Review Article

Use of Monoterpenes as Potential Therapeutics in Diabetes Mellitus: A Prospective Review

Table 3

In vitro antidiabetic effects of monoterpenes.

MonoterpenesModelEffects/markersReferences

CatalpolMyeloblasts C2C12 cellsCatalpol elevates MyoD/MyoG expression and improves skeletal muscle myogenesis. Enhanced myogenesis results in activation of the insulin signaling pathway in skeletal muscle cells (via PI3K/AKT), which may help improve glucose homeostasis.[29]
CatalpolHuman hepatocellular carcinoma cells (HepG2)Catalpol decreased in gluconeogenesis and increased in hepatic glycogen synthesis, through the regulation of the AMPK/NOX4/PI3K/AKT pathway[30]
CatalpolHuman hepatocellular carcinoma cells (HepG2)Catalpol attenuated the decrease in ATP levels and mitochondrial membrane potential, thereby reducing the formation of reactive oxygen species induced by elevated glucose levels[31]
CymeneBovine serum albumin (BSA) glycationInhibition of BSA protein glycation[32]
CymeneBovine serum albumin (BSA) glycationInhibition of BSA protein glycation[33]
CitralMouse 3T3-L1 fibroblast preadipocytesInhibition of adipogenesis in 3T3-L1 adipocytes through modulation of adipogenic transcription factors and inflammatory markers[34]
CitralHuman hepatocellular carcinoma cells (HepG2)Protection against oxidative stress through inhibition of the ROS-activated MAPK signaling pathway in HepG2 cells[35]
GenipinRat renal proximal tubular cells (NRK-52E)A UCP2 (uncoupling protein-2) inhibitor, boosted oxidative stress, attenuated antioxidative capacity, and exacerbated cell apoptosis accompanied with caspase-3 activation in rat renal proximal tubular cells (NRK-52E)[36]
GeniposideMouse INS-1 pancreatic β cellsGeniposide reduces apoptosis of pancreatic cells by inhibiting the Txnip protein[37]
GeniposidePancreatic cells from C57BL/6J miceGeniposide protected β cells against hyperglycemia and toxicity mediated by proinflammatory cytokines, through activation of β-catenin signaling and upregulation of TCF7L2 expression and activation of the JAK2/STAT3 pathway[38]
LimoneneC2C12 skeletal muscle cellsLimonene induces osteoblast differentiation and glucose uptake through activation of p38MAPK and Akt signaling pathways[39]
LimoneneOsteoblastic cells MC3T3-E1Limonene reduced ROS, inflammatory cytokines, and mitochondrial dysfunction and increased AMPK, PGC-1α, and NO levels[40]
LoganinSchwann cell line RSC96 cellsLoganin attenuates hyperglycemia-induced Schwann cell pyroptosis by inhibiting ROS generation and NLRP3 inflammasome activation[41]
PaeoniflorinMouse INS-1 pancreatic β cellsPaeoniflorin prevented oxidative stress and cellular apoptosis in STZ-treated INS-1 cells through inhibition of p38 MAPK and JNK pathways[42]
PaeoniflorinHuman retinal pigmented epithelial cells (ARPE-19)Paeoniflorin dose-dependently attenuated RAL-induced cell injury by reducing oxidative stress associated with Nox1/ROS, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in ARPE-19 cells[43]
PaeoniflorinMicroglial cells BV2Paeoniflorin suppressed expression of cytokine 3 signaling (SOCS3) and reduced MMP-9 activation, attenuating diabetic retinopathy in BV2 cells[44]
PaeoniflorinCellsSuppression of ROCK activation and IRS-1 expression, promoting phosphorylation of Akt and GSK-3β[45]
PaeoniflorinHuman umbilical vein endothelial cells (HUVEC)Paeoniflorin reduced AOPP-induced oxidative damage in HUVECs, decreasing ROS production by inhibiting Nox2/Nox4 and RAGE expression, and restored ATP depletion and mitochondrial dysfunction via suppression of ROS[46]
PaeoniflorinGlomerular mesangial cells HBZY-1Paeoniflorin attenuates mesangial cell damage induced by advanced glycation end products (AGEs) and combats autophagy through inhibition of RAGE and upregulation of p-mTOR level[47]
PaeoniflorinSchwann cell lineage (RSC96)Paeoniflorin suppressed the oxidative stress of Schwann cells induced by hyperglycemia, decreasing ROS and MDA levels and increasing GST and GPX activity, promoted the dissociation of Nrf2 from Keap1, and upregulated the Nrf2 pathway[48]
PaeoniflorinMethylglyoxal- (MG-) induced MC3T3-EI osteoblastic cellsPaeoniflorin reduced MG-induced apoptosis and ROS formation in MC3T3-E1 osteoblastic cells. It increased GSH level and reduced MG-induced mitochondrial dysfunction.[49]
PineneHuman skin epidermal keratinocytes (HaCaT cells)Pinene inhibited ROS formation, lipid peroxidation, and DNA breakdown through its antioxidant property. It also suppressed the expression of NF-κB, TNF-α, and IL-6 in HaCaT cells[50]
SwertiamarinHuman hepatocellular carcinoma cells (HepG2)Swertiamarin increased the expression of key insulin signaling proteins such as IR, PI(3)K, and pAkt, with concomitant reduction in IRS-1, activated AMPK, modulated PPAR-α, and decreased levels of the gluconeogenic enzyme PEPCK[51]
Swertiamarin5-HT2 receptorNormalize the mRNA expression of Glut 4, adiponectin, SREBP-1c, PPARγ, LPL-1, and leptin. Increase in PI3K expression.[52]
ThymolHuman podocytes stimulated by AGE (taken from the serum of diabetic patients with diabetic neuropathy)Thymol restored the expression of RhoA, ROCK, vimentin, nephrin, and podocin and the phosphorylation of p65 and IκBα. It inhibited the induction of proinflammatory cytokines and cell apoptosis. Thymol improves migration capacity in human podocytes induced by AGEs.[53]
ThymolIsolated lenses from goat eyesThymol stopped the progression of high-glucose-induced cataracts through its antioxidant and aldose reductase (AR) inhibitory activities[54]

