Cloves

When moving from the molecular properties of cloves to their application as a nutritional intervention, it becomes clear that eugenol and its derivatives do not act in isolation on a single parameter, but rather exert a systemic action involving glucose metabolism, adipose tissue, gut microbiota, inflammation, and cellular regeneration processes. This makes cloves particularly interesting in the context of chronic metabolic and inflammatory diseases, where multiple systems are simultaneously compromised.

One of the first areas explored is glycemic control and hormonal regulation in type 2 diabetes. In an animal model of diet-induced obesity, dietary supplementation with cloves resulted in a significant reduction in glycemia, accompanied by a decrease in serum leptin levels, a hormone often elevated in contexts of obesity and insulin resistance (Abdulrazak et al., 2018) [6]. This finding is particularly relevant because it suggests that the hypoglycemic action of cloves does not depend solely on an increase in insulin secretion, but on a modulation of insulin sensitivity and adipocyte signaling. In other words, cloves seem to reduce the “metabolic noise” that forces the body to maintain high levels of insulin and leptin to achieve the same biological effect.

This observation finds initial confirmation in humans through a pilot study conducted on healthy volunteers and subjects with slightly elevated fasting glycemia. The daily intake of a water-soluble polyphenolic extract of cloves resulted in a significant reduction in postprandial glycemia after just 12 days, with a more marked and progressive effect in subjects with baseline values between 101 and 125 mg/dL (Mohan et al., 2019) [7]. The most interesting finding is that preprandial glycemia is reduced significantly only in the most metabolically fragile subjects, suggesting a normalizing effect rather than an indiscriminate hypoglycemic one. From a physiological standpoint, this behavior is consistent with the idea of a spice that helps the body better manage glycemic load when the system is under stress, without forcing it when it is already in balance.

In vitro studies associated with this work help to understand the mechanisms underlying these effects. Clove extract increases glucose uptake in myocytes, reduces hepatic glucose production, and inhibits digestive enzymes, slowing down carbohydrate absorption at the intestinal level (Mohan et al., 2019) [7]. It is as if the action of cloves is distributed along the entire glucose pathway, from the intestine to peripheral tissues, avoiding sudden spikes and promoting a more gradual and efficient management.

Alongside glucose metabolism, an increasingly central role is emerging for the gut-microbiota-adipose tissue axis. In mouse models fed a high-fat diet, eugenol has been shown to significantly reduce body weight gain, visceral adipose tissue volume, and adipocyte size, while improving fasting glycemia. These phenotypic changes are accompanied by a profound modulation of the gut microbiota, with an increase in genera associated with a favorable metabolic profile and a reduction in those related to inflammation and obesity. In parallel, transcriptomic analysis of adipose tissue shows a reprogramming of pathways involved in lipid metabolism, thermogenesis, and insulin sensitivity (Li et al., 2022) [8]. This suggests that eugenol does not act only “from the outside,” but communicates directly with adipose tissue metabolism, helping to make it less inflamed and more metabolically flexible.

A further level of complexity emerges when eugenol is combined with other bioactive compounds. A combined supplement based on spermidine (a natural substance present in cells and various foods) and eugenol has been shown to protect human intestinal cells from an induced inflammatory state by reducing the production of reactive oxygen species, attenuating the expression of inflammatory mediators, and, above all, stimulating autophagic flux (Truzzi et al., 2023) [9]. Autophagy, a fundamental process of cellular recycling and maintenance, is often compromised in chronic and autoimmune diseases. The fact that eugenol contributes to reactivating functional autophagy, while also improving the integrity of the intestinal barrier, reinforces the idea of a profound action on the “biological terrain” that precedes and accompanies disease.

Finally, the supplementation of eugenol derivatives shows relevant effects even in contexts that are apparently distant, such as skin photoaging, but which share the same pathophysiological bases of oxidative stress and chronic inflammation. In mouse models exposed to UVB rays, dietary supplementation with isoeugenol reduces wrinkle formation, preserves dermal collagen, limits epidermal thickening, and attenuates skin dryness. Interestingly, these effects are associated with a normalization of the gut dysbiosis induced by chronic UV exposure, suggesting the existence of a gut-skin axis that can be modulated through diet and phytocompounds (Geng et al., 2024) [10]. Once again, it emerges that the action of cloves is not confined to a single organ, but manifests as a systemic regulation of inflammation and the stress response.

