Micronutrients and nutritional adequacy

The mere availability of a supplement does not automatically imply a health benefit. Over the last few decades, the nutritional supplementation market has grown exponentially, fueled by the belief that vitamins and minerals can improve health status, prevent diseases, or slow down aging. Although these molecules are essential for the proper functioning of the body, the most recent scientific evidence paints a much more complex picture. The effectiveness of supplementation actually depends on the clinical context, initial nutritional status, age, physiological conditions, and the presence of any documented deficiencies. In other words, supplements cannot be considered a universal solution, but rather represent therapeutic tools that are truly useful when they correct a deficit or meet an increased physiological requirement.

This principle emerges with particular clarity during pregnancy, a phase of life in which the requirement for vitamins and minerals increases considerably to support fetal growth, placental development, and the mother's metabolic adaptation. Two of the largest systematic reviews published on the subject have analyzed a total of 72 clinical trials and over 450,000 pregnant women, comparing different vitamin-mineral supplementation strategies. The results show that traditional supplementation with iron and folic acid significantly reduces the risk of maternal anemia and contributes to decreasing the incidence of low birth weight. However, the greatest benefits were observed with supplements containing multiple micronutrients (Multiple Micronutrient Supplements, MMN), which proved superior in reducing the risk of low birth weight, small-for-gestational-age infants, and stillbirths, while also improving some indicators of infant development and the newborn's nutritional status (Oh et al., 2020) [7] (Keats et al., 2021) [8].

A particularly interesting aspect concerns the composition of the supplements. Formulations containing a higher number of vitamins and minerals produced better results than those consisting of only a few nutrients, suggesting that during pregnancy, proper fetal development depends on the interaction of numerous simultaneous biological processes, such as DNA synthesis, mitochondrial energy production, placental angiogenesis (the formation of blood vessels in the placenta), and nervous system development. None of these mechanisms depends on a single micronutrient, but rather on their coordinated action. It is important to emphasize that these benefits were obtained without any increase in maternal, neonatal, or infant mortality, confirming the good safety profile of multiple supplementation when used in populations characterized by a high risk of nutritional deficiencies (Oh et al., 2020) [7]; (Keats et al., 2021) [8].

The same logic has also been observed in public health interventions aimed at the entire population. A Cochrane review (which rigorously analyzes the results of multiple scientific studies on the same topic) analyzed 43 studies and nearly 20,000 participants, evaluating the effects of food fortification with multiple micronutrients. Compared to non-fortified foods, this strategy resulted in a marked reduction in anemia, iron-deficiency anemia, and deficiencies of iron, vitamin A, vitamin B2, vitamin B6, and vitamin B12, confirming how the simultaneous correction of multiple nutritional deficits can significantly improve the population's nutritional status. This highlights how the improvement of nutritional biomarkers does not automatically translate into a measurable clinical benefit and underscores the need for longer-term prospective studies (Das et al., 2019) [9].

The most recent evidence also suggests that the very concept of nutritional deficiency should be re-evaluated. For many years, international programs have focused almost exclusively on preventing deficiencies of iron, iodine, vitamin A, folates, and zinc. A recent review promoted by the Micronutrient Forum instead draws attention to at least nine other frequently overlooked micronutrients, including thiamine, riboflavin, niacin, vitamins B6 and B12, vitamin D, vitamin K, calcium, and selenium. The authors emphasize that so-called "hidden hunger" represents one of the main global nutritional emergencies today and that the scarcity of epidemiological data for many of these nutrients should not be interpreted as an absence of the problem, but rather as a consequence of the limited nutritional surveillance available. According to this view, the future of prevention should be based on a broader approach, capable of assessing the individual's entire micronutrient profile rather than focusing exclusively on a few vitamins or minerals (Brown et al., 2025) [10].

Interest in nutritional supplementation concerns not only the prevention of deficiencies but also the possible role of vitamins and minerals in improving the prognosis of already diagnosed pathologies. In oncology, for example, many patients spontaneously resort to supplements with the goal of supporting the body during treatments or reducing the risk of recurrence. A systematic review with meta-analysis that evaluated the available studies suggests that some micronutrients may indeed be associated with favorable outcomes, while still calling for a cautious interpretation of the results.

In particular, calcium intake after a cancer diagnosis was found to be associated with a reduction in total mortality and cancer-specific mortality, while vitamin D was correlated with an improvement in overall survival. Furthermore, in women with breast cancer, vitamin C, vitamin E, and multivitamin preparations were associated with a lower risk of recurrence and better survival. However, the authors emphasize that most of the evidence comes from observational studies, in which it is difficult to distinguish the effect of the supplement from that of an overall healthier lifestyle. For this reason, although these are promising results, supplementation cannot be recommended indiscriminately to all cancer patients, but should be personalized based on nutritional status, the type of neoplasm, ongoing therapies, and any documented deficiencies (Kanellopoulou et al., 2021) [11].

