Micronutrients and type 2 diabetes prevention
Chronic low-grade inflammation resulting from oxidative stress and imbalances in the innate immune system has been associated with obesity and insulin resistance – critical stages in the development and progression of type 2 diabetes (4–6). Therefore, inflammation may play a causal role in the development of diabetes, and reducing it by modulation of oxidative stress and the innate immune response via antioxidant micronutrients could lead to a status of improved insulin sensitivity and delayed disease onset. Many micronutrients exhibit well-characterized anti-inflammatory or immuno-modulatory functions. The vitamins A, B6, B9, B12, C, D, and E as well as essential fatty acids and several trace elements (e.g., zinc, iron and selenium) are known to improve the overall function of the immune system, for example, preventing excessive expression of inflammatory signaling proteins (7). Some of these micronutrients have been linked in studies to prevention of type 2 diabetes.
The role of vitamin D in calcium and phosphorous regulation and bone metabolism is well understood. However, more recently, vitamin D and calcium have also been linked to a number of conditions, such as cancer, autoimmune diseases, atherosclerosis, obesity, cardiovascular diseases, diabetes, and associated conditions such as insulin resistance (8–10). In type 2 diabetes, the role of vitamin D was suggested from the presence of vitamin D receptors (VDR) in the pancreatic insulin-producing cells. In these cells, the biologically active metabolite of vitamin D (1,25-dihydroxy-vitamin D) enhances insulin production and secretion via its action on the VDR (11). Further studies have shown a reduced overall risk of type 2 diabetes in subjects who ingest more than 800 IU/day of vitamin D (9, 12). An alternative, perhaps related, explanation was recently proposed for the role of vitamin D in the prevention of type 2 diabetes based on its potent immunomodulatory functions (13). In this respect, supplementation with vitamin D (14) or its bioactive form, 1,25(OH)2D (7) improved insulin sensitivity by preventing the excessive synthesis of inflammatory mediator proteins (cytokines). The observational Women’s Health Study showed that among middle-aged and older women, taking over 511 IU/day of vitamin D reduced the risk of developing type 2 diabetes compared to ingesting 159 IU/day (15). Furthermore, data from the Nurses’ Health Study also found a significant correlation between higher total vitamin D intake and lower type 2 diabetes risks, even after adjusting for BMI, age, and non-dietary factors (12). Intervention studies have shown conflicting results about the effect of vitamin D on type 2 diabetes incidences (16–19). Taken together, the available information warrants exploring the possibility that vitamin D, either alone or in combination with calcium supplementation, can be employed in developing population-based strategies for type 2 diabetes prevention and control (20).
Vitamin C is the primary water-soluble antioxidant found in human plasma. Recent epidemiologic findings suggest that for some individuals, the current dietary recommendations may not provide tissue-saturating ascorbate concentrations (21) and that serum ascorbic acid deficiency may be relatively common (22). Vitamin C has an important role in immune function and various oxidativeand inflammatory processes, such as scavenging reactive oxygen species and protecting against their lipid damaging effects (23). In addition, vitamin C can recycle vitamin E back from its oxidized forms. For this reason, there has been interest in determining whether vitamin C might be used as a preventive agent against oxidative stress and subsequent inflammation associated with type 2 diabetes. A variety of epidemiologic studies have shown that higher intakes of fruit, vegetables and vitamin C are associated with decreased levels of biomarkers of oxidation, inflammation, and/or type 2 diabetes risk (24, 25). The European Prospective Investigation of Cancer-Norfolk Prospective Study examined the association between fruit and vegetable intake and plasma levels of vitamin C and risk of type 2 diabetes (26). A significant association was found between higher plasma levels of vitamin C and a reduced risk of diabetes. In the same study, a similar association was observed between fruit and vegetable intake and diabetes risk. Despite these epidemiologic findings, intervention trials assessing the effect of vitamin C supplementation on various markers of type 2 diabetes have yielded inconsistent results (27–30). Small sample sizes, genetic variation, short intervention duration, insufficient dosage, and disease status of the assessed cohorts may account for the lack of effect and the inconsistent outcomes observed in randomized controlled trials. Therefore, further research and long-term prospective studies are needed to elucidate the role of vitamin C as a modulator of inflammation and diabetes risk and to evaluate its potential role as a preventive agent at a population level (20).
