Cloves, Eugenol, and Metabolic Regulation: Properties, Supplementation, and Uses in Chronic Diseases.

When discussing cloves, eugenol, and metabolism in humans, the most important factor is the discrepancy between the biological rationale and the amount of available clinical evidence. Human studies are few, but they suggest that a standardized polyphenolic extract—that is, a preparation rich in polyphenols made homogeneous in composition—can influence glycemia, or the concentration of glucose in the blood, especially in the post-meal period, which is when the glycemic response is most sensitive to dietary composition [2]. This does not mean that cloves should be interpreted as a treatment, but rather that their potential should be viewed as nutritional support in selected contexts. It is also useful to distinguish the spice used in cooking from a concentrated formulation, because the quantities, bioavailability (i.e., the amount of substance that actually reaches circulation or tissues), and repeatability of the effect are not comparable. In other words, the clinical value observed in studies depends on the preparation, the dose, and the metabolic profile of the participants, not on a generic and indiscriminate use of the spice. Furthermore, the biological rationale of eugenol intertwines with known pathways of metabolic regulation, including oxidative stress (an imbalance between the production of reactive species and antioxidant capacity), low-grade inflammation, and insulin sensitivity (the ability of tissues to respond to insulin), all of which are central to chronic metabolic alterations. Precisely for this reason, readers should consider clove extracts as possible modulators, not as alternatives to established treatments or lifestyle corrections.

An open-label pilot trial, a preliminary study without blinding of participants and researchers, evaluated 250 mg/day for 30 days in 13 volunteers, stratified into 7 normoglycemic and 6 prediabetic individuals, reporting a reduction in pre- and post-prandial glycemia [2]. This is an interesting, but still initial, signal. For this reason, in scientific interpretation, not only the final result but also the robustness of the study design and consistency with preclinical evidence (obtained previously in experimental models before human studies) are very important, indicating a possible interaction with clove polyphenols, oxidative stress, and broader metabolic signals [3,4]. The most solid idea is that the extract can attenuate some metabolic peaks, especially in subjects with suboptimal glycemic control, but not that it produces glycemic control equivalent to pharmacological treatment. In the overall picture, clove supplementation therefore remains a promising nutritional hypothesis, to be carefully evaluated without overestimating what human data can truly support today. For this reason, too, the quality of the formulation and consistency with the subject's clinical profile are decisive elements in practical evaluation.

To guide the reading of human studies, it is useful to keep some key points in mind:

• Standardized extracts show more measurable results than culinary spice.
• The most observed response concerns pre- and post-prandial glycemia.
• The human sample size so far is small and requires cautious interpretation.
• The participant's metabolic context greatly changes the meaning of the data.
• Nutritional interpretation must be distinguished from the promise of a therapeutic effect.

In type 2 diabetes, the rationale for cloves primarily concerns the containment of hyperglycemia, oxidative stress, and low-grade inflammation. Experimental data indicate that eugenol can act at multiple levels of metabolic regulation, but its clinical significance should be interpreted with caution. In a model of diabetic rats induced by a high-fat diet and streptozotocin, a substance used to selectively damage pancreatic cells, eugenol improved insulin resistance, oxidative stress, and inflammation, supporting the idea of systemic modulation [4]. In parallel, a meta-analysis, i.e., a statistical analysis combining multiple studies, on hyperglycemic murine models confirmed that the effect of eugenol is consistent, but not uniform across all models [7]. This focus is valuable because it addresses the reader's most frequent question without promising certain pharmacological effects. Type 2 diabetes, in fact, does not depend on a single mechanism but on an intertwining of insulin resistance, hepatic alterations, inflammation, and peripheral tissue dysfunction. In this context, cloves can be seen as a possible biological support, not as a substitute for therapies.