A similar message also emerges in the prevention of melanoma. A recent review highlighted how various micronutrients participate in the regulation of biological processes involved in carcinogenesis, including immune response, DNA repair, control of oxidative stress, and cell proliferation. Among all, vitamin D is supported by the most solid epidemiological evidence: low serum levels have been associated with a higher risk of developing melanoma, more aggressive tumors, and a worse prognosis. Vitamins A, C, and E, along with selenium, zinc, and copper, also play important antioxidant and immunomodulatory functions. However, the review highlights a fundamental concept: the effect of some micronutrients is strongly dose-dependent. Vitamin C and selenium, for example, can exert favorable effects when correcting a deficiency, but excessive dosages could alter the cellular redox balance, producing different biological effects depending on the clinical and genetic context. It follows that the principle that "more is better" has no scientific foundation in vitamin supplementation. Correcting a deficiency represents a rational intervention, while the indiscriminate use of high doses currently lacks sufficient evidence to be recommended as a melanoma prevention strategy (Pec et al., 2026) [12].

The same cautious approach also characterizes the literature regarding the pediatric age. A systematic review that analyzed the use of supplements in major chronic childhood diseases shows that many products are biologically active, but not always capable of producing relevant clinical benefits. Probiotics, omega-3, vitamins, minerals, and other supplements have been shown to modulate the gut microbiota, reduce some inflammatory markers, and improve specific metabolic parameters in children affected by autism spectrum disorders, cystic fibrosis, type 1 diabetes mellitus, gastrointestinal diseases, and juvenile idiopathic arthritis.

However, these biological modifications have only rarely translated into consistent and reproducible clinical improvements. The most promising evidence concerns probiotics in cystic fibrosis and in some subgroups of children with autism spectrum disorders, while for many other conditions, the available studies are still too small and heterogeneous to allow for definitive recommendations (Inchingolo et al., 2026) [13].

Taken together, this evidence outlines a common principle. Nutritional supplementation should not be considered an alternative to a balanced diet nor a preventive intervention to be applied indiscriminately to the entire population. The most consistent benefits emerge when it is used to correct documented deficiencies, meet increased physiological needs, such as during pregnancy, or support specific clinical conditions where there are solid biological bases and adequate scientific evidence. Conversely, in people with good nutritional status, the indiscriminate intake of vitamins and minerals has not shown consistent benefits. Supplementation should therefore be interpreted as a tool of personalized nutritional medicine, guided by the clinical and laboratory assessment of the individual rather than by the idea that a higher intake of micronutrients is always synonymous with better health.

The onset of insulin resistance is traditionally attributed to caloric excess, obesity, and a sedentary lifestyle. Although these are determining factors, an additional element capable of influencing glucose metabolism has emerged in recent years: the body's micronutrient status. Vitamins and minerals do not merely play a supportive role; they participate directly in the mechanisms that regulate insulin secretion, insulin receptor signal transduction, ATP production, mitochondrial function, and defense against oxidative stress. When one or more of these micronutrients are deficient, numerous enzymatic reactions lose efficiency, and the entire metabolic response to insulin tends to deteriorate progressively. It is a phenomenon comparable to a gear mechanism missing several small components simultaneously: each one, taken individually, might seem unimportant, but their combined absence compromises the functioning of the entire system.

For a long time, research focused on the role of individual micronutrients, such as magnesium or vitamin D. Today, however, it is becoming increasingly clear that nutritional deficiencies rarely occur in isolation. More frequently, multiple deficits coexist and influence each other, making it more realistic to evaluate the overall micronutrient profile rather than a single nutrient. This shift in perspective was confirmed by a study conducted on patients with type 2 diabetes, in which circulating levels of magnesium, zinc, calcium, potassium, and vitamin D were analyzed simultaneously. Through an analysis of nutritional profiles, the authors identified two different patterns of micronutrient distribution, both closely associated with metabolic control. Subjects in the quartiles with the lowest concentrations had a nearly fourfold higher risk of poor glycemic control and high insulin resistance compared to those with more favorable nutritional profiles. Particularly significant is the fact that these associations primarily concerned glycated hemoglobin and the HOMA-IR index, indicators of chronic metabolic control and insulin sensitivity, while they were not evident for fasting glycemia. This suggests that micronutrient deficiencies exert a progressive effect over time, contributing more to the deterioration of the insulin response than to acute glycemic fluctuations (Santos et al., 2024) [14].

