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

Monoterpenes are secondary metabolites of plants belonging to the terpenoid class of natural products. They are the most abundant components of essential oils that are generally considered to have various pharmacological properties. These compounds are reported to have antidiabetic effects in recent years. Due to nature's complex biosynthetic machinery, they also exhibit a reasonable degree of structural complexity/diversity for further analysis in structure-activity studies. Therefore, monoterpenes as antidiabetic agents have been investigated by recent in vitro and in vivo studies extensively reported in the scientific literature and claimed by patent documents. The purpose of this survey is to provide a comprehensive and prospective review concerning the potential applications of monoterpenes in the treatment of diabetes. The data for this research were collected through the specialized databases PubMed, Scopus, Web of Science, and ScienceDirect between the years 2014 and 2022, as well as the patent databases EPO, WIPO, and USPTO. The research used 76 articles published in the leading journals in the field. The main effect observed was the antidiabetic activity of monoterpenes. This review showed that monoterpenes can be considered promising agents for prevention and/or treatment of diabetes as well as have a marked pharmaceutical potential for the development of bioproducts for therapeutics applications.


Introduction
Diabetes mellitus is a chronic disease that afects about 3% of the world's population and its prevalence has increased given the aging population.In 2015, the International Diabetes Federation (IDF) estimated that one in 11 adults aged 20 to 79 years had type 2 diabetes mellitus.Diabetes mellitus ranks ninth among diseases that cause loss of healthy life years.Around 422 million people worldwide have DM and 1.6 million deaths are directly attributed to the disease each year [1].Tere has also been an increase in the number of deaths from DM between 1990 and 2019, from 1,278,866 to 2,988,924 (an increase of 133.71%).For disability-adjusted life years (DALYs), growth was observed from 28,586,671 in 1990 to 70,888,154 in 2019 (148% increase).In Brazil, the scenario is similar, with DM accounting for 43,787 deaths in 1990 and 107,760 in 2019 (7.64% of the total), as well as causing 1,730,460 DALYs in 1990 and 3,750,735 in 2019 (5.73% of the total) [2].
Diabetes mellitus (DM) has a complex and multifactorial etiology, involving genetic and environmental components, resulting from altered insulin production by the pancreas and/or inability to adequately exert its function in the body [3].Diabetes can be classifed into four main types: (a) type 1 diabetes (T1D), characterized by the autoimmune destruction of pancreatic β cells, causing defciency in insulin production; (b) MODY type diabetes, caused by idiopathic insulin defciency; (c) type 2 diabetes (T2D), caused by the progressive loss of insulin secretion combined with insulin resistance; and (d) gestational diabetes characterized by hyperglycemia of varying degrees, diagnosed during pregnancy [4].
Type 1 diabetes (T1D) presents itself as an autoimmune disorder marked by the destruction of β cells in the islets of Langerhans of the pancreas, mediated by T lymphocytes.Tis destruction leads to an almost complete loss of the ability to synthesize insulin [5].As a result of this depletion of β cells, the body loses the ability to regulate blood sugar levels, requiring, as a classic alternative treatment, the administration of exogenous insulin.Besides, T2DM is characterized by the progressive and irreversible loss of β cell function [6].
Conventional treatment of DM1 continues to be based mainly on the therapeutics use of insulin, more recently making use of various synthetic analogues of the hormone with diferent pharmacokinetic profles.In addition to insulin and its analogues, some noninsulin drugs, such as biguanides, are used as therapeutics adjuvants in the treatment of DM1.Currently, metformin is the most prescribed noninsulin drug in Brazil, although the percentage of patients who use this therapy does not reach 5% of the total [7].Current treatment of T2DM basically consists of changes in diet and lifestyle with the progressive addition of more complex antidiabetic regimens (including metformin, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, thiazolidinediones, and so on) and eventually supplemental insulin therapy [8].
DM evolves with micro-and macrovascular complications, which result in repercussions on target organs, such as the heart, blood vessels, eyes, kidneys, and brain [9].One of the reasons to these outcomes is correlated to a low total adherence (1.4%) to the suggested clinical treatment, as pointed out by Faria et al. [10] who found an adherence of 84.4% of diabetics to drug treatment, 58.6% to regular physical activity practice, and 3.1% to a diet plan appropriate to the disease.
Te low adherence to DM treatment has a huge economic impact on today's society, afecting not only health systems but also individuals and their families, in addition to generating a loss of quality of life for the patient, with a high degree of limitation in work and leisure activities [11].In this context, patients with DM have a higher risk of presenting polypharmacy (35.8%) than other patients that can lead to risk of drug interactions (15.1%) and impairment to the diabetic's glycemic control [12].Te challenge is to reduce polypharmacy, especially in the elderly, choosing safe, effective options without risk of interactions.In this sense, the use of food supplements (vitamins, phenolic compounds, omega 3, and other bioactive compounds) has gained space, especially in the treatment of T2D.In the search for an antioxidant and anti-infammatory efect adjacent to the hypoglycemic efect, the search for bioactive compounds has gained increasing importance, among which we highlight the monoterpenes.
Several studies have already proven the therapeutics importance of products of natural origin in the control, treatment, and prevention of several diseases.Substances called phytochemicals are extracted from these natural products.Among the phytochemicals most studied for therapeutics purposes, polyphenols, favonoids, alkaloids, tannins, coumarins, and terpenoids stand out, the latter being the object of study in this work.Among the main pharmacological activities attributed to many of these substances, especially to terpenes, anti-infammatory, gastrointestinal tract protective, cardioprotective, antioxidant, and antidiabetic activity stand out [13].Terpenoids are secondary metabolites of various types of plants, synthesized by the mevalonic acid pathway and contribute to their direct defense mechanism and their favor profle [14].