Taken together, these studies show that the supplementation of cloves and their main components does not produce isolated, point-like effects, but contributes to reducing metabolic variability, improving glucose management, modulating the microbiota, and reactivating cellular protection and repair processes. Integrated into a lifestyle oriented toward glycemic stability and the reduction of hyperinsulinemia, cloves are therefore configured not as a symptomatic remedy, but as a modulator of the biological context in which chronic diseases take shape and persist over time.

When observing the action of cloves in various chronic conditions, a surprisingly consistent picture emerges: eugenol, their main bioactive component, acts on pathophysiological nodes common to many modern diseases, particularly the alteration of glucose metabolism, the dysfunction of the gut-liver-brain axis, low-grade chronic inflammation, and the overactivation of pro-survival pathways such as PI3K/AKT/mTOR.

In the context of diabetes mellitus, eugenol has demonstrated a marked anti-hyperglycemic effect in established experimental models. In rats with streptozotocin-induced diabetes, the administration of eugenol significantly reduced fasting glycemia and glycated hemoglobin, accompanying these effects with an increase in plasma insulin levels and a normalization of key enzymes of hepatic glucose metabolism (Srinivasan et al., 2014) [11]. This finding is particularly relevant because it suggests that eugenol does not act simply as a direct hypoglycemic agent, but contributes to restoring hepatic metabolic balance, reducing the need for compensatory insulin hyperproduction.

The same logic of rebalancing emerges in metabolic liver diseases. In non-alcoholic fatty liver disease, eugenol has shown the ability to reduce lipid accumulation in the liver, improve serum profiles of triglycerides and cholesterol, and restore hepatic architecture in animal models fed a high-fat diet (Li et al., 2022) [12]. What makes this study particularly innovative is the identification of an integrated neuroendocrine mechanism: eugenol activates the gut-brain-liver axis, strengthening the intestinal barrier, stimulating the vagus nerve, and improving communication between the gut and the liver. It is as if eugenol helps the body to "reorganize metabolic traffic," intervening not only on the liver as a target organ, but on the entire regulatory system.

A central role for eugenol also emerges in the relationship between the gut, microbiota, and opportunistic infections. In a mouse model of intestinal Candida albicans infection, clove essential oil showed potent antifungal and anti-biofilm activity, reducing the fungal load and improving the integrity of the intestinal mucosa (Gao et al., 2025) [13]. In parallel, the treatment resulted in a significant reduction of intestinal inflammatory cytokines, such as IL-6, IL-8, and IL-17A, and a restoration of microbiota diversity, with an increase in beneficial genera such as Lactobacillus and Bifidobacterium. This finding is crucial because it shows how eugenol does not just target the pathogen, but contributes to rebuilding the intestinal ecosystem, reducing the inflammatory environment that favors persistent infections.

The ability of eugenol to modulate inflammation and cell proliferation also becomes particularly evident in benign prostatic hyperplasia (BPH), a condition strongly associated with chronic inflammation, oxidative stress, and the activation of pro-growth pathways. In experimental models of testosterone-induced BPH, eugenol reduced the prostate index, attenuated epithelial hyperplasia, and inhibited the activation of the PI3K/AKT/mTOR pathway, while simultaneously reducing levels of inflammatory cytokines and oxidative markers (Abdali et al., 2025) [14]. Particularly interesting is the link with uric acid, identified as a mediator of prostatic inflammation: eugenol, especially in combination with a uricosuric (a substance that promotes the elimination of uric acid through the kidneys and urine), showed a synergistic effect in reducing pro-survival and proliferation signals, suggesting a potential role even in human clinical conditions characterized by hyperuricemia and chronic inflammation.