From a physiological standpoint, these results are consistent with the functions performed by the main micronutrients involved. Magnesium is an essential cofactor for hundreds of enzymes and is indispensable for insulin receptor activity, ATP production, and the translocation of the GLUT4 transporter to the cell membrane. Zinc participates in the synthesis, storage, and secretion of insulin, in addition to protecting pancreatic β-cells from oxidative damage. Calcium is involved in insulin exocytosis and intracellular signal transduction, while potassium regulates the membrane potential of pancreatic β-cells, influencing hormone release. Finally, vitamin D acts through its receptor expressed in the pancreas, skeletal muscle, liver, and adipose tissue, contributing to the modulation of chronic inflammation and insulin sensitivity (Santos et al., 2024) [14]. Taken together, these mechanisms explain why the concomitant reduction of multiple micronutrients can compromise the efficiency of the entire glucose regulation system.

A second aspect that has recently emerged concerns the overall quality of the diet. For many years, the prevention of insulin resistance focused primarily on reducing caloric intake. However, research conducted on women of childbearing age at high metabolic risk has shown that it is not only important how much one eats, but above all the nutritional density of the foods consumed. The authors also evaluated the achievement of recommended requirements for vitamins and minerals and adherence to a correct energy intake, observing that many participants consumed sufficient or even excessive calories without meeting the requirements for numerous essential micronutrients. This phenomenon, now defined as "hidden hunger," describes a condition in which the body receives energy in abundance but remains deficient in nutrients essential for the proper functioning of metabolism (Piyathilake et al., 2022) [15].

Among all the micronutrients analyzed, the most interesting results concerned folates and vitamin C. Women who reached the recommended levels of these nutrients within an energetically balanced diet had a significantly lower probability of developing insulin resistance compared to those with inadequate intake. However, this association did not emerge when vitamin requirements were met through an excessively caloric diet. This suggests that energy excess may attenuate or even nullify the favorable metabolic effects of micronutrients. These results introduce a particularly relevant concept: the nutritional quality of the diet can be just as important as the amount of energy introduced and represents a fundamental element in the prevention of metabolic alterations that precede type 2 diabetes (Piyathilake et al., 2022) [15].

The observations emerging from clinical studies are also confirmed by population analyses. The largest systematic review available to date, including 132 studies and over 52,000 patients with type 2 diabetes, demonstrates that nearly one in two subjects has at least one clinically significant micronutrient deficiency. The most frequent deficiencies concerned vitamin D, magnesium, and, in patients treated with metformin, vitamin B12. This data is particularly relevant when considering that these nutrients are involved in fundamental processes for glucose metabolism, including insulin secretion, insulin receptor phosphorylation, ATP production, mitochondrial function, and antioxidant defense systems. The review also highlights that deficiencies are even more frequent in women and in patients already suffering from diabetic complications, suggesting that micronutrient status may influence not only the onset of the disease but also its progression (Mangal et al., 2025) [16].

These results do not allow us to establish whether deficiencies represent a cause or a consequence of diabetes, but they reinforce the hypothesis that so-called "hidden hunger" contributes to fueling a vicious cycle in which chronic inflammation, oxidative stress, and insulin signaling alterations reinforce each other. For this reason, the authors suggest that the assessment of micronutrient status should become part of the clinical management of the diabetic patient, with particular attention to levels of vitamin D, magnesium, and vitamin B12, especially in subjects on chronic metformin therapy (Mangal et al., 2025) [16].

If micronutrient deficiency represents a possible risk factor, a question arises: can their correction improve glucose metabolism? An interesting answer comes from one of the most innovative precision nutrition studies conducted in recent years. Through a multi-micronutrient intervention containing twelve vitamins and five minerals, followed for two years using genomic, metabolomic, and proteomic technologies (studying genes, proteins, and metabolic products), it was possible to observe how supplementation at physiological dosages is capable of simultaneously modifying numerous metabolic processes. In children with a poor-quality diet, the intervention resulted in a reduction of fasting glycemia and LDL cholesterol, accompanied by an increase in circulating levels of numerous B vitamins and vitamin E. In parallel, changes in lipid metabolism, inflammatory response, and the expression of proteins involved in energy homeostasis were observed.

One of the most innovative aspects of the study, however, concerns the marked individual variability of the response. Not all participants obtained the same benefits, and the main predictor of the intervention's efficacy was the initial level of the biomarker: the greatest improvements were observed in subjects who had the most marked deficiencies. This result reinforces the concept of personalized nutrition, according to which the efficacy of a nutritional intervention depends on the biological characteristics of the individual and cannot be considered identical for the entire population (Kaput and Monteiro, 2024) [17].