Terpenes are the most abundant natural products, present in higher plants, citrus, conifers, and eucalyptus, and are widely distributed in the leaves, fowers, stems, and roots of these plants.Terpenes show signifcant structural variation, including linear hydrocarbons or carbocyclic skeletons.Terpenes undergo oxygenation, hydrogenation, or dehydrogenation to form terpenoids [15].Te classifcation of terpenes is based on the isoprene units proposed by Wallach in 1887 (C5H8), a 5-carbon compound that forms the skeletons of terpenes, and can be didactically described as follows: hemiterpenes are the simplest, with a single unit of isoprene; monoterpenes are highly diverse and have two isoprenoid units; sesquiterpenes are abundant natural compounds with three isoprene molecules; diterpenes are nonvolatile C20 hydrocarbons derived from four isoprene units; triterpenes are derived from the C30 precursor, squalene, made up of two molecules of sesquiterpenes; and tetraterpenes (carotenoids) are 8-isoprene units [16].
Monoterpenes occur in monocotyledonous and dicotyledonous angiosperms, fungi, bacteria, and gymnosperms and have two isoprenoid units.Tey are aromatic compounds responsible for the odor of many fowers and fruits.Monoterpenes include acyclic, monocyclic, and bicyclic forms.Tey are widely used as active ingredients for agricultural, pharmaceutical, cosmetic, and food applications.Pinenes, carveol, camphor, menthol, and limonene, for example, are active ingredients in a wide variety of industrial applications.
Monoterpenes, like sesquiterpenes and diterpenes, are secondary metabolites because they are classifed as nonessential for viability and mediate important interactions between plants and their environment [17].Several monoterpenes are widely used in the agricultural, cosmetic, and food industries and as a general antiseptic in medical practice [18], in addition to clinical use for their pharmacological properties, including antifungal, antibacterial, antioxidant, anticancer, and antispasmodic [19][20][21][22][23]. Monoterpenes

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Advances in Pharmacological and Pharmaceutical Sciences can also have signifcant efects in diabetes by promoting hypoglycemic activity [24].Studies have shown that monoterpenes include a wide variety of substances that possess antioxidant activity [25], which may prevent diabetic complications associated with oxidative stress [26,27].Te general efects of monoterpenes on diabetes are schematized in Figure 1.
In this context, monoterpenes may be useful as agents for the prevention and/or treatment of diseases such as diabetes, a pathology with high mortality rates.In an attempt to reduce this impact, the search for substances of natural origin that have an antidiabetic efect has intensifed.In this feld, the study of the efects of some monoterpenes on diabetes stands out, such as limonene and carveol [28].Considering the functional multicomplexity linked to diabetes, monoterpenes draw attention for demonstrating in pharmacological studies diverse and interesting in vitro and in vivo efects of several of their chemical constituents present in essential oils of medicinal plants on diabetes.Tus, the objective of this work was to carry out a bibliographic review of the studies that deal with the efects of monoterpenes on diabetes, highlighting the types of research carried out (in vitro and in vivo), experimental models used, and main results obtained.In addition, we carry out technological prospecting for product patents containing monoterpenes developed for the treatment and/or prevention of diabetes and its main complications.
Te technological prospection of patents and the inclusion in the research of more recent articles on the subject: monoterpenes as a therapeutics alternative to conventional treatments for diabetes, not yet mentioned in previous reviews, undoubtedly constitute factors of scientifc innovation of this work.

Methodology
Tis systematic review used a literature search to fnd articles published in the last eight years.Te search was conducted using the specialized databases PubMed, Scopus, Web of Science, and ScienceDirect, using a combination of the English descriptors: "Monoterpenes" and "Diabetes."A total of 1410 articles were found, of which 76 articles were used for the literature survey.Te following inclusion criteria were adopted: years 2014 to 2022, clinical and nonclinical studies using monoterpenes in the prevention and/or treatment of diabetes, written in English, full text in electronic media, and articles that presented results of monoterpenes alone or in combination.Articles that were found in more than one database (duplicates) were included in the fnal count of articles used in the study only once.As for the exclusion criteria, we did not use abstracts, monographs, theses, thesis chapters, books, book chapters, congress or conference proceedings, and technical and scientifc reports, in addition to excluding articles considered "irrelevant" to the study after a thorough reading.
Te search for patents was conducted in the European Patent Ofce (EPO), World Intellectual Property Organization (WIPO), and United States Patent and Trademark Ofce (USPTO) databases using the combination of descriptors in English "monoterpenes" and "diabetes," in addition to a search in the Brazilian National Institute of Industrial Property (INPI) database with descriptors in Portuguese.No time frame was established for the search.

Important Aspects of the Analyzed Manuscripts
As for the type of study, in vivo trials were the most prevalent being recorded in 54 manuscripts (71.05%), while in vitro studies appeared in 22 studies (28.95%), with 4 articles from in vivo trials that also did in vitro trials.A synthesis of the studies was performed according to their characteristics.Te main study models were rats with 33 In in vitro studies, the concentrations used of the monoterpenes analyzed ranged from 0.01 to 200 µM, with 57.70% of the manuscripts evaluating monoterpenes at doses lower than 50 µM.Te in vivo manuscripts presented doses ranging from 5 to 500 mg/kg, with 49.10% of studies with doses less than or equal to 50 mg/kg and 47.27% of studies testing doses ranging from 50 to 200 mg/kg.It is worth noting that in this universe of studies, there was a greater emphasis on testing the doses of monoterpenes at 50 mg/kg and 100 mg/kg.Te main activity of the monoterpenes analyzed was antidiabetic, found in 45 manuscripts (59.21%).Te main route of administration used in the analyzed articles was oral with 36 studies (67.92%).

Pharmacological Activity of Monoterpenes, Observed
Effects, and Underlying Markers.Te main pharmacological activities found in the studies reviewed were antidiabetic, antihyperlipidemic, antioxidant, anti-infammatory, hepatoprotective, nephroprotective, cytoprotective, cardioprotective, vasorelaxant, and hypoglycemic.Te main monoterpenes identifed in this review as well as the type of study, study model, the observed efects, and the markers involved are listed in Tables 3 and 4.