Finally, the potential of eugenol in the oncological context has been analyzed systematically in a broad and rigorous review that gathered preclinical evidence on numerous types of tumors (Begum et al., 2022) [15]. Eugenol has proven capable of inducing apoptosis, cell cycle arrest, inhibition of angiogenesis, and reduction of metastases in models of breast, gastric, hepatic, lung, prostate, and skin carcinoma. These effects are mediated by the coordinated modulation of the PI3K/AKT/mTOR pathway, outlining a profile of action that selectively targets pathological cells without showing significant toxicity on healthy tissues. It is important to emphasize that eugenol has also shown positive synergies with conventional chemotherapy drugs, suggesting a possible role as a therapeutic adjuvant, rather than an isolated alternative.

Taken together, these findings show that cloves, through eugenol, do not act on individual diseases in a fragmentary way, but intervene on common biological mechanisms: hyperglycemia, insulin dysfunction, chronic inflammation, microbiota alteration, and mTOR overactivation. Incorporated into a lifestyle oriented toward metabolic stability and the reduction of hyperinsulinemia, they represent not a symptomatic remedy, but a modulator of the pathophysiological terrain upon which chronic diseases develop and are maintained over time.

One of the most interesting aspects of cloves concerns their ability to act directly on the biological mechanisms underlying insulin resistance, a central condition in the development of type 2 diabetes, metabolic syndrome, and non-alcoholic fatty liver disease. In the presence of insulin resistance, peripheral tissues become progressively less sensitive to insulin signaling, forcing the pancreas to produce increasing amounts of insulin to maintain stable glycemia. This state of chronic hyperinsulinemia fuels inflammation, mitochondrial dysfunction, lipid accumulation, and continuous activation of the PI3K/AKT/mTOR pathway.

In this context, eugenol and the polyphenols in cloves appear to act as multifactorial metabolic modulators, capable of simultaneously improving glucose homeostasis, oxidative stress, and cellular energy function. One of the most solid pieces of evidence comes from a meta-analysis including 16 preclinical studies on animal models of diabetes, in which treatment with eugenol resulted in a significant reduction in glycemia, an improvement in the lipid profile, and a marked attenuation of oxidative stress. The authors also highlight that eugenol increases cellular glucose uptake through the modulation of the PI3K pathway, suggesting a direct involvement of the main insulin sensitivity pathways (Carvalho et al., 2021) [16].

From a pathophysiological point of view, this finding is particularly important because oxidative stress represents one of the main factors fueling insulin resistance. Excessive production of reactive oxygen species alters insulin signaling, damages mitochondria, and promotes a state of chronic low-grade inflammation. By reducing oxidative damage and improving endogenous antioxidant defenses, eugenol appears to help "defuse" one of the deepest mechanisms of metabolic dysfunction (Carvalho et al., 2021) [16].

This relationship between redox homeostasis (the dynamic balance between oxidizing molecules, such as free radicals, and antioxidant ones) and insulin sensitivity emerges even more clearly in clinical studies conducted on clove polyphenols. In a randomized, controlled, double-blind study conducted on subjects with metabolic syndrome, supplementation with Clovinol®, a polyphenolic extract derived from the clove plant, resulted in a reduction of the HOMA-IR index of over 50%, accompanied by significant improvements in fasting glycemia, post-prandial glycemia, and HbA1c (Thomas et al., 2022) [17]. In parallel, marked increases were observed in intracellular levels of glutathione (a powerful antioxidant produced naturally by cells) and in the activity of the Nrf2 factor, one of the main regulators of the cellular antioxidant response.

This step is extremely relevant because it directly links the improvement of insulin sensitivity to the rebalancing of the intracellular oxidative state. In other words, clove polyphenols do not appear to act simply by "lowering sugar," but by improving the metabolic environment in which insulin signaling must function. It is as if the cell, by reducing its oxidative and inflammatory load, progressively returns to correctly recognizing the insulin message.

The study also showed a significant reduction in IL-1β and TNF-α, two cytokines closely involved in the genesis of insulin resistance. This finding is particularly important because chronic low-grade inflammation represents one of the main links between visceral obesity, hyperinsulinemia, and progressive alteration of glucose metabolism.

Skeletal muscle, the main site of peripheral glucose uptake, also appears to benefit deeply from the action of eugenol. In a mouse model of type 2 diabetes induced by a high-fat diet and streptozotocin, eugenol significantly improved insulin sensitivity, increased muscle glucose uptake, and reduced glycemia. At the molecular level, the compound increased GLUT4 translocation and AMPK phosphorylation in skeletal muscle through the activation of the axis involving AMPK (Jiang et al., 2022) [18].