Despite this evidence, it is important to interpret the role of micronutrients with balance. A recent meta-analysis evaluated the overall association between multiple micronutrient deficiencies and glycemic control in type 2 diabetes, observing that this relationship, while statistically significant, has a relatively modest magnitude. Among all the nutrients analyzed, magnesium was the one most associated with both glycated hemoglobin and the HOMA-IR index, confirming its central role in insulin receptor phosphorylation, ATP metabolism, and GLUT4 transporter translocation. Vitamin D showed significant associations with fasting glycemia, post-prandial glycemia, and glycated hemoglobin, while for zinc, iron, and vitamin B12, the correlations were much weaker (Mangal et al., 2026) [18].

Taken together, these findings outline a coherent picture. Micronutrients are not merely accessory elements of the diet, but essential components of the biological networks that regulate insulin sensitivity, pancreatic β-cell function, energy metabolism, and defense against oxidative stress. Multiple deficiencies are frequent in patients with type 2 diabetes and are associated with poorer metabolic control, especially when they involve nutrients such as magnesium and vitamin D. At the same time, research demonstrates that the efficacy of nutritional interventions depends on the clinical context and individual nutritional status, confirming that the prevention of insulin resistance cannot be limited to simple calorie control, but must also consider diet quality and the adequacy of micronutrient intake. In this light, nutritional assessment becomes an integral part of a truly personalized approach to the prevention and management of metabolic diseases.

An individual's metabolic health does not depend solely on dietary habits adopted in adulthood. Scientific evidence from recent years shows that a significant portion of the risk of developing obesity, insulin resistance, and type 2 diabetes is determined long before the appearance of the first symptoms, during pregnancy, breastfeeding, and the first years of life. These phases represent a true "critical biological window," during which the body is particularly sensitive to nutritional stimuli. During this period, vitamins and minerals do not only support growth, but also participate in the formation of organs, the development of the endocrine system, the maturation of the pancreas, the regulation of energy metabolism, and the definition of numerous mechanisms that will accompany the individual for the rest of their life.

This concept is the basis of the Developmental Origins of Health and Disease (DOHaD) theory, according to which the nutritional environment encountered during fetal development and in the first years of life can "program" the body's metabolism, influencing the risk of developing chronic diseases even many decades later. While in the past the focus was primarily on the mother's caloric and protein intake, it is now increasingly evident that micronutrients also play a decisive role: vitamins and minerals participate in DNA synthesis, epigenetic regulation (control of which genes are activated or deactivated, without modifying the DNA), cell differentiation, the maturation of pancreatic β-cells, insulin secretion, insulin sensitivity, and antioxidant defense systems. Their insufficient availability during pregnancy can therefore permanently alter the development of metabolic organs and predispose the child to obesity, metabolic syndrome, and type 2 diabetes in adulthood (Wu et al., 2021) [19].

Among the most innovative aspects emerging from this research is the role of epigenetics. Epigenetic modifications do not alter the DNA sequence, but regulate gene activity through processes such as DNA methylation, histone modifications (proteins that organize DNA and help control gene expression), and the action of microRNAs. In other words, maternal nutrition can leave a sort of "biological memory" that conditions the functioning of genes involved in the regulation of glucose metabolism, inflammation, and lipid metabolism. Experimental studies show, for example, that a maternal magnesium deficiency compromises the offspring's insulin sensitivity, while alterations in the intake of calcium, chromium, zinc, vitamin D, vitamin A, vitamin B12, and folates can modify pancreatic function, insulin response, and the child's body composition (Wu et al., 2021) [19].

Experimental observations concretely confirm these theoretical principles. In a study conducted on Wistar rats (rats specifically bred as an experimental model in scientific research), a chronic restriction of maternal vitamin intake initiated before conception and maintained during pregnancy and lactation did not change the offspring's birth weight, but induced profound metabolic alterations during growth. The pups developed an increase in fat mass, a reduction in lean mass, higher concentrations of triglycerides, and a marked increase in oxidative stress, despite maintaining apparently normal glycemia and insulinemia values in the first months of life. These results suggest that metabolic programming precedes the appearance of clinically evident alterations by many years. Insulin resistance was not yet manifest, but the biological terrain was already favorable to its development. Particularly significant was the observation that restoring an adequate vitamin intake immediately after birth corrected most of the metabolic alterations, while a later nutritional intervention produced much more limited benefits. This confirms the existence of a time window in which nutrition exerts a particularly profound influence on future metabolic health (Venu et al., 2004) [20].