Paeoniforin (PF) ameliorated the inhibitory efect caused by streptozotocin (STZ) on cell viability and insulin secretion capacity in INS-1 cells, reduced caspase-3 activity and Bax expression, and induced Bcl-2 expression in STZtreated INS-1 cells.Treatment with paeoniforin resulted in a decrease in the production of reactive oxygen species and malondialdehyde (MDA) and an increase in superoxide dismutase (SOD) activity in STZ-treated INS-1 cells.In addition, this monoterpene inhibited the phosphorylation of p38 and JNK, which is induced by STZ in INS-1 cells, and suppressed the activation of p38 MAPK and JNK pathways in STZ-treated INS-1 cells.Paeoniforin may be a natural antidiabetic agent by ameliorating pancreatic β cell injury through inhibition of p38 MAPK and JNK signaling pathways [42].For Wang et al. [96], paeoniforin signifcantly attenuated STZ-induced mitochondrial dysfunction and improved impaired insulin signaling by positively regulating p-PI3K and pAkt protein expression, while negatively regulating p-IRS-1 protein expression.
Reduced germ cell apoptosis. [60] Carvacrol STZ-induced diabetic C57BL/6J mice-10, 20, and 40 mg/kg/day A signifcant improvement in glucose tolerance and a signifcant 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.Te 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] Te serum levels of TC, TG, and LDL-C were markedly reduced, whereas HDL-C levels were signifcantly increased Decreased serum ALT and AST levels Protective efects 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 signifcant improvement in the levels of Hb and insulin.Te 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]
Paeoniforin also has an action at the level of increasing the expression of mitochondrial processing peptidase α (PMPCA) and small ubiquitin 1 (Sumo1) which are responsible for increasing mitochondrial Trx2 (thioredoxin 2) protein processing and increasing Trx2 levels, TrxR2, and Prx3 in the sciatic nerve of rats with diabetic neuropathy, a severe consequence of diabetes mellitus, thereby reducing demyelination as well as improving mechanical pain threshold, thermal pain threshold, motor nerve conduction velocity (MNCV), and sensory nerve conduction velocity (SNCV).Overall, these results suggest that paeoniforin could provide protection for the diabetic neuropathy (ND) condition by regulating Trx2 [98].Paeoniforin is, therefore, a natural glycoside with antihyperglycemic efect.
Catalpol is a natural product isolated from Rehmannia glutinosa root, which has been reported to produce antidiabetic efect [30].Catalpol possesses hypoglycemic efect via modulation of various gene expressions such as SOCS3, Irs1, Idh2, and G6pd2 [65].Catalpol enhanced hepatic NADPH oxidase type 4-(Nox4-) mediated oxidative stress and activated hepatic AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) via AKT in vivo and in vitro.Te suppressive efect of catalpol on NOX4 was weakened by silencing AMPK with siRNA.Catalpol improved hepatic insulin resistance in type 2 diabetes through action on the AMPK/NOX4/PI3K/AKT pathway [30].Catalpol has a protective efect on the endothelium in type 2 diabetes mellitus and its mechanism may be associated with the negative regulation of Nox4 and p22phox expression, inhibiting the oxidative stress reaction response [67].According to Xu et al. [29], catalpol treatment in mice reduced blood glucose and improved insulin sensitivity via phosphatidylinositol-3-kinase (PI3K)/via protein kinase B (AKT) activation.Furthermore, catalpol-treated mice exhibited increased myogenesis, as evidenced by increased expression of myogenic diferentiation (MyoD), myogenin (MyoG), and myosin heavy chain (MHC).In vitro experimental results showed that catalpol increased glucose uptake via activation of PI3K/AKT pathway that was dependent on MyoD/MyoG-mediated myogenesis.
Oral administration of catalpol at 100 mg/kg signifcantly improved fasting glucose and insulin levels, glucose tolerance, and insulin tolerance.In addition, macrophage infltration of adipose tissue was markedly reduced by catalpol.Interestingly, catalpol also signifcantly reduced the mRNA expressions of proinfammatory M1 cytokines but increased the expressions of anti-infammatory M2 genes in adipose tissue.Simultaneously, catalpol signifcantly suppressed c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways in adipose tissue.Catalpol can improve HFD-induced insulin resistance in mice by attenuating adipose tissue infammation and suppressing JNK and NF-κB pathways [66].In the manuscript of Yang et al. [48], catalpol treatment abrogated the elevated expression of Grb10 in diabetic kidneys.IGF-1 mRNA levels and IGF-1R phosphorylation were signifcantly higher in the kidneys of treated diabetic mice than those in untreated diabetic mice.Elevated Grb10 expression may play an important role in nephropathy pathogenesis through suppression of the IGF-1/IGF-1R signaling pathway, which may be a potential molecular target of catalpol for the treatment of diabetic nephropathy.
Geniposide is a naturally occurring iridoid glycoside.Tis monoterpene inhibited G6PC and PEPCK transcription in L02 cells and in mice and was able to inhibit FOXO1 transcriptional activity by inducing AKT phosphorylation at Ser473.Geniposide also alleviates high-fat diet-induced hyperglycemia in mice and can reduce blood glucose and suppress hepatic gluconeogenesis through regulation of the AKT-FOXO1 pathway [76].Geniposide accelerates the degradation of Txnip (thioredoxin-interacting protein) by the proteasome pathway in pancreatic β-cells INS-1.Furthermore, the combination of geniposide and Txnip shows substantial synergistic efects to reduce glucose uptake, metabolism, and GSIS in INS-1 cells treated with high glucose [37].Te levels of the proinfammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor α were decreased by geniposide in diabetic db/db mice.Te expression levels of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα were signifcantly reversed by treatment with the said monoterpene, which demonstrated that geniposide exhibits a protective efect on diabetic liver infammation [75].For Hu et al. [74], Dusabimana et al.
