Table 1.
In vivo/In vitro Studies of Geniposide in Glucose Metabolism
| Effect on Glucose Metabolism | In vivo/In vitro | Model | Dose and Duration | Experimental Outcome | References |
|---|---|---|---|---|---|
| Increasing the Utilization of glucose | In vivo | C57BL/6 wild-type mice were fed a high-fat diet for 9 weeks | Geniposide 25mg/kg for 1 week | ↑glucose utilization ↑fast-twitch muscle phenotype ↓the mRNA/protein levels of PDK4 in skeletal muscle ↓the mRNA/protein levels of FoxO1/PDK4/p-PDH/GAS |
[30] |
| In Vitro | Mouse C2C12 myoblasts treated with 2% horse serum to replace FBS in culure medium for 48 h | Geniposide 0.4mg/mL for 12 h | ↑glucose utilization ↑fast-twitch muscle phenotype ↓the mRNA/protein levels of FoxO1/PDK4/p-PDH/GAS |
[30] | |
| Increasing Insulin Production | In Vitro | Rat INS-1 insulinoma cells exposed to 10 mol/L geniposide for 1 h | Geniposide 0.01/0.1/1/10/100μM for 1 h | ↑insulin secretion ↑glucose-stimulated insulin secretion |
[33] |
| Rat INS-1 pancreatic β cell exposed to 5.5,11,33 mM glucose for 20 min | Geniposide 10μM for 2 h | ↑insulin secretion ↑glucose uptake ↓content of ATP ↓the mRNA and protein levels of pyruvate carboxylase gene |
[34] | ||
| Rat INS-1 pancreatic β cell exposed to 5.5 mM glucose for 1 h | Geniposide 10μM for 1 h | ↑the phosphorylation of PDK1 ↑the phosphorylation of Akt473 and GSK3β ↑the protein level of Glut2 |
[35] | ||
| INS-1 pancreatic β cell exposed to 5/11/25 mmol/l glucose for 1 h | Geniposide 10μM for 2 h | ↑the glycosylation of Glut2 ↑the mRNA and protein levels of GnT-IVa, galectin-9, clathrin |
[36] | ||
| INS-1 pancreatic β cell exposed to 5/25 mM glucose for 1 h | Geniposide 10 μM for 2 h | ↑insulin secretion and ATP content ↓glucose uptake ↑ACC phosphorylation |
[37] | ||
| Protecting Pancreatic Islet β Cells | In Vitro | INS-1 pancreatic β cell exposed to 5/11/25 mM glucose for 24 h | Geniposide 10 μM for 1 h | ↑Insulin serection ↓The accumulation of H2O2 ↑the protein levels of protein disulfide isomerase ↓the protein levels of endoplasmic reticulum oxidoreductin 1 (ERO1) ↓the content of thiol group in INS-1 cells. |
[38] |
| Rat INS-1E insulinoma cell were incubated with 2.0 and 5.0 μM HIAPP | Geniposide 1.0/10/100μm for 2 h | ↑cell viability ↑the proten levels of insulin-degrading enzyme ↑the aggregation of HIAPP |
[39] | ||
| INS-1 pancreatic β cell incubated5/11/25 mM glucose for 24.48 or 72 h | Geniposide 10μm for 5 minutes, 24 h, 48 h, and 72 h | ↓glucose-induced impairment of insulin release ↑the phosphorylation of AMPK ↓the protein levels of HO-1 ↑the Bcl-2/BAX protein ratio ↑the cleavage of Caspase-3 |
[40] | ||
| INS-1 pancreatic β cell exposed to 16.7 mM glucose/0.2mM palmitate for 24 h | Geniposide 10 μM for 24 h | ↑cell viability ↑the protein expression of HO‐1, Bcl‐2 ↓the protein expression of Bax ↑PERK/eIF2α/IRE1α phosphorylation (Unfolded protein response) |
[40] | ||
| INS-1 pancreatic β cell exposed to 25 mM glucose for 24 h | Geniposide 10 μM for 24 h | ↓ protein levels of Txnip ↓Insulin serection ↑glucose and ATP content |
[41] | ||
| INS-1 pancreatic β cell exposed to 25mM glucose for 12 h | Geniposide 10 μM for 2 h | ↓PERK/eIF2α/IRE1α phosphorylation (Unfolded protein response) |
[42] | ||
| INS-1 rat insulinoma cell were incubated with palmitate for 18 h |
Geniposide 1μm for 2 h | ↓palmitate-induced cell apoptosis ↓the protein levels of caspase-3 ↓the phosphorylation of Akt (Thr308), Akt (ser473) and Foxo1 ↓the protein levels of PDX-1 |
[44] | ||
| Rat Islets cells were stimulated with 2.8 mM or 8.3 mM glucose for 0.5 h | Geniposide 10㎛ for 0.5 h | ↑insulin secretion ↑cAMP accumulation ↓ Kv channels ↑action potential duration ↑currents through voltage-dependent Ca2 channels |