The consequences of multiple micronutrient deficiencies do not seem to be limited to the body's tissues, but also involve the gut microbiota, now recognized as one of the main regulators of energy metabolism. To better understand these mechanisms, an innovative experimental model of multiple micronutrient deficiencies was developed that faithfully reproduces the situation observed in malnourished children. Animals fed a diet poor in vitamins and minerals showed profound alterations in glucose and lipid metabolism, accompanied by a significant functional reorganization of the gut microbiota. In addition to the reduction of the micronutrients provided by the diet, deficiencies in copper, selenium, and molybdenum appeared unexpectedly, along with alterations in the balance of other minerals, demonstrating how micronutrient metabolism constitutes a highly integrated network in which the deficit of one element can modify the availability of many others.

At the same time, a persistent reduction in glycemia, modifications in fatty acid metabolism, and a lower capacity of the microbiota to mature correctly were observed, maintaining characteristics typical of the earliest stages of development. According to the authors, these alterations could represent one of the mechanisms through which childhood malnutrition increases the risk of obesity, metabolic syndrome, and type 2 diabetes in adulthood (Littlejohn et al., 2023) [21].

The repercussions of micronutrient deficiencies are particularly evident during childhood, a period in which body growth, brain development, and immune system maturation proceed with extreme rapidity. A narrative review highlights how so-called "hidden hunger" represents one of the most widespread forms of pediatric malnutrition today and can also affect children of normal weight or even those who are overweight. Iron, vitamin A, vitamin D, and zinc are the micronutrients that most frequently result in being insufficient. The consequences do not exclusively concern the appearance of anemia or growth alterations, but include cognitive deficits, reduced learning capacity, greater susceptibility to infections, and an increased risk of developing obesity, type 2 diabetes, osteoporosis, and cardiovascular diseases over the course of life. The authors emphasize how these deficits rarely occur in isolation: in most cases, multiple deficiencies coexist and reinforce each other, making it even more important to promote a varied and nutritionally complete diet from the first months of life. Breastfeeding, the correct introduction of complementary foods, and the limitation of ultra-processed foods represent the most effective preventive tools, which can be supplemented by targeted supplementation programs in at-risk populations (Weffort and Lamounier, 2024) [22].

A particularly interesting aspect concerns the so-called "childhood obesity paradox." Although these children often consume amounts of energy exceeding their requirements, they frequently present multiple micronutrient deficiencies, configuring a form of qualitative malnutrition. A diet rich in ultra-processed foods, sugary drinks, and refined products guarantees a caloric excess but a reduced intake of vitamins, minerals, and dietary fiber. Added to this dietary component are the chronic inflammatory state typical of obesity, alterations in intestinal absorption, and changes in the distribution of nutrients within the body. The most frequently observed deficiencies concern iron, vitamins A, C, D, E, B-group vitamins, folic acid, zinc, and copper. These deficits do not represent a simple consequence of obesity, but actively contribute to the appearance of insulin resistance, endothelial dysfunction, oxidative stress, and chronic inflammation.

Among all the alterations, iron deficiency is one of the best documented. Chronic inflammation stimulates the production of hepcidin, a hormone that reduces intestinal iron absorption and limits its release from body stores, causing a functional deficiency even when stores appear normal. The consequences are particularly significant during the developmental age, as they compromise cognitive development, memory, learning, concentration capacity, and the immune response. Similarly, reduced availability of vitamin D, also favored by sequestration in adipose tissue and less sun exposure, has been associated with greater insulin resistance and a worse cardiometabolic profile. Antioxidant vitamins, folates, vitamin B12, and zinc are also frequently reduced and contribute to increasing oxidative stress, hyperhomocysteinemia, and the deterioration of metabolic function (Calcaterra et al., 2023) [23].

Taken together, this evidence shows that the prevention of metabolic diseases must begin long before adulthood. The mother's nutritional status, the quality of nutrition during the first thousand days of life, and childhood dietary habits profoundly influence the development of metabolic organs, gut microbiota function, epigenetic regulation, and insulin sensitivity. Multiple micronutrient deficiencies do not only compromise the child's growth and neurological development, but can leave a true "metabolic memory" capable of increasing the risk of obesity, type 2 diabetes, and other chronic pathologies many years later. For this reason, the prevention of hidden hunger should not be considered exclusively a nutritional goal, but a public health strategy aimed at improving the health of future generations through a balanced maternal diet, the promotion of breastfeeding, adequate nutritional education, and the monitoring of micronutrients in the most vulnerable subjects.