Geniposide protected β-cells through activation of Wnt signaling, increased expressions of TCF7L2 and O GLP-1R, activated AKT, inhibited GSK3 activity, and promoted catenin nuclear transactivation.Te protective efect of geniposide was remarkably suppressed by siRNAs against β-catenin or by ICG001 (inhibitor of β-catenin/TCFmediated transcription).Moreover, geniposide promoted β cell regeneration in vivo to normalize blood glucose on highfat diet in mice.Increased β cells and proliferation were observed in the pancreas of diabetic mice treated with geniposide.More importantly, geniposide triggered formation of small cell clusters that was well correlated with increased TCF7L2 expression.In exocrine cells isolated from mouse pancreas, geniposide can induce diferentiation of duct cells through positive regulation of TCF7L2 expression and activation of JAK2/STAT3 pathway [38].
In mice with diabetic retinopathy, geniposide inhibited the accumulation of reactive oxygen species, activating NF-κB and Müller cells and being able to reduce infammation via cytokine secretion, mediated by the Nrf2 pathway.Geniposide decreased hyperglycemia-induced damage to Müller cells and the blood-retinal barrier in the retinas of mice with diabetic retinopathy [78].
Carvacrol (CAR) is a monoterpene phenol that has good antioxidant activity.Increasing doses of CAR decreased tissue malondialdehyde (MDA) and 8-OH-dG levels as well as reduced lipase and amylase levels [59].For Shoorei et al. [60], carvacrol treatment reduced the tissue activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) and decreased elevated tissue malondialdehyde (MDA) levels.In addition, carvacrol signifcantly decreased Bax and increased Bcl-2 in gene and protein expression levels as well as reduced the rate of germ cell apoptosis.
Treatment with carvacrol in HFD-induced mice showed a decrease in plasma glucose and glycosylated hemoglobin as well as increased insulin and hemoglobin levels.Te activities of carbohydrate metabolic enzymes such as glucose-6phosphatase and fructose-1,6-bisphosphatase decreased, while the activities of glucokinase and glucose-6-phosphate dehydrogenase increased in the liver of HFD mice.Te activities of liver marker enzymes such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase decreased in HFD mice [58].For Ezhumalai et al. [57], carvacrol treatment further showed a decrease in total cholesterol (TC), triglycerides (TG), phospholipids (PL), and free fatty acids (FFAs) in plasma and tissues.In addition, decreased levels of very lowdensity lipoprotein cholesterol (VLDL-c) and low-density lipoprotein cholesterol (LDL-c) and increased levels of high-density lipoprotein cholesterol (HDL-c) were observed in the plasma of diabetic rats.Histopathological analysis of adipose tissues and immunohistochemical analysis of liver tissue showed that infammatory cytokines (TNF-α and IL-6) were in agreement with biochemical parameters.
Carvacrol in STZ-induced rats decreased random plasma glucose and fasting plasma glucose levels signifcantly in a dose-dependent manner.Carvacrol at a dose of 20 mg/kg in diabetic mice caused the decrease in plasma triglyceride level and signifcantly reduced plasma LDH level, but not AST, ALT, or ALP, and there was increased activity of hexokinase (HK), 6-phosphofructokinase (PFK), and citrate synthase (CS) [61].Te study by Zhao et al. [62] showed improvement in glucose and insulin resistance of T2DM db/db mice treated with 10 mg/kg carvacrol.After treatment with carvacrol for 6 weeks, serum levels of total cholesterol, triglycerides, and LDL-cholesterol were markedly reduced, while level of HDL-cholesterol was signifcantly increased.Serum ALT and AST levels were signifcantly reduced in mice after the use of carvacrol, suggesting improvement of liver damage.Histological examinations confrmed that carvacrol can protect mouse liver by ameliorating T2DM-induced liver injury via mediating insulin, TLR 4/NF-κB, and AKT1/mTOR signaling pathways.
Tymol is a monoterpene phenol with many pharmacological activities.Treatment with thymol decreased plasma glucose, insulin, insulin resistance, HbA1c, leptin, and adiponectin.Tymol supplementation signifcantly reduced plasma concentrations of triglycerides (TG), total cholesterol (TC), free fatty acids (FFAs), and low-density lipoprotein (LDL) and increased HDL-cholesterol [100].Tymol inhibited the activation of transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF).In addition, it signifcantly increased antioxidants and suppressed lipid peroxidation markers in erythrocytes and kidney tissue.Tymol negatively regulates the expression level of sterol regulatory element-binding protein-1c (SREBP-1c) and reduces lipid accumulation in kidney.Histopathological study of kidney tissues showed that extracellular mesangial matrix expansion and glomerulosclerosis in diabetic mice were suppressed by thymol.Furthermore, thymol administration conferred remarkable protection against HFD-induced diabetic nephropathy [101].
Tymol also showed potent inhibitory activity against the enzyme aldose reductase as well as was able to signifcantly reduce oxidative stress, suggesting that thymol may be a potential therapeutics in preventing diabetic complications through its inhibitory and antioxidant activities [54].Fang et al. [102] observed that thymol treatment signifcantly reversed body weight gain and peripheral insulin resistance.Tymol improved cognitive impairment and decreased HFD-induced Aβ deposition and hyperphosphorylation of tau protein in the hippocampus, which may correlate with inhibition of oxidative stress and infammation in the hippocampus.Furthermore, thymol negatively regulates the level of P-Ser307 IRS-1 and thus increases the expression ofP-Ser473 AKT and P-Ser9 GSK-3β.Te protective efects of thymol on cognitive defcits were associated with positive regulation of the nuclear respiratory factor (Nrf2)/ heme oxygenase-1 (HO-1) pathway.Tymol exhibited benefcial efects on cognitive defcits by improving insulin resistance in the hippocampus and activating Nrf2/HO-1 signaling [102].Advances in Pharmacological and Pharmaceutical Sciences Tymol can markedly suppress infammatory responses, apoptosis cells, and disordered cytoskeleton by restoring podocin expression.In western blot analysis, thymol indicated that it could restore the expression of RhoA, ROCK, vimentin, nephrin, and podocin and phosphorylation of p65 and IκBα.In addition, si-RhoA also suppressed the expression of proinfammatory cytokines, ROCK, and vimentin and the phosphorylation of p65 and IκBα [53].