This mechanism is particularly interesting because it acts independently of the classic insulin pathway mediated by AKT. In conditions of advanced insulin resistance, insulin signaling is compromised; however, the activation of AMPK allows for increased glucose uptake even when the insulin signal is altered. From a biological point of view, it is as if eugenol opens an "alternative route" to allow glucose to enter the cell without further overloading the insulin system.

In parallel, eugenol reduced the expression of certain markers of muscle atrophy and attenuated NF-κB phosphorylation, suggesting an overall improvement in systemic inflammation and muscle energy metabolism. This aspect is particularly important because skeletal muscle represents one of the main target organs of insulin resistance and the loss of metabolic flexibility (Jiang et al., 2022) [18].

Similar results also emerge in studies focused directly on the AMPK-GLUT4 pathway. In diabetic rats treated with eugenol, a significant reduction in glycemia, an improvement in serum insulin levels, and a marked decrease in the HOMA-IR index were observed. Concurrently, eugenol increased the translocation of GLUT4 in skeletal muscle through the activation of AMPK, improving peripheral glucose uptake.

The authors also emphasize that eugenol significantly reduces markers of oxidative stress and major pro-inflammatory cytokines, including IL-6. This finding confirms once again that the effect on insulin resistance does not depend on a single molecular target, but on an integrated regulation of energy metabolism, inflammation, and redox homeostasis (Al-Trad et al., 2019) [19].

Overall, the available evidence shows that cloves do not act simply as an aromatic spice or a generic antioxidant, but as true modulators of metabolic physiology. Through eugenol and bioactive polyphenols, this spice appears to improve insulin sensitivity, increase peripheral glucose utilization, reduce inflammation and oxidative stress, and restore a more efficient energy balance.

In this sense, the relationship between cloves and insulin resistance represents one of the most interesting examples of how a natural compound can interact with the main nodes of modern metabolic pathophysiology, helping to counteract the effects of chronic hyperinsulinemia and the continuous activation of the insulin pathway.

To fully understand the role of cloves in modern chronic diseases, it is essential to focus on their relationship with the PI3K–AKT–mTOR pathway, one of the primary regulatory systems for cell growth, survival, and energy metabolism. mTOR can be considered the “central sensor of abundance”: when nutrients, insulin, and growth signals are high, this pathway remains constantly active, pushing cells toward proliferation, accumulation, and a reduction in recycling processes. In pathological conditions, this chronic activation becomes a cross-cutting risk factor involved in the development of type 2 diabetes, cancer, inflammation, and tissue degeneration.

In this context, eugenol, the main bioactive component of cloves, stands out for its ability to modulate mTOR in a context-dependent manner, reducing its pathological hyperactivation without completely blocking its physiological function. Studies conducted on human colon carcinoma cells have shown that an active fraction extracted from cloves inhibits the phosphorylation of PI3K, AKT, and mTOR in a dose-dependent manner, leading to cell cycle arrest and the induction of apoptosis (Zhao et al., 2021) [20]. The effect was found to be reversible in the presence of IGF-1 (insulin-like growth factor), confirming that the action of the active fraction acts directly along the insulin–PI3K–AKT–mTOR axis, the same axis that is chronically stimulated in states of hyperinsulinemia.

This modulation of mTOR does not lead exclusively to apoptosis but also involves autophagy, a process of cellular maintenance that is strongly inhibited when mTOR is hyperactive. In a 2018 study, also conducted on colon carcinoma cells, the active fraction of cloves simultaneously induced apoptosis and autophagy through the suppression of the PI3K/AKT/mTOR pathway (Liu et al., 2018) [21]. Pharmacological inhibition of autophagy further increased apoptotic cell death, suggesting that autophagy initially represents a cell's attempt to adapt to the stress induced by the treatment. This finding is extremely relevant because it shows that eugenol does not “kill indiscriminately,” but forces the pathological cell to reveal its metabolic fragility, especially when it is dependent on mTOR for survival.