Eugenol has also been studied in the liver, where the modulation of SREBP1, AMPK, and mTOR led to a 45% reduction in hepatic triglycerides and a 72% reduction in the steatosis score in mice treated for 10 weeks, as well as a decrease in α-SMA, Col-I, and PAI-1 by 36%, 63%, and 40% respectively [8]. SREBP1 is a transcription factor that promotes lipid synthesis, AMPK is a cellular energy sensor, and mTOR is a signaling pathway that regulates growth and metabolism. Along the same lines, another study in rats showed an attenuation of non-alcoholic liver disease through a gut-brain-liver circuit involving GLP-1, an intestinal hormone involved in glycemic regulation [9]. This makes the topic very interesting for those seeking information on "eugenol and liver," but here too, clinical translation remains cautious. In a model of benign prostatic hyperplasia, i.e., benign prostate enlargement, induced by testosterone, eugenol and probenecid attenuated inflammation and pro-survival pathways, confirming that the compound can act in environments characterized by proliferation and inflammatory signals [10]. On the antifungal front, the in vitro synergy, i.e., observed in the laboratory, of eugenol and methyleugenol with fluconazole against clinical isolates of Candida indicates a real biological interest, but confined to the laboratory [11]. Overall, the message is clear: cloves are not a single therapy, but a phytocompound, i.e., a plant substance with biological activity, with mechanisms that may be relevant in chronic conditions. The areas to connect are primarily these:

• The control of glycemia and post-prandial peaks in glucose disorders.
• The modulation of insulin resistance in metabolically more vulnerable tissues.
• Support for liver function in forms of steatosis and fibrosis.
• Experimental interest in selected inflammatory and proliferative conditions.

mTOR is a kinase, meaning an enzyme that regulates other proteins through phosphorylation and functions as a central node to integrate nutrient availability, growth signals, and energy status. When this axis remains overly active, the cell tends to prioritize synthesis and survival even in contexts of caloric excess or metabolic stress. When it rebalances, however, adaptation processes, including autophagy—the cell's internal recycling mechanism—can become more efficient. In cloves, the interest arises because eugenol and some bioactive fractions appear to intervene in this network in experimental models, suggesting a possible link between cloves eugenol metabolism and the regulation of cell growth [12,13,14].

In this context, cloves should not be interpreted as an mTOR "blocker," but as a possible modulator of its hyperactivation under experimental conditions. A useful example comes from HCT116 colorectal carcinoma: an active fraction of cloves inhibited PI3K/Akt/mTOR, inducing apoptosis, i.e., programmed cell death, while in another study on the same cell line, the same fraction linked the effect to autophagy mediated by the same axis [12,13]. Eugenol, in different models, has also shown mTOR modulation in association with AMPK, the AMP-activated protein kinase that signals energy scarcity, reinforcing the idea of broader control over cellular balance [14,15]. For the reader, the key point is this: the relationship between cloves and mTOR makes sense primarily as a biological interpretative key, useful for understanding why these compounds are studied in metabolism and chronic diseases, but not as a therapeutic shortcut.

To correctly interpret this data, it is useful to keep the different levels of observation together and connect them coherently:

• the PI3K/Akt/mTOR pathway can reduce pro-growth signals in pathological cells [12,13];
• autophagy can increase when the mTOR signal is contained [13,15];
• eugenol can also act in metabolic networks linked to oxidative stress, i.e., an imbalance between free radical production and antioxidant defenses, and chronic inflammation [16,14];
• preclinical results do not equate to a direct clinical effect in humans [12,13,14].

The central point when discussing cloves eugenol metabolism is not a generic "energetic effect," but rather the ability of certain phytocompounds to shift the cell towards a more prudent use of resources. AMPK is an energy state sensor: when available energy decreases, it tends to favor saving and adaptation processes, while mTOR coordinates growth and synthesis signals. In conditions of metabolic imbalance, this axis becomes interesting because it links oxidative stress, chronic inflammation, and the regulation of autophagy, which is the controlled recycling of cellular components. In cloves, eugenol and the polyphenolic fraction seem to act precisely in this direction, with an experimental rationale that should be interpreted as biological support and not as an autonomous therapy [1,3].

To navigate the data, it's useful to distinguish the levels of interpretation that recur in experimental and preclinical studies. The idea is not that a single compound "turns on" or "turns off" metabolism, but that it makes the response to available energy more efficient. This is relevant in conditions where the cell remains exposed to nutritional overload, redox stress, and persistent inflammatory signals. In such contexts, AMPK can reduce excessive anabolic signals, while mTOR can be remodulated to allow for defense and repair. The practical consequence is a cellular profile less prone to disordered lipid accumulation, suppression of autophagy, and loss of metabolic flexibility.