In a 12-week treatment performed on streptozotocin-(STZ-) induced diabetic rats with induced diabetic neuropathy, thymol isolated from the fruit Trachyspermum ammi showed improvement in blood glucose, initially with a concentration of 308.27 ± 0.37 mg/dL and reducing on day 28 of use, respectively, to 129.01 ± 3.45 mg/dL on treatment with 10 mg/kg and to 117.12 ± 1.35 mg/dL with 10 mg/kg, in addition to improvement in lipid profle, such as triglycerides, LDL-cholesterol, and VLDL-cholesterol.Te biomarker studies (SOD, NO, LPO, Na + K + ATPase, and TNF-α) further confrmed the protective action of thymol in diabetic neuropathy [103].
Genipin is the main active component of Gardeniae fructus and has been shown to improve diabetes and insulin resistance in rat models.Tis monoterpene reduced body weight, food intake, and visceral fat mass.It improved dyslipidemia, glucose intolerance, insulin intolerance, adipocyte hypertrophy, and hepatic steatosis as well as reduced the serum level of tumor necrosis factor α in diet-induced obese mice.Moreover, genipin promoted lipolysis and β-oxidation of fatty acids by increasing gene expression of hormone-sensitive lipase and adipose triglyceride lipase in white adipose tissue (WAT) and peroxisome proliferatoractivated receptor-α and carnitine palmitoyltransferase 1α in liver tissue.Te said monoterpene also promoted browning of WAT by increasing mRNA and protein levels of uncoupling protein 1 and PRD1-BF1-RIZ1 gene.In addition, it inhibited the gene expressions of activin receptor kinase 7, tumor necrosis factor α, and interleukin 6 in WAT [71].
Genipin acts in regulating methylamine metabolism, energy metabolism, and amino acid metabolism [73].Detailed analysis of altered metabolite levels indicated that genipin signifcantly ameliorated disruption in glucose metabolism, tricarboxylic acid cycle, lipid metabolism, and amino acid metabolism [72].Genipin, a UCP2 inhibitor, dramatically increased oxidative stress, attenuated antioxidant capacity, and exacerbated cell apoptosis, accompanied by caspase-3 activation in rat proximal kidney cells (NRK-52E) incubated with high glucose.Tese data suggest that manipulation of UCP2 could be important in preventing oxidative damage in renal tubular epithelial cells induced by hyperglycemia in vitro [36].
Geraniol is an acyclic monoterpene alcohol found in medicinal plants and is traditionally used for various medical purposes, including diabetes.Administration of geraniol in a dose-dependent manner (100, 200, and 400 mg/kg b.c.) signifcantly improved insulin levels and Hb and decreased plasma glucose and HbA1C in diabetic rats.Geraniol at its efective dose (200 mg/kg b.w.) improved altered carbohydrate and metabolic enzyme activities.Treatment with geraniol in diabetic rats improved liver glycogen content, suggesting its potential hyperglycemic action.Geraniol supplementation was found to preserve the normal histological appearance of liver cells and pancreatic b-cells in diabetic rats [80].
Geraniol suppressed exaggerated oxidative stress, evidenced by prevention of 8-isoprostane increase.In diabetic heart tissue, geraniol prevented inhibition of catalase activity but did not afect heart SOD.Geraniol partially reduced hyperglycemia and prevented hypercholesterolemia but did not afect serum adiponectin level in diabetic animals.Te fndings suggest that geraniol provides a potent protective efect against diabetes-induced cardiac dysfunction.Tis benefcial efect can be attributed to the suppression of oxidative stress [81].According to Prasad and Muralidhara [82], geraniol reduced oxidative markers, decreased levels of CP, Ca2+, and AChE, and restored the activities of enzymes, SDH, and CS.
Myrtenal is a monoterpene, a constituent of essential oils found mainly in herbs such as mint, pepper, and cumin.It exerts admirable pharmacological activities against many diseases, including diabetes.Myrtenal improves plasma glucose, pancreatic insulin, and lipid profles (TC, TG, FFAs, phospholipids, LDL, VLDL, and atherogenic index) in addition to improving the histopathological feature of the liver [90].Myrtenal treatment decreases plasma glucose levels, and increases insulin levels, as well as promote upregulation of GLUT2, Akt, and IRS2 in liver, and GLUT4, Akt, and IRS2 in skeletal muscle.Positive regulation of glucose transporters increases glucose uptake in liver and skeletal muscle [88].
Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats resulted in a signifcant reduction in plasma glucose levels and glycosylated hemoglobin (HbA1c) and increased insulin and hemoglobin (Hb) levels.Te altered activities of major metabolic enzymes involved in carbohydrate metabolism were noted, such as hexokinase, glucose-6-phosphatase, fructose-1,6biphosphatase, and glucose-6-phosphate dehydrogenase, and the liver enzymes AST, ALT, and ALP of diabetic rats were signifcantly improved by myrtenal administration in STZ-induced diabetic rats.In addition, myrtenal treatment improved liver and muscle glycogen content in diabetic rats.Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions upon myrtenal treatment in STZ-induced diabetic rats.An alteration in liver architecture was also prevented by myrtenal treatment.Te results suggest that myrtenal possesses antihyperglycemic and β cell protective efects and can be considered a potent phytochemical for development as a novel antidiabetic agent [89].
