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| Monoterpenes | Study model/dose(s) | Effects/markers | References |
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| Beta-pinene | Alloxan-induced diabetic rats—25, 50, 100, and 200 mg·kg−1 | Beta-pinene decreased plasma glucose, triglyceride, VLDL, LDL, and HDL levels, when compared to those of the control group. Carrageenan induced paw edema and leukocyte migration in the peritoneum. | [55] |
| Borneol | STZ-induced diabetic rats—25 and 50 mg·kg−1 | Increase in the biochemical indices, i.e., fasting blood glucose concentration, glycated hemoglobin, urea, alanine aminotransferase, aspartate aminotransferase, malondialdehyde concentration, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and atherogenic index, with a significant decrease in body weight, plasma insulin, HOMA-β-cell functioning index, glycogen, high-density lipoprotein cholesterol, and antioxidant enzyme activities, i.e., superoxide dismutase, catalase, and reduced glutathione | [56] |
| Carvacrol | HFD-induced C57BL/6J mice—20 mg/kg | Activation of IR, IRS, PI3K, and Akt/PKB. Induce STAT3 and SOCS. Suppress TC, TG, elevated phospholipids and FFAs, VLDL-C, and LDL-C in plasma and tissues. Suppress inflammatory cytokines in liver tissue (TNF and IL-6) and increase high-density lipoprotein cholesterol (HDL-C). | [57] |
| Carvacrol | HFD-induced type 2 diabetic C57BL/6J mice—20 mg/kg | The activities of carbohydrate metabolic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase increased, whereas glucokinase and glucose-6-phosphate dehydrogenase activities decreased in the liver of HFD mice. Normalize liver markers (ASP, ALA, ALP, and GGT). | [58] |
| Carvacrol | Rats with cerulein-induced pancreatic injury—50, 100, and 200 mg/kg | Mechanism of antioxidant action | [59] |
| Carvacrol | STZ-induced diabetic rats—75 mg/kg | Carvacrol decreased Bax and increased Bcl-2 in gene and protein expression levels. Reduced germ cell apoptosis. | [60] |
| Carvacrol | STZ-induced diabetic C57BL/6J mice—10, 20, and 40 mg/kg/day | A significant improvement in glucose tolerance and a significant decrease in the plasma level of TG were observed in carvacrol-treated diabetic mice at a dose of 20 mg/kg. Reduced the plasma level of LDH but not AST, ALT, or ALP, compared with that in the vehicle-treated diabetic group. The activity of hexokinase (HK), 6-phosphofructokinase (PFK), and citrate synthetase (CS) was increased. | [61] |
| Carvacrol | Diabetic C57BL/KsJ-db/db male mice—10 mg/kg | Carvacrol improved blood glucose and insulin resistance of T2DM db/db mice | [62] |
| The serum levels of TC, TG, and LDL-C were markedly reduced, whereas HDL-C levels were significantly increased |
| Decreased serum ALT and AST levels |
| Protective effects on the liver in T2DM db/db mice, which could be related to insulin, TLR 4/NF-κB, and AKT1/mTOR signaling pathways |
| Carvone | STZ-induced diabetic rats—50 mg·kg−1 | Decline in the levels of plasma glucose, HbA1c, and significant improvement in the levels of Hb and insulin. The reversed activities of carbohydrate metabolic enzymes, enzymic antioxidants, and hepatic marker enzymes in diabetic rats were restored to near normal level by the administration of carvone. | [63] |
| Catalpol | Diabetic db/db mice—200 mg/kg | Lowered blood glucose and improved insulin sensitivity via activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway. Exhibited enhanced myogenesis and increased myogenic differentiation (MyoD), myogenin (MyoG), and myosin heavy chain (MHC) expressions. | [29] |
| Catalpol | STZ-induced diabetic rats—10 mg/kg | The treatment improved diabetes-associated impaired renal functions | [64] |
| Reduced the elevated Grb10 expression in diabetic kidneys, suppressing IGF-1/IGF-1R signaling pathway |
| Catalpol | db/db mice—25, 50, 100 and 200 mg/kg | Hypoglycemic and therapeutics effect via modulation of various gene expressions such as SOCS3, Irs1, Idh2, and G6pd2 | [65] |
| Catalpol | C57BL/6J mice with type 2 diabetes induced by the combination of HFD and STZ—100 and 200 mg/kg | Regulation of the AMPK/NOX4/PI3K/AKT pathway | [30] |
| Catalpol | Mice fed HFD—100 mg/kg | Reduced mRNA expressions of M1 proinflammatory cytokines, but increased M2 anti-inflammatory gene expressions | [66] |
| Suppressed the c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathway |
| Catalpol | Diabetic mice induced by the combination of HFD and STZ—50, 100, and 200 mg/kg | Catalpol decreased fission protein 1 and protein 1 expression as well as increased mitofusin 1 expression in HepG2 cells | [31] |