In experimental models, eugenol has shown a consistent relationship with this setup. In ischemia-reperfusion injury, i.e., the sequence in which a tissue receives blood and oxygen again after a period of deficiency, it contributed to a protective response associated with AMPK activation, mTOR inhibition, and autophagy recovery [15]. A similar picture has also been described in reviews on the therapeutic potential of eugenol in ischemia-reperfusion injuries [19], confirming that the topic is not limited to metabolism in the strict sense. In parallel, in fatty liver models, it reduced hepatic triglycerides by 45% and the steatosis score by 72%, suggesting that energy rebalancing concerns not only cell survival but also how the liver manages lipids [8]. In the same study [8], in vivo in HFD mice for 10 weeks, a-SMA also decreased by 36%, Col-I by 63%, and PAI-1 by 40%, while in vitro the effect was observed up to 100 µM. These data reinforce the idea that AMPK modulation intertwines with anti-fibrotic signals and with the regulation of SREBP1, which is one of the key nodes of lipogenesis. Studies on the PI3K/Akt/mTOR pathways, a circuit that integrates growth, cell survival, and protein synthesis, in other cellular models also recall the same underlying logic: balancing growth, survival, and autophagy [12,13].

In the metabolic context, this approach has also been explored for glucose and insulin resistance, i.e., the reduced ability of tissues to respond to insulin. A water-soluble extract rich in clove polyphenols, PCE 250 mg/day for 30 days, lowered pre- and post-prandial glycemia in n=13 subjects, of whom 7 were normoglycemic and 6 prediabetic [2]. This does not allow for definitive clinical conclusions, but it shows how the profile of clove compounds can affect the management of energy substrates. From a pathophysiological perspective, reducing glycemic peaks and containing the overactivation of nutrient-sensitive pathways is consistent with the call for AMPK, which is activated precisely when the cell needs to optimize fuel use. Preclinical studies on hyperglycemic models and type 2 diabetes have indeed linked eugenol to the modulation of glucose metabolism enzymes, oxidative stress, and inflammation [16,4,7,20].

The most useful data, from an institutional perspective, is that cloves do not act on a single target, but on an integrated network of signals. AMPK, mTOR, autophagy, lipogenesis, and antioxidant response are not separate processes: they mutually influence each other and determine the tissue's ability to remain functional over time. This is why the literature on eugenol, liver, muscle, and brain converges towards a single cautious interpretation: the compound can promote better adaptation to metabolic stress, but the clinical significance depends on dose, food matrix, duration of exposure, and initial health status [1,3,19]. In other words, cloves offer an interesting example of a phytocomplex capable of interacting with the main axes of energy regulation, without replacing validated dietary and therapeutic strategies.

• AMPK activation can reduce excessive anabolic signals.
• mTOR modulation can promote autophagy and adaptation.
• Eugenol can attenuate lipid accumulation and cellular stress.
• The response varies depending on the tissue and context.

When the insulin response weakens, glucose enters tissues with more difficulty, and the body compensates with a greater hormonal load. Over time, this promotes alterations in glycemia and lipid management. In this context, cloves and insulin resistance are of interest because some of their compounds, especially eugenol, seem to act on multiple levels simultaneously: reduction of oxidative stress, attenuation of inflammation, and improved tolerance to metabolic load [4,7]. A preliminary study on diabetic rats showed that eugenol improved insulin resistance, oxidative stress, and inflammation [4]. In parallel, in a murine model, i.e., an experimental model conducted in mice, of type 2 diabetes induced by a high-fat diet and streptomycin, eugenol increased glucose uptake in skeletal muscle, reducing local inflammation [20]. These outcomes are relevant because insulin resistance often arises from an altered dialogue between the liver, muscle, and adipose tissue, with inflammatory signals blocking the normal transduction of the insulin signal, i.e., the transfer of information from the receptor to cellular responses. If the receptor and intracellular pathways respond poorly, glucose remains in the blood longer, and the cell uses available nutrients less efficiently. Eugenol, at least in the models studied, seems to intervene precisely in this circuit, reducing the mediators that hinder tissue response and improving peripheral energy availability.