Cymene, a monoterpene commonly found in Cuminum cyminum, improved HbA1c and serum fructosamine, where levels were normalized.Nephropathic parameters such as albumin excretion rate, serum creatinine, and creatinine clearance rate were improved.Cymene treatment further improved the solubility profle of collagen.In in vitro studies, cymene inhibited the total fuorescence of AGEs and pentosidine.Te glycation-specifc decline in the α-helix Advances in Pharmacological and Pharmaceutical Sciences content of BSA and increase in the B-sheet were prevented by cymene in vitro, implying its stabilizing efect.Te results suggest that cymene could have therapeutics potential in preventing glycation-mediated diabetic complications [33].Cymene strongly inhibits the formation of AGEs in a concentration-dependent manner, inhibiting protein glycation [32].
In a study with STZ-induced diabetic rats, p-cymene caused improvement in blood glucose and lipid profle (triglyceride, LDL-cholesterol, and VLDL-cholesterol), although the rates were close to the control group.p-Cymene administration improved the amount of malondialdehyde (MDA) in diabetic rats (p ≤ 0.001).Administration of pcymene (100 mg/kg) can improve islet of Langerhans changes in diabetic rats and increase the expression of Akt, phospho-Akt, and mTOR, reducing liver and pancreatic injury [69].
Swertiamarin, a secoiridoid glycoside, is an antidiabetic drug with hypolipemic activity that improves insulin resistance in the condition of type 2 diabetes.Swertiamarin, at a concentration of 25 μg/ml, decreased triglyceride content by 2-fold and efectively reduced LDH release activity (50%), protecting membrane integrity, preventing apoptosis evidenced by reduced Caspase 3 and PARP1 cleavage.Swertiamarin was observed to signifcantly increase the expressions of key insulin signaling proteins such as insulin receptor (IR), PI3K, and pAkt with concomitant reduction in p307 IRS-1.AMPK was activated by the action of swertiamarin, restoring insulin sensitivity in hepatocytes.Swertiamarin efectively modulated PPAR-α, an important potential regulator of carbohydrate metabolism, which in turn decreased levels of the gluconeogenesis enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis.Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-α, through which it regulates hepatic glycemic load, fat accumulation, insulin resistance, and ROS in hepatic steatosis, which emphasizes the clinical importance of swertiamarin in regulating metabolism and as a suitable candidate for the treatment of hepatic steatosis [51].
Swertiamarin at dosages of 15, 25, and 50 mg/kg bw for 28 days resulted in a signifcant reduction in fasting blood glucose, HbA1c, TC, TG, and LDL and increased levels of hemoglobin, plasma insulin, TP, body weight, and HDL.Te efect of swertiamarin on carbohydrate metabolizing enzymes had normal therapeutic activity.Histopathological studies of the pancreas of diabetic rats treated with swertiamarin showed regeneration of islets when compared to STZ-induced diabetic rats.Swertiamarin has been shown to have antihyperglycemic, antihyperlipidemic, cytoprotective, and immunological reactivity.Tese properties allow for a wide range of treatment options for diabetes and its complications, making it a potentially efective oral antidiabetic [99].
Citral is a bioactive compound widely found in a variety of foods that are consumed daily.Citral treatment signifcantly decreased levels of triglyceride accumulation in a concentration-dependent manner.Cells treated with citral signifcantly suppressed the expression of PI3K/AKT, PPARc, SREBP-1c, FAS, CPD, TNF-α, IL-6, and MCP-1 in a dose-dependent manner [34].According to Subramaniyan and colleagues [35], citral treatment (30 μM) signifcantly decreased cellular cytotoxicity, ROS generation, DNA damage, and lipid peroxidation and increased antioxidant enzymes in high glucose-induced HepG2 cells.In addition, cells treated with high glucose showed increased expression of extracellular signal-regulated protein kinase 1 (ERK-1), N-terminal c-Jun kinase (JNK), and p38 in HepG2 cells.On the other hand, citral treatment signifcantly suppressed the expression of ERK-1, JNK, and p38 in high glucose-induced HepG2 cells.Citral protected against glucose-induced oxidative stress through inhibition of ROS-activated MAPK signaling pathway in HepG2 cells.
Loganin reduced renal to body weight ratio, 24 h urine protein levels, and serum urea nitrogen and creatinine levels in diabetic mice to diferent degrees.In addition, loganin improved the histology of the pancreas and kidney and alleviated structural changes in endothelial cells, mesangial cells, and podocytes in the renal cortex.In addition, loganin reduced AGE levels in serum and kidney and negatively regulated mRNA and protein expression of receptors for AGEs in the kidney in diabetic mice [84].Loganin treatment decreased serum concentrations of IL-6 and TNF-α.Loganin treatment also signifcantly restored body weight gain and attenuated blood glucose changes in diabetic mice [85].
Loganin has been shown to have neuroprotective, antioxidant, and anti-infammatory properties by reducing the intracellular generation of reactive oxygen species.At high blood glucose, there is increased expression of NLRP3, ASC, and caspase-1 protein; however, when treated with loganin, there was upregulation of these proteins that infuences by decreasing NF-κB phosphorylation and reducing oxidative stress, which may suggest a potential as a therapeutics in peripheral diabetic neuropathy [41] by improving insulin resistance, decreasing mRNA and protein levels of the proinfammatory factors IL-1 and TNF, and treating diabetes-associated complications [86].
Menthol signifcantly reduced blood glucose and glycosylated hemoglobin levels and signifcantly increased total hemoglobin, plasma insulin, and liver glycogen levels in diabetic rats.Te altered activities of hepatic glucose metabolic enzymes and serum biomarkers of liver damage were restored to near normal.Pathological abnormalities in the hepatic and pancreatic islets of diabetic rats were signifcantly ameliorated by menthol.Tese efects were mediated by suppression of pancreatic β cell apoptosis and were associated with increased expression of antiapoptotic Bcl-2 and reduced proapoptotic Bax expression.Menthol alleviates STZ-NA-induced hyperglycemia via modulation of glucose-metabolizing enzymes, suppression of pancreatic cell apoptosis, and altered pancreatic and liver morphology.Tis uniqueness and paucity of any perceived adverse efcacy proposes the opportunity to use this monoterpene as an efective adjuvant in the treatment of diabetes mellitus [87].