[39] | ||
| In vivo | C57BL/6 male mice were fed a high-fat diet for 12 weeks | Geniposide solution was prepared in 0.9% NaCl and delivered by oral gavage at dosage of 100 mg/kg daily | ↓pancreatic islet β cell apoptosis ↑the protein and mRNA levels of TCF7L2 ↑the mRNA levels of insulin,PDX1,IL1β, and CyclinD1 ↑β-catenin/TCF7L2 signaling ↑β-cell regeneration |
[46] | |
| Inhibiting Insulin Resistance | In vivo | Spontaneously obese Type 2 diabetic (TSOD) mices | 0.1%/0.3% geniposide for 8 weeks | ↓Plasma Glucose levels in Oral Glucose Tolerance Test | [47] |
| Male C57BL/6 J mice fed with High-Fat Diet for 8 weeks | Geniposde 25 or 50 mg/kg for 8 weeks | ↓the body weight gain ↓the random blood glucose and fasting blood glucose levels ↓the area under the curve of glucose tolerance tests and insulin tolerance tests ↓hepatic glycogen content and serum insulin ↑the phosphorylations of hepatic IR, Akt (S473) and GSK3β in liver and GAS ↓the mRNA/protein levels of FoxO1 and PDK4 ↑the mRNA levels and protein levels of Glut4 ↓serum RBP4 levels and the mRNA/protein levels of RBP4 and TTR |
[31] | ||
| In Vitro | 3T3-L1 adipocyte cells cultured with 33 mM glucose and 100 nM insulin for 48 h | Geniposide 10㎛ for 2 h | ↑Glucose uptake ↓the protein levels of p-IRS-1, IRS-1, GLUT −1, and IR-β ↑Txnip deregulation ↑the phosphorylation of AMPK |
[49] | |
| HepG2 cell treated with 50, 100, 200 or 500 nmol/l insulin for 48h | Geniposide 62.5 mg/l for 20 h | ↓supernatant glucose centent ↑the mRNA and protein levels of Glut4 ↑Autophagy (↑the protein levels of LC3,P62) ↑the protein levels of P62,P65 |
[48] | ||
| Primary mouse hepatocytes were isolated from the C57BL/6 J mice |
Geniposide 50 mg/l for 24 h | ↓the mRNA/protein levels of RBP4 and TTR ↓RBP4 levels in the culture medium |
[31] | ||
| Inhibiting Hepatic Glucose Production | In Vitro | HepG2 treated with 5.5mM D-glucose | Geniposide 0.1/1/10/100㎛ for 6 h | ↓Glucose production ↑the phosphorylation of AMPK, ACC, and FoxO1 ↓The G6Pase and PEPCK activities |
[50] |
| Suppressing Gluconeogenesis | In vivo | C57BL/6 male mice were fed a high-fat diet | Geniposide (100 or 10 mg/kg) was injected intraperitoneally every day for two weeks | ↓Glucose tolerance | [51] |
| C57BL/6 male mice were fed a high-fat diet | Geniposide (100, 200, and 400 mg/kg) for two weeks | ↓plasma glucose, body weight, TC, TG and insulin levels ↓GP and G6Pase activities and mRNA/protein expression |
[52] | ||
| In Vitro | L02 treated with 1 mmol/L insulin plus 25 mmol/L glucose for 24 h | Geniposide 1/10/100μmol/L for 24 h | ↓Glucose production ↓The G6Pase and PEPCK activities ↑DEX induced FOXO1 nuclear accumulation ↑phosphorylation of AKT |
[51] |
Abbreviations: FoxO1, forkhead box O1; PDK4, pyruvate dehydrogenase kinase 4; PDH, Propane Dehydrogenation; GAS, gasoline; ATP, Adenosine Triphosphate; PDK1, pyruvate dehydrogenase kinase 1; Akt, AKT serine/threonine kinase; GSK3β, glycogen synthase kinase 3 beta; GLUT2, glucose transporter 2; GnT-IVa, glucosaminyl (N-acetyl) transferase family member 7; ERO1, endoplasmic reticulum oxidoreductin 1; IAPP, amyloid polypeptide; AMPK, activated protein kinase; HO-1, heme oxygenase 1; Bcl-2, B cell leukemia/lymphoma 2; BAX, BCL2 associated X, apoptosis regulator; Txnip, thioredoxin-interacting protein; PERK, Protein kinase R (PKR)-like endoplasmic reticulum kinase; eIF2α, eukaryotic translation initiation factor 2 subunit alpha; IRE1α, Inositol-requiring enzyme-1α; PDX-1, Pancreatic duodenal homeobox-1; ACaCa, acetyl-CoA carboxylase; TC, total cholesterol; TG, total triglyceride.