A useful element is that the signal does not appear isolated: a review of murine hyperglycemic models described a consistent but still preclinical picture [7]. Furthermore, a water-soluble polyphenolic clove extract lowered pre- and post-prandial glycemia with 250 mg/day for 30 days in 13 subjects, 7 of whom were normoglycemic and 6 prediabetic [2]. This data is important because it moves the discussion beyond the laboratory alone, although without authorizing definitive clinical conclusions. The result suggests that clove compounds can modulate the glycemic response to a meal, a crucial moment for those with initial insulin resistance or unstable glycemic control. However, the study remains small, short, and insufficient to define efficacy, long-term safety, or superiority over established strategies. It is therefore essential to contextualize: a spice can accompany a broader dietary path, but not replace structured clinical and behavioral interventions. In other words, the potential is interesting, but it should be interpreted as biological support and not as an autonomous therapy.

These results help to view the spice as a potential metabolic adjuvant, not as an autonomous solution. The biological plausibility also derives from the fact that the insulin response is strongly conditioned by inflammatory tone and oxidative stress, two conditions that feed each other. In affected tissues, especially skeletal muscle and the liver, the accumulation of lipids and the excess of reactive oxygen species, i.e., excessively produced oxidizing molecules, compromise downstream insulin signaling. Cloves can therefore be seen as a source of bioactive compounds capable of influencing the overall metabolic environment, especially when the picture is supported by an unbalanced diet and a sedentary lifestyle. The following points clarify why muscle is a decisive target, how adipose tissue influences insulin resistance, and how clove polyphenols can be involved in controlling the oxidative and inflammatory environment:

• Skeletal muscle represents the main site of glucose uptake.
• Local inflammation can reduce tissue sensitivity to insulin.
• Visceral adipose tissue amplifies systemic metabolic disorder.
• Clove polyphenols can support redox balance.
• The evidence remains preclinical and should be interpreted with clinical caution.

In skeletal muscle, the control of glucose entry also depends on a very precise chain of events. AMPK, a protein sensitive to the cell's energy state, can promote the phosphorylation of AS160 and make GLUT4 translocation to the membrane more efficient. AS160, a regulatory protein of intracellular trafficking, acts as a "brake" on the vesicles that transport GLUT4. When that brake is released, glucose enters more easily. This step is particularly relevant in models of insulin resistance, because it shows that the problem is not only related to the hormonal signal, but also to the final availability of the transporter, i.e., the protein that allows glucose to cross the cell membrane.

In this context, the interest in eugenol is not about a generic effect, but its ability to converge on a concrete mechanism that links cellular energy and glycemic management. In vitro and in vivo, i.e., in isolated cells and living organisms, compounds similar to cloves have shown AMPK activation and increased GLUT4 translocation, supporting the hypothesis of support for peripheral glucose uptake [21,22,23,24]. A useful example is isoeugenol, a compound structurally similar to eugenol, which in muscle cells increased the expression and passage of GLUT4 to the plasma membrane; the result, however, remains preliminary and does not equate to a certain clinical effect. The most correct interpretation is therefore mechanistic: these phytocompounds, i.e., bioactive compounds of plant origin, can contribute to making a pathway already central to muscle metabolism more efficient, without replacing dietary or pharmacological interventions when necessary.

On this basis, data on Syzygium aromaticum and its phenolic compounds, plant-derived substances with biological properties studied in experimental models, appear to act along the same functional axis in some contexts. The key points can then be read more linearly:

• AMPK can initiate the signal that facilitates GLUT4 movement.
• AS160 represents a crucial intermediate node for enabling transport.
• The cell membrane receives more GLUT4 and improves glucose uptake.
• Clove compounds can integrate into this circuit.