Carvone reduced STZ-induced damage to liver and β cells of the pancreas.Carvone regulates carbohydrate metabolism by enhancing key enzymes in liver tissues of STZ-induced diabetic rats.Te activities of carbohydrate metabolic enzymes, glycogen, and enzymatic antioxidants in pancreatic contents and liver markers were also altered.Daily oral administration of carvone (50 mg/kg b.w.) to diabetic rats for 30 days resulted in a signifcant decline in plasma glucose levels and HbA1c and signifcant improvement in hemoglobin and insulin levels.Te reversed activities of carbohydrate metabolic enzymes, enzymatic antioxidants, and liver marker enzymes in diabetic rats were renewed to near-normal levels by carvone administration [63].
Alpha-pinene (AP) prevented ROS generation, lipid peroxidation, and DNA disruption, probably through its antioxidant property.AP also inhibited UVA-induced infammatory mediators such as NF-κB, TNF-α, and IL-6 expression in HaCaT cells.Furthermore, AP modulates NER proteins by activating p53 and p21 subsequently preventing the formation of UVA-induced cyclobutane pyrimidine dimers (CPDs).Alpha-pinene inhibits apoptotic cell death by preventing UVAinduced loss of mitochondrial membrane potential through modulation of Bax/Bcl-2 expression in HaCaT cells.Alpha-pinene prevents UVA-induced oxidative stress, infammation, DNA damage, and apoptosis in human skin cells [50].
β-Pinene showed hypoglycemic and hypolipemic efects, which may involve some common mechanisms of glibenclamide.Oral administration of β-pinene in diabetic rats for seven days revealed an important anti-infammatory efect that was the inhibition of infammatory mediators that participate in the 2nd phase of the process, possibly decreasing the migration of leukocytes, indicating that its action may be linked to the inhibition of cytokine production [55].
Borneol is a monoterpene that acts by inhibiting Grb10 expression.In addition, treatment with this monoterpene is able to decrease blood glucose and aHbA1c, increase blood insulin, restore body weight loss, increase liver glycogen level, reverse the increase in levels of TC, TGs LDLcholesterol, and VLDL-cholesterol induced by diabetes, restore the levels of urea, ALT, and AST, increase the antioxidant status of superoxide dismutase and catalase, and reduce glutathione in liver and kidney besides reducing the level of malondialdehyde [56].
Citronellol is a health benefcial monoterpene alcohol that occurs naturally in citrus oils.Citronellol improved insulin, hemoglobin, and liver glycogen levels, with significant decreases in glucose and HbA1C levels.Altered carbohydrate metabolic enzyme activities and liver and kidney markers were restored to near normal.Citronellol supplementation was found to be efective in preserving the normal histological appearance of liver cells and insulin-positive β cells in STZ mice.Citronellol administration attenuates hyperglycemia in STZ-induced diabetic rats by improving key carbohydrate metabolic enzymes and may be efective in combating diabetes mellitus [68].
Limonene (LM) is a monoterpene which is abundantly present in the peel of citrus fruits and can be obtained for a relatively low cost [104].Several studies have been conducted to demonstrate the efects of this monoterpene.Hirota et al. [105] suggested that limonene may be efective in the treatment of bronchial asthma due to its antiinfammatory efect, which probably occurs by inhibition of cytokines, production of reactive oxygen species (ROS), and inactivation of eosinophil migration.For Rozza et al. [106], limonene possesses gastroprotective activity in indomethacin-and ethanol-induced gastric ulcer models.In addition, limonene exhibits chemopreventive activity for breast, lung, skin, and liver cancer [107].Limonene also possesses antinociceptive activity probably due to inhibition of synthesis or action of infammatory mediators and antihyperglycemic activity in streptozotocin-induced diabetic rats [108,109] in addition to vasorelaxant efect on isolated rat aorta [110].
Pretreatment of cells with limonene prevented methylglyoxal-(MG-) induced protein adduct formation, tumor necrosis factor-alpha and interleukin-6 release, mitochondrial superoxide production, and cardiolipin peroxidation.In addition, limonene increased glyoxalase I activity and glutathione and heme oxygenase-1 levels in the presence of MG.Pretreatment with limonene prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation and adenosine triphosphate loss and reduced levels of adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor coactivator 1α, and nitric oxide and may prevent the development of diabetic osteopathy [40].D-limonene treatment was found to signifcantly decrease DNA damage, GR enzyme activity, and MDA levels, signifcantly increase GSH levels and CAT, SOD, and GSH-Px enzyme activities, and alter lipid and liver parameters in diabetic rats [83].