Eugenol's interference with mTOR also emerges in different oncological contexts. In human lung carcinoma cells, eugenol showed a suppressive effect on cell proliferation, migration, and invasion, associated with a significant reduction in AKT phosphorylation and the inhibition of enzymes crucial for metastatic progression (Li and Yang, 2018) [22]. Although mTOR is not always measured directly in this study, the reduction of phosphorylated AKT indicates a functional suppression of the entire PI3K/AKT/mTOR axis, confirming the consistency of the mechanism of action.

A particularly interesting aspect is that the modulation of mTOR by cloves is not limited to the oncological field. In a model of acrylamide-induced testicular toxicity, eugenol showed a markedly protective effect, improving sperm quality, hormonal profile, and tissue integrity (Saleh et al., 2024) [23]. In this case, eugenol did not simply inhibit mTOR, but restored a dynamic balance between AKT and mTOR, promoting functional autophagy and reducing excessive apoptosis. This demonstrates a key point: mTOR is not an “enemy” to be turned off, but a regulator to be brought back into balance, and eugenol seems capable of adapting its action to the pathophysiological context.

The ability of cloves to target the mTOR axis also emerges through innovative biotechnological approaches. The green synthesis of silver nanoparticles (a method that uses natural substances, such as plant extracts, to produce tiny particles) using extracts of Syzygium aromaticum has produced nanostructured systems capable of inducing selective apoptosis in leukemic cells, with a marked reduction in AKT and mTOR activity (Guo et al., 2025) [24]. In this case as well, the insulin pathway is confirmed as the central target through which clove compounds exert their biological action, regardless of the form of administration.

Taken together, these studies outline a coherent picture: cloves, through eugenol and derived bioactive fractions, act as metabolic modulators of mTOR, capable of reducing the pathological hyperactivation of the pathway, reactivating autophagy, limiting uncontrolled cell proliferation, and improving tissue resilience. This behavior is particularly relevant in the modern context, characterized by chronic hyperinsulinemia, nutritional overload, and persistent inflammation, conditions that keep mTOR constantly switched on.

In this sense, cloves cannot be interpreted as a simple anti-tumor or antioxidant agent, but as a metabolically intelligent spice capable of interacting with one of the most central nodes of human pathophysiology. Included within a lifestyle oriented toward the reduction of glycemic variability and hyperinsulinemia, its effect on mTOR contributes to shifting the organism from a mode of forced and dysfunctional growth toward a mode of balance, adaptation, and cellular maintenance.

If the relationship between eugenol and mTOR is already of significant biological relevance, the picture becomes even more interesting when observing the role of AMPK, the primary cellular energy sensor. As discussed in previous chapters, AMPK and mTOR represent two opposite and complementary metabolic programs: when nutrients, glucose, and insulin are abundant, mTOR promotes growth, protein synthesis, and energy storage; conversely, when the cell perceives metabolic stress or energy deficiency, AMPK slows down anabolic processes, promotes autophagy, and directs metabolism toward energy conservation and cellular survival. In this dynamic balance, eugenol appears to act as a modulator capable of restoring the proper dialogue between these two systems.

One of the clearest examples emerges from studies on cerebral ischemia-reperfusion injury. In experimental models of ischemic stroke, eugenol has been shown to significantly reduce cerebral infarct volume, improve neurological function, and attenuate neuronal apoptosis through the activation of the AMPK/mTOR pathway (Sun et al., 2020) [25]. The most interesting aspect is that eugenol does not merely block mTOR, but induces functional and controlled autophagy, increasing the main molecular biomarkers used to evaluate and measure autophagy. From a physiological perspective, this means that neuronal cells are able to eliminate damaged components and improve their ability to adapt to ischemic stress.

The study also showed that rapamycin, a potent mTOR inhibitor and autophagy activator, further enhances the neuroprotective effects of eugenol, while pharmacological inhibition of AMPK cancels out most of the observed benefits (Sun et al., 2020) [25]. This finding confirms that AMPK represents the true “metabolic switch” through which eugenol coordinates the cellular response. It is as if eugenol helps the cell temporarily exit the forced growth mode imposed by mTOR, allowing it to enter a maintenance and energy survival mode.