Metabolic prevention with cloves works best when it remains anchored to daily cooking and not to the search for an immediate "curative" effect. In this context, the practical value of the spice derives mainly from the presence of eugenol, a natural aromatic compound with biological activity, and other clove polyphenols, which are plant molecules with antioxidant potential. These components can accompany a dietary pattern already oriented towards weight control, glycemia, and fat quality. Regular but moderate use is more sensible than episodic high doses, because the goal is to build sustainable habits and not to chase the effects of concentrated supplementation. In the small human study with 250 mg/day of polyphenol extract for 30 days, on 13 participants including normoglycemic individuals (i.e., with normal blood sugar levels) and prediabetics (i.e., with initial alterations in glucose metabolism), an improvement in glycemic values was observed, suggesting a possible practical utility within a coherent dietary framework [2]. This result is interesting because it fits into a logic of primary prevention: it does not promise a substitute effect for therapy, but indicates that a mild and continuous modulation can be plausible when starting from a well-structured diet.

The clinical sense of this approach is reinforced by the fact that metabolic dysfunction often arises from an intertwining of caloric excess, low-grade inflammation, insulin resistance (i.e., a reduced tissue response to insulin), and alterations in the lipid profile. Clove compounds alone do not correct these mechanisms, but can act as dietary cofactors, especially when the diet already reduces free sugars, unfavorable fats, and energy density. Eugenol, in particular, is studied for its antioxidant, anti-inflammatory effects and for modulating cellular pathways involved in metabolism, but such activities emerge under very controlled experimental conditions [1,16]. For this reason, practical prevention must remain cautious: the expected benefit is additive, meaning it adds to that of the diet, not definitive, and depends on the continuity of intake, the quality of the rest of the diet, and the presence of clinically relevant risk factors. In other words, the value of the spice increases when it is part of a stable and well-constructed eating habit.

This approach helps to place cloves within a realistic metabolic prevention: they can enrich the diet, but the benefit depends mainly on the overall context. In experimental models, in fact, eugenol is studied at doses and times very different from domestic use, and the results on adiposity (i.e., accumulation of adipose tissue), glycemia, and inflammation must be interpreted with caution before being translated into practice [8,5,16]. In the work on steatosis (i.e., fat accumulation in the liver) and hepatic fibrosis (i.e., excessive scar tissue formation in the liver), eugenol showed in vitro effects (i.e., in the laboratory on controlled cells or biological systems) up to 100 µM and, in HFD mice (i.e., fed a high-fat diet) for 10 weeks, it reduced hepatic TG by 45%, steatosis score by 72%, a-SMA by 36%, Col-I by 63%, and PAI-1 by 40% [8]. These numbers suggest significant biological potential, but also the distance between the experimental model and current dietary use. In other words, the spice can play a useful role if it remains part of a stable dietary strategy that prioritizes regularity, moderation, and continuity.

To translate this information into daily behavior, it is advisable to distinguish between culinary use, infusion, and concentrated products, so as not to overlap very different levels of exposure. The practical points to keep in mind are clear:

• Whole spice is useful when aroma and simple quantity control are needed.
• Powder distributes better but requires more attention to portion size.
• Infusions offer easy use, without equating to standardized concentrates.
• Extracts should be considered functional products, not cooking spices.

In nutritional comparison, cloves should be understood as a spice with a high density of bioactive compounds—molecules present in foods that can interact with biological processes—and not as a solution equivalent to an extract or a drug. Nutritional comparison means precisely this: comparing the food matrix, the concentration of active ingredients, and the context of use, so as to avoid attributing effects observed only in standardized preparations to daily cooking. In the case of cloves, the most discussed rationale concerns eugenol, the main phenolic aromatic component, and the set of clove polyphenols—plant substances with potential antioxidant activity that can support the control of oxidative stress (i.e., an excess of reactive species harmful to cells) and chronic inflammation in experimental models [1,30]. However, the fact that a spice is biologically interesting does not automatically imply a broad or consistent clinical impact on glycemia, weight, or insulin resistance (i.e., the reduced tissue response to insulin).