Limonene treatment increased diferentiation, lipid accumulation, and expression of adipogenic and lipogenic markers, such as C/EBP-α, C/EBP-β, PPARc, SREBP-1, RXR, FAS, and adiponectin.However, LM concentration at 10 μM decreased adipogenesis and lipogenesis via regulation of key transcription factors.LM treatment increased Akt activation by increasing its phosphorylation, but p44/42 activation was not altered.MK-2206, a specifc inhibitor of Akt, reduced the activation of Akt phosphorylation while LM treatment aborted the MK-2206-mediated inhibition of Akt activation.Limonene increased glucose uptake in Advances in Pharmacological and Pharmaceutical Sciences Extract of Toona sinensis from supercritical fuid extraction for treating diabetes and metabolic diseases, the preparation method and the use thereof A61K36/58 2011 China Toona sinensis extract should be used as a food supplement or in pharmaceutical compositions.It can lower blood sugar levels, promote lipid breakdown, and treat metabolic disorders.[112] Synergistic composition of (−)-hydroxycitric acid with monoterpene and a method to enhance satiety A61K31/ 194 2011 EUA Pharmaceutical or synergistic food composition comprising (−)-hydroxycitric acid, its salts, amides, and esters together with monoterpenes to increase satiety and help control obesity and prevent diabetes [113] Use of monoterpenes compound in preparation of medicine against diabetes mellitus A61K31/ 015 2006 China An application of the monoterpene compounds, especially d-limonene, in the preparation of the drug in oily liquid form for the treatment of diabetes is disclosed [114] Nutritional and therapeutical preparations having antioxidant activity A23D7/00 2004 EUA Pharmaceutical and dietary compositions for the treatment and prevention of aging processes and related conditions, among them diabetes, comprising a lipid blend rich in polyunsaturated fatty acids and vitamins, in combination or not with monoterpenes and/or sesquiterpenes [115] IPC: International Patent Classifcation.16 Advances in Pharmacological and Pharmaceutical Sciences diferentiated adipocytes.Overall data suggested that LM treatment favored lipid storage and glucose uptake in adipocytes via activation of key transcription factors through activation of Akt phosphorylation in 3T3-L1 adipocytes [39].
3.3.Technological Prospecting.Te database search returned a total of 22 patents to be analyzed.Among these, only fve directly mentioned diabetes and/or its complications among the health problems that can be treated or prevented with the use of monoterpenes, which are detailed in Table 5.All the patents analyzed, according to the International Patent Classifcation, are intended for human needs (Section A), with medical (A61K) or food (A23) purposes.
Patents that only cited diabetes as a risk factor or disorder associated with other therapies that were subject to patent protection were excluded.In addition, the technological prospection excluded products with cosmetic purposes or those that reported agricultural applications related to this species.
Table 5 points out the lack of recent papers for the applicability of monoterpenes in the prevention or treatment of diabetes, since the identifed patents date from 2012 or earlier years.Tis scenario is contradictory, since research released between the years 2014 and 2019 was included in the present review.It can therefore be assumed that the voluminous academic production in this theme has not yet been proportionally converted to patent protection object, so as to enable its industrial applicability and, consequently, commercial exploitation of the inventions by the pharmaceutical and food markets.
Among the patents analyzed, it is worth mentioning the work of Pei-Jung et al. [112], which claims ownership over the extract of Toona sinensis leaves, obtained by the supercritical fuid extraction method.Te apolar fraction in question had its antidiabetic efect evaluated in vitro in adipocytic cell model and showed signifcant reduction of glucose concentration in the medium.In the composition of the extract, the presence of the monoterpenes α-pinene and β-pinene, as well as the derivative monoterpene, D(+)limonene, stands out.
In the work of Shu Gang et al. [114], on the other hand, protection is claimed for diferent pharmaceutical forms containing the compound D-limonene, such as hard capsules, soft capsules, tablets, or powders.Extraction was performed by fractional distillation of the volatile oils of Citrus limon (L.) Burm.f., Citrus reticulata Blanco, and Citrus aurantium, among other plant species.Tis group evaluated the in vivo efect of D-limonene (2.4 ml/kg) and demonstrated its hypoglycemic action in rats up to 2 hours after oral administration, showing that preparations containing this monoterpene derivative are promising for diabetes control.
In the other patents evaluated, monoterpenes are cited as integrating pharmaceutical and/or dietary compositions, as well as for functional foods, useful for treating and generally preventing immune system [111] or metabolic disorders [113], as well as preventing aging processes and related conditions, such as atherosclerosis, hypertension, diabetes, tumors, and obesity.However, although the therapeutics potential of these inventions in the face of diabetes is clear, in these works, a clear relationship between the pharmacological actions played by monoterpenes in specifc for diabetes mellitus is not established.

Conclusion
Te hyperglycemia associated with diabetes mellitus and its associated diseases can be controlled with oral hypoglycemic agents, insulin, diet, and physical activity, but this review showed the therapeutics potential of monoterpenes with a wealth of specifc efects and important markers that were able to act in blood glucose control and action to treat diabetic neuropathy, diabetic retinopathy, and possible liver damage associated with the evolution of this pathology.Geraniol, D-limonene, catalpol, cymene, geniposide, gentiopicroside, paeoniforin, borneol, carvacrol, carvone, menthol, myrtenal, thymol, genipin, pinene, citronellol, citral, eucalyptol, swertiamarin, and loganin were the monoterpenes described with actions to reduce glycemia, triglycerides, total cholesterol, LDL-cholesterol, regeneration of islets of Langerhans, suppression of infammatory cytokines, inhibition of reactive oxygen species, and reduction of oxidative markers, stimulating the search for new drugs.Terefore, the search for new drugs with antidiabetic and hypoglycemic actions that expand the phytotherapeutics collection is of utmost importance in order to unveil other activities of these monoterpenes, better elucidating their mechanisms of action and knowing their therapeutics doses.

Table 5 :
Patents related to the use of monoterpenes in diabetes therapy.composition containing monoterpenoids, intended for the treatment of immune disorders, associated with conditions such as diabetes, alcohol or drug abuse, or obesity[111]

Table 1 :
Year of publication of the manuscripts and number of publications per year.

Table 2 :
Monoterpenes used in the study.

Table 4 :
Continued.Te blood glucose levels were found signifcantly lower at the 21st and 28th days of treatment Te serum AST and GGT levels, LDL, total cholesterol, and triglyceride levels in the D-limonene treated diabetic group were found to be signifcantly lower.Te CAT, SOD, GSH-Px enzyme activities, and GSH levels in plasma, liver, and kidney -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 surfcial spinal dorsal horn of PDN rats.Loganin inhibited oxidative stress and NF-B activation and decreased the levels of mRNA and protein of proinfammatory