional programs of hepatic SREBPs, LXRα, and PPARα [34]
Mouse primary hepatocyte	Upregulated HNF4α expression to induce hepatic glucokinase activity [35]
Mouse primary hepatocyte	Upregulated HNF6 mRNA expression and induced hepatic glucokinase activity [36]
HepG2 cells	Increased hepatic glucose consumption [37]
Wistar rats	Elevated IRS-1, IRS-2, and p85 mRNA expression in the peripheral tissues [38]
Sprague Dawley rats	Increased the content of GLU4 mRNA in skeletal muscles, increased the content of GLUT4 protein in cells, and enhanced insulin activity in the peripheral tissues [39]
Kunming mice	Inhibited gluconeogenesis and/or stimulated glycolysis [40]
Diabetic rat model	Stimulated GLP-1 release [41]
Wistar rats	Regulated INS and GH levels by enhancing SS levels through the hypothalamus-pituitary-pancreatic axis system [42]
HepG2 cells	Increased InsR mRNA transcription and protein expression [43]
Alloxan-induced diabetic mice	Upregulated the activity of Akt [44]
Wistar rats	Stimulated GK activity and expression [45]
3T3-L1 adipocytes and L6 myocytes	Inhibited PTP 1B activity and increased phosphorylation of IR, IRS1, and Akt in 3T3-L1 adipocytes [46]
Streptozotocin-induced; diabetic rats	Enhanced GLP-1-(7-36) amide secretion [47]
Mammalian cells	Functioned as an agonist of the fatty acid receptor GPR40 [48]
T2DM rat models	Lowered serum RBP4 levels and upregulated the expression of tissue GLUT4 protein [49]
Streptozotocin-induced; diabetic rats	Exhibited inhibitory effects on intestinal disaccharidases and β-glucuronidase [50]
L6 rat skeletal muscles	Stimulated glucose uptake through the AMP-AMPK-p38 MAPK pathway [51]
3T3-L1 adipocytes	Enhanced GLUT1 expression and stimulated the GLUT1-mediated glucose uptake by activating GLUT1 [52]
Alloxan-induced diabetic; C57BL/6 mice	Upregulated Akt activity via insulin signaling pathways [53]
Molecular model	Inhibited H-PTP 1B [54]
Streptozotocin-induced; diabetic rats	Involved PKA-dependent pathways [55]
Normal animals; (dogs and rats)	Acutely inhibited α-glucosidase [56]
Molecular model	Inhibited DPP IV [57]
L929 fibroblast cells	Significantly activated GLUT1 transport [58]
Diabetic rats	Directly inhibited gluconeogenesis in the liver [59]
Rat model	Inhibition of glucose oxidation in mitochondria may contribute to increased AMP/ATP ratio and AMPK activation [60]
Caco-2 cell line	Inhibited α-glucosidase activity and decreased glucose transport across the intestinal epithelium [61]

T2DM: type 2 diabetes mellitus; TNF: tumor necrosis factor; FFA: free fatty acid; HNF: hepatocyte nuclear factor; ER: endoplasmic reticulum; ORP: oxygen-regulated protein; AMPK: AMP-activated protein kinase; ASK: apoptosis signal-regulating kinase; mRNA: messenger RNA; IRI: insulin resistant index; PEPCK: phosphoenolpyruvate carboxylase kinase; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator 1α; CYP7A1: cholesterol 7 𝛼-hydroxylase; GCK: glucokinase; PI-3K: phosphatidylinositol 3-kinase; GLUT4: glucose transporter type 4; PPAR: peroxisome proliferator-activated receptor; FAT/CD36: fatty acid translocase; PKC: protein kinase C; BBR: berberine; IKKβ: inhibitor kappa B kinase β; LXRs: liver X receptors; SREBPs: sterol regulatory element binding proteins; IRS: insulin receptor substrates; GLP: glucagon-like peptide; INS: insulin; GH: growth hormone; SS: somatostatin; Akt: protein kinase B; PTP1B: protein tyrosine phosphatase 1B; IR: insulin resistance; GPR40: G protein-coupled receptor 40; RBP4: retinol-binding protein 4; H-PTP 1B: human protein tyrosine phosphatase 1B; DPP IV: dipeptidyl peptidase IV; AMP: adenosine monophosphate; ATP: adenosine triphosphate.