One of the most common myths is to think that cloves "lower blood sugar" directly and always predictably. In reality, available data suggest, if anything, potential metabolic support dependent on the form of intake, product quality, and the overall dietary profile. Referring to dietary guidelines remains useful because it places the spice within a balanced eating model and not as a substitute for it [31,32]. From this perspective, comparing it with other spices helps clarify differences in composition and intensity of use, while the myth to debunk is the idea that a single spice can solve complex metabolic problems. The most correct interpretation is therefore cautious: cloves can play a contextual role, but not a shortcut [1,30].

To guide the reader between realistic expectations and simplifications, it is useful to distinguish some key points, because it is precisely here that one understands how easy it is to confuse practical utility and popular myth:

• Culinary spice and concentrated extract are not equivalent in exposure.
• Preclinical observations, i.e., obtained in the laboratory or in animal models, do not automatically authorize extensive clinical conclusions.
• The role of eugenol must be interpreted together with the food matrix.
• Online promises often ignore dose, context, and duration of use.
• Correct comparison helps separate practical utility and health myth.

Evaluating the safety of cloves starts with a simple principle: the spice used in cooking is not equivalent to a standardized extract, nor, especially, to essential oil. A standardized extract refers to a preparation in which the quantity of active compounds is made constant, thus providing a more predictable content compared to the raw material. Criticality of use means precisely this: the risk profile changes based on the concentration of active compounds, the frequency of intake, and the individual context. In daily food practice, the margin of use generally remains broad, but when moving to concentrated formulations, exposure to eugenol increases, and with it, the need for caution. For this reason, rather than seeking "strong" effects, it makes sense to consider proportion, duration, and compatibility with the intended use.

This approach is also important because eugenol does not act in a single way. In experimental literature, for example, effects on glycemia, inflammation, oxidative stress, and lipid metabolism have been described [8,16,9,4,7,20]. Glycemia refers to the concentration of glucose in the blood, while inflammation is the body's defensive response to a harmful stimulus; oxidative stress indicates an imbalance between reactive species and antioxidant systems, and lipid metabolism concerns all the processes by which the body manages fats and cholesterol. However, biological potential does not equate to an indiscriminate practical indication. The same pathways that make the compound interesting, such as the modulation of enzymes, inflammatory signals, and hepatic metabolism, can become less predictable when the dose increases or when other clinical factors are combined. From this perspective, hepatic metabolism refers to the chemical transformations that occur in the liver and influence the elimination and activity of substances. In the logic of prevention, therefore, safety is not a separate issue from efficacy: the two dimensions are evaluated together, with attention to the form of intake and the person's profile.

A useful piece of information for guidance is that, in the available clinical study, a water-soluble extract rich in clove polyphenols was administered at 250 mg/day for 30 days to 13 subjects, 7 of whom were normoglycemic and 6 prediabetic, with a favorable effect on pre- and post-prandial glycemia [2]. Polyphenols are plant compounds known for their antioxidant activity, while prediabetic refers to people with blood glucose levels higher than normal but not yet in the diabetic range. This information helps to avoid inappropriately equating food doses with supplement doses. The result should be read as a signal of interest, but also as an example of measured use, limited in time and in a small sample. Precisely for this reason, the data cannot be transferred to scenarios of prolonged self-medication. On the experimental side, clove essential oil showed hypoglycemic activity in STZ diabetic rats at 20 mg/kg BW, with a significant reduction in glycemia and total cholesterol and with an IC50 against α-amylase of 298.0±2.75 μg/mL [33]. Essential oil refers to the concentrated and volatile aromatic fraction of the plant, while STZ indicates streptozotocin, a substance used to induce diabetes in animal models; α-amylase is an enzyme that contributes to starch digestion, and IC50 represents the concentration required to achieve 50% of the observed inhibitory effect. However, the biological potency observed in animal models does not coincide with a sufficient safety profile for free use. From a cautious perspective, cloves remain interesting as a food, but concentrated formulations should be considered carefully, especially if the goal is prolonged use or in fragile individuals.

Before extending the reasoning to practice, it is useful to distinguish the points that make this topic central:

• The actual dose varies greatly between spice, extract, and essential oil.
• Tolerability also depends on the duration of exposure.
• People undergoing therapy require greater caution.
• Concentrated uses should not be confused with food uses.