PI3K: phosphatidylinositol-3-kinase; AKT: protein kinase B; NOX4: NADPH oxidase type 4; AMPK: AMP-activated protein kinase; HepG2: human hepatocellular carcinoma cell line; AGEs: advanced glycation end products; 3T3-L1: mouse preadipocyte cell lines; PPARγ: peroxisome proliferator-activated receptor γ; SREBP-1c: sterol regulatory element binding protein; TNF-α: tumor necrosis factor-alpha; IL-6: interleukin-6; MCP-1: macrophage chemotactic protein-1; ROS/EROS: reactive oxygen species; MAPK: mitogen-activated protein kinase; ERK-1: extracellular signal-regulated protein kinase; JNK: c-Jun N-terminal kinase; NRK-52E: rat proximal renal tubular cells; UCP2: uncoupling protein 2; Txnip: thioredoxin-interacting protein; INS-1: mouse pancreatic β cell line; TCF7L2: T cell factor 7 type 2; MC3T3-E1: osteoblastic cell line; NO: nitric oxide; PGC-1α: peroxisome proliferator-activated receptor gamma-1 coactivator; MMP-9: microglial matrix metalloproteinase 9; GSK-3β: glycogen synthase kinase-3β; IRS-1: insulin receptor-1 substrate; MMP: mitochondrial membrane potential; NF-κB: nuclear factor-κB; HIF-1α: hypoxia-inducible factor-1α; VEGF: vascular endothelial growth factor; NOX2: NADPH oxidase 2; Nrf2: factor 2 related to nuclear factor E2; ARE: antioxidant response element; PEPCK: phosphoenolpyruvate carboxykinase. RAGE: advanced glycation end product induction receptor.