| Catalpol | Rats with type 2 diabetes induced by the combination of HFD and STZ—10, 50, and 100 mg/kg | Negative regulation of Nox4 and p22phox expression, inhibiting the oxidative stress reaction response | [67] |
| Citronellol | | Citronellol improved the levels of insulin, Hb, and hepatic glycogen with significant decrease in glucose and HbA1C levels | [68] |
| Diabetic rats induced by STZ—25, 50, and 100 mg/kg | The altered activities of carbohydrate metabolic enzymes and hepatic and kidney markers were restored to near normal |
| Cymene | STZ-induced diabetic rats—20 mg/kg | Inhibition of glycation. Improves HbA1c and nephropathic parameters (such as albumin excretion rate, serum creatinine, and creatinine clearance rate). | [33] |
| p-Cymene | STZ-induced diabetic rats—25, 50, and 100 mg/kg | Improve serum levels of Glu, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), and the expression of mTOR, Akt, and phospho-Akt protein | [69] |
| Eucalyptol | Diabetic db/db mice—10 mg/kg | It increased the expression of nephrin, podocin, FAT-1, CD2AP, α-actinin-4, and integrin. Blocked ERK-c-Myc signaling. | [70] |
| Genipin | HFD-induced obese rats—12.5 and 25 mg/kg | Genipin increased the levels of PRD1-BF1-RIZ1. Inhibited the gene expressions of activin receptor kinase 7, TNF-α, and IL-6. | [71] |
| Genipin | Alloxan-induced diabetic rats—25, 50 and 100 mg/kg | Genipin reduced disturbance in glucose metabolism, ACT, lipid metabolism, and amino acid metabolism | [72] |
| Genipin | Diabetic rats—25, 50, and 100 mg/kg | Regulation of methylamine metabolism, energy metabolism, and amino acid metabolism
Nephroprotective effect | [73] |
| Geniposide | STZ-induced diabetic rats—25, 50 and 100 mg/kg | Inhibition of ICAM-1, TNF-α, IL-1, and IL-6 expression and inhibition of NF-kB activation by NF-κB, IKKα, and IκBα expression | [74] |
| Geniposide | Diabetic C57BL/KsJ-db/db mice—20 and 40 mg/kg | Inhibition of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα expression | [75] |
| Geniposide | HFD-induced diabetic mice—10 and 100 mg/kg | Inhibited transcription of G6PC and PEPCK. Suppress hepatic gluconeogenesis by regulating the AKT-FOXO1 pathway | [76] |
| Geniposide | STZ-induced diabetic C57BL/6 mice)—50 mg/kg | Geniposide increased the activities of PKA and GSK-3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction, and ameliorating the progression of DN | [77] |
| Geniposide | STZ-induced diabetic C57BL/6 mice—50 mg/kg/day | GEN inhibited ROS accumulation, NF-κB activation, Müller cell activation, and inflammatory | [78] |
| Geniposide | STZ-induced diabetic rats—200, 400, and 500 mg/kg | Geniposide significantly reduced inflammatory cell infiltration and proliferation of fibroblasts in the central lesion regions, and the levels of proinflammatory factors (tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b)) and IL-6 were significantly reduced | [79] |
| Geraniol | STZ-induced diabetic rats—100, 200, and 400 mg/kg | Administration for 45 days significantly improved the levels of insulin and Hb and decreased plasma glucose and HbA1C | [80] |
| Geraniol | STZ-induced diabetic rats—150 mg/kg | Geraniol suppressed the exaggerated oxidative stress as evidenced by preventing the increase in 8-isoprotane. Geraniol partially reduced hyperglycemia and prevented the hypercholesterolemia but did not affect the serum level of adiponectin in diabetic animals
Potent protective effect against cardiac dysfunction | [81] |
| Geraniol | STZ-induced diabetic rats—100 mg/kg | Reduced oxidative markers, decreased levels of PC, Ca2+, and AChE, restored enzyme activities, SDH, and CS | [82] |
| Gentiopicroside | HFD-induced diabetic mice—10 and 100 mg/kg | Regulation of the AKT-FOXO1 pathway | [76] |
| D-Limonene | STZ-induced diabetic rats—50 mg/kg | The blood glucose levels were found significantly lower at the 21st and 28th days of treatment
The serum AST and GGT levels, LDL, total cholesterol, and triglyceride levels in the D-limonene treated diabetic group were found to be significantly lower. The CAT, SOD, GSH-Px enzyme activities, and GSH levels in plasma, liver, and kidney increased | [83] |
| Loganin | STZ-induced diabetic mice—20 mg/kg | Reduces AGE levels and negatively regulates mRNA and protein expression of receptors for AGEs. Inhibition of AGE pathway. | [84] |
| Loganin | STZ-induced diabetic rats—40 mg/kg | Inhibition of proinflammatory cytokines | [85] |