This regulation also appears particularly relevant in conditions of chronic metabolic damage. An updated review on the properties of eugenol in ischemia-reperfusion injury highlights that one of the main cytoprotective mechanisms involves the modulation of the AMPK–mTOR axis (Randhawa et al., 2026) [26]. The activation of AMPK reduces cellular energy consumption, limits oxidative stress, and promotes protective autophagy, while the simultaneous inhibition of mTOR hyperactivation allows the cell to better adapt to stress conditions. This concept is particularly important in the modern context, characterized by continuous energy abundance and chronic anabolic overstimulation.

The authors also highlight that eugenol modulates the AMPK axis and the PI3K/AKT pathway, two systems closely linked to cellular survival, mitochondrial function, and the regulation of apoptosis (Randhawa et al., 2026) [26]. From a biological perspective, this suggests that eugenol does not act as a simple “inhibitor” of individual pathways, but as an integrated regulator of the cellular energy response, intervening simultaneously on inflammation, autophagy, metabolism, and mitochondrial protection.

This ability to rebalance AMPK and mTOR also emerges with extreme clarity in hepatic metabolism. In experimental models of fatty liver disease induced by a high-fat diet, eugenol significantly reduced intracellular lipid accumulation, hepatic triglycerides, and fibrotic progression through the activation of AMPK and the concomitant suppression of mTOR. In parallel, a reduction in the expression of SREBP1 (a primary transcription factor that regulates lipid metabolism) and lipogenic enzymes associated with fatty acid synthesis was observed (Jo et al., 2014) [27].

This step is extremely relevant because it directly connects the relationship between AMPK and mTOR with one of the main metabolic problems of chronic hyperinsulinemia: fatty liver disease. When mTOR remains constantly active, the liver is pushed toward continuous lipogenesis (a metabolic process through which the body produces fats, mainly starting from excess nutrients), triglyceride accumulation, and progressive loss of metabolic flexibility. The activation of AMPK by eugenol, on the other hand, represents an opposite metabolic signal: it increases lipid oxidation, reduces fat synthesis, and returns hepatic metabolism to a more energy-efficient mode.

A particularly interesting aspect that emerged from the study is that the effects of eugenol are abolished in the presence of specific AMPK or mTOR inhibitors, confirming the direct involvement of these pathways. In other words, the improvement of fatty liver disease does not derive from a generic antioxidant effect, but from a true metabolic reprogramming mediated by the AMPK–mTOR axis (Jo et al., 2014) [27].

Eugenol also demonstrates an extraordinary adaptive capacity in testicular tissue. In models of reproductive toxicity induced by acrylamide (a chemical contaminant that forms naturally in starchy foods during high-temperature cooking), eugenol improved sperm quality, steroidogenesis, and the integrity of the blood-testis barrier by modulating the AMPK/PI3K/AKT/mTOR pathway. Acrylamide intoxication, in fact, caused severe cellular energy dysfunction, with depletion of ATP (the main energy molecule in our body) and pathological hyperactivation of AMPK. Eugenol restored intracellular energy balance, normalizing metabolism and reducing both aberrant autophagy and excessive apoptosis (Saleh et al., 2024) [23].

This finding is very important because it shows how the action of eugenol is deeply context-dependent. In some pathological conditions, such as fatty liver or ischemic damage, the activation of AMPK and the reduction of mTOR are protective; in other conditions characterized by extreme energy collapse, eugenol instead contributes to restoring a physiological balance between AMPK, AKT, and mTOR, avoiding both excessive anabolic suppression and uncontrolled cell death.

Overall, the available evidence outlines cloves as one of the most interesting spices from the perspective of cellular energy regulation. Through eugenol, this spice can modulate the delicate balance between AMPK and mTOR, promoting autophagy, mitochondrial protection, control of lipogenesis, stress adaptation, and tissue resilience.

In a context characterized by chronic hyperinsulinemia, caloric excess, and continuous anabolic stimulation, the relationship between eugenol, AMPK, and mTOR therefore assumes a meaning extremely consistent with what was discussed in the previous chapters: bringing the cell out of a mode of continuous growth and metabolic dysfunction, restoring its ability to adapt, repair itself, and manage its energy resources more efficiently.