| Loganin | STZ-nicotinamide-induced diabetic Sprague Dawley rats—5 mg/kg | Loganin improved PDN rats’ associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase, and glutathione. Loganin also reduced pain-associated channel protein CaV3.2 and calcitonin gene-related peptide (CGRP) in the surficial spinal dorsal horn of PDN rats. Loganin inhibited oxidative stress and NF-B activation and decreased the levels of mRNA and protein of proinflammatory factors IL-1 and TNF-α | [86] |
| Menthol | STZ-nicotinamide-induced diabetic rats—25, 50, and 100 mg/kg | Suppression of pancreatic β cell apoptosis, increased Bcl-2 expression, and reduced Bax expression. Modulation of glucose-metabolizing enzymes. | [87] |
| Myrtenal | STZ-induced diabetic rats—80 mg/kg | Myrtenal decreases plasma glucose, and increases plasma insulin, as well as upregulates IRS2, Akt, and GLUT2 protein expressions in liver, and IRS2, Akt and GLUT4 protein expressions in skeletal muscle | [88] |
| Myrtenal | STZ-induced diabetic rats—20, 40, and 80 mg/kg | The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6- bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats | [89] |
| Myrtenal | STZ-induced diabetic rats—80 mg/kg | Myrtenal improved plasma glucose levels while lowering levels of lecithin cholesterol acyltransferase (54.61 moles of cholesterol esterified/h/L), high-density lipoprotein (29.12 mg/dL), and pancreatic insulin (97.48 ng/mg) | [90] |
| Paeoniflorin | Mouse—70 and 140 mg/kg | Cardioprotection possibly by TRPV1/CaMK/CREB/CGRP signaling pathway | [91] |
| Paeoniflorin | STZ-induced diabetic mice—20 and 40 mg/kg | Induced suppression of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells | [44] |
| Paeoniflorin | Diabetic rats induced by a diet rich in sucrose, fat and low dose of streptozotocin—15 and 30 mg/kg | Paeoniflorin was correlated with its abilities of reducing the brain inflammatory cytokines (IL-1β and TNF-α), decreasing suppressor of cytokine signaling 2 (SOCS2) expressions, and promoting insulin receptor substrate-1 (IRS-1) activity. Additionally, we also found that paeoniflorin administration significantly promoted the phosphorylation levels of protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β). | [92] |
| Paeoniflorin | C57BL/6J mice with STZ-induced diabetic nephropathy—25, 50, and 100 mg/kg | Inhibition of toll-like receptors (TLR-2) pathway | [93] |
| Paeoniflorin | db/db mice with type 2 diabetic nephropathy—15, 30, and 60 mg/kg | Inhibit macrophage infiltration and activation by blocking the TLR2/4 signaling pathway | [94] |
| Paeoniflorin | Sprague Dawley rats with fructose-induced hepatic steatosis—10, 20, and 40 mg/kg | Activation of LKB1/AMPK and in insulin signaling, activation of β-oxidation and glycogenolysis | [95] |
| Paeoniflorin | Mice with cognitive deficits induced by intracerebroventricular injection of STZ in mice—10 mg/kg | Positive regulation of PI3K and Akt protein expression, while negatively regulating IRS-1 protein expression | [96] |
| Paeoniflorin | Type 1 diabetic mice induced by STZ—25, 50, and 100 mg/kg | Inhibition of the JAK2/STAT3 signaling pathway | [97] |
| Paeoniflorin | STZ-induced diabetic rats—10 μM | PF enhanced peroxiredoxin 3 (Prx3), mitochondrial processing peptidase α (PMPCA) expression, small ubiquitin-related modifier 1 (Sumo1) to enhance mitochondrial protein processing of Trx2, and mitochondrial protein processing of Trx2. In the sciatic nerve of DPN rats, PF elevated the levels of Trx2, TrxR2, and Prx3. PF increased the Trx2, TrxR2, and Prx3 levels in sciatic nerve of DPN rats. | [98] |
| Swertiamarin | STZ-induced diabetic rats—15, 25, and 50 mg/kg | Swertiamarin decreased fasting blood glucose, HbA1c, TC, TG, and LDL and increased the levels of hemoglobin, plasma insulin, TP, body weight, and HDL significantly | [99] |
| Thymol | C57BL/6J mice with HFD-induced DT2—10, 20, and 40 mg/kg | Thymol increased activities of LCAT and LPL and decreased activities of HMG-CoA reductase | [100] |
| Thymol | High-fat diet (HFD)-induced diabetic C57BL/6J mice—40 mg/kg | Thymol inhibited the activation of transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF) | [101] |
| Thymol | C57BL/6J mice on HFD diet—20 and 40 mg/kg | Thymol downregulated the level of P-Ser307 IRS-1, hence enhancing the expression of P-Ser473 AKT and P-Ser9 GSK-3β | [102] |
| Thymol | STZ-induced diabetic rats—10 and 20 mg/kg | Antidiabetic and neuroprotective
Biomarkers such as SOD, NO, LPO, Na + K + ATPase, and TNF-α further confirmed the protective action of thymol in diabetic neuropathy | [103] |
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