Vitamin E (major form: alpha-tocopherol) has been shown in several studies to block LDL oxidation, to prevent the oxidative stresslinked to type 2 diabetes-associated abnormal metabolic patterns, and, subsequently, to attenuate gene expression of proteins mediating inflammatory processes (31–33). A number of epidemiological studies demonstrated an association between higher vitamin E intakes and a reduction of markers of oxidation and inflammation, as well as type 2 diabetes incidences (34–36). In contrast, various epidemiologic studies and intervention trials (see below) reported inconsistent findings
(37, 38). Research indicates that – given the role of vitamin C in regeneration of oxidized vitamin E – a combination of vitamin C and vitamin E intake may be more effective in reducing oxidative stress and inflammation than administering either micronutrient on its own (39). According to recent findings higher consumption of dietary antioxidants in fruit, vegetables, legumes and non-alcohol beverages may be associated with a lower risk of type 2 diabetes in healthy individuals, as well as in pre- diabetic and diabetic ones (40). One study, which evaluated the effects of daily supplementation of a combination of vitamin C (20,000 IU) and vitamin E (400 IU) for 4 weeks on insulin sensitivity in out-of-shape and fit, healthy young men, suggested that such a regimen may preclude the exercise-induced amelioration of insulin resistance in humans (41). However, a recent randomized controlled trial showed that administration of antioxidants during strenuous endurance training has no negative effect on the training-induced increase in insulin sensitivity in healthy individuals (42).
The inconsistent results of some studies evaluating the effect of vitamin E on inflammation, oxidation, and risks of type 2 diabetes may result partly from genetic differences between individuals that could lead to variations in response to micronutrient exposure. For example, a variant (polymorphism) of a gene coding for a protein, which enhances inflammatory processes, has been associated with higher concentrations of this protein in the body and with decreased levels after supplementation of vitamin E (273 IU/day) for one year (43). It was concluded that the anti-inflammatory effects of vitamin E are specific to those who are genetically predisposed to develop inflammatory responses upon exposure to stimuli. This observation is critical in identifying individuals of the general population who will benefit more from vitamin E supplementation based on their genetic predisposition to disease-related factors.
Limited evidence from human and animal studies suggests that increased intakes of vitamin K (phylloquinone) may be associated with reduced insulin resistance. In an observational study, for example, higher dietary and supplemental vitamin K intakes were associated with greater insulin sensitivity and better blood glucose status in men and women (44). A randomized controlled trial showed that vitamin K supplementation (500 μg/day) for 36 months may reduce progression of insulin resistance in older non- diabetic men (45). Vitamin K and vitamin K–dependent proteins have been identified in organs important for glucose and insulin metabolism, such as liver and pancreas (46). However, biological mechanisms behind the association between vitamin K and insulin and glucose metabolism are uncertain.
Similarly, some trace elements could play a role in preventing type 2 diabetes by regulating disturbed blood sugar regulation and decreasing insulin insensitivity (7). For example, it is well known that type 2 diabetes can be accompanied by a slow loss of intracellular zinc and an excess of zinc in the blood (47). Supplementation with zinc, therefore, has been shown to lower oxidative stress-related by-products and to attenuate the synthesis of inflammatory mediator proteins (48–50). This observation may substantiate an anti- diabetes action for zinc, and perhaps other trace elements, via its antioxidative and anti-inflammatory characteristics.
In addition, a preventive role of selenium on the risk of diabetes has been reported. Studies have suggested that selenium could enhance insulin sensitivity by mediating insulin-like actions (51). Moreover, selenium-dependant enzymes are known to have antioxidant properties potentially protecting tissues and membranes from oxidative stress (52). Results from human studies on selenium and diabetes are conflicting: Two studies found lower serum selenium concentrations in diabetic patients than in control subjects (53, 54) while in other studies higher serum selenium concentration were associated with a higher prevalence of diabetes (55, 56). In the randomized controlled SUVIMAX trial, no effect of supplementation with a mixture of antioxidants, including 100 μg/day selenium, on plasma glucose levels was found after 7.5 years of follow-up (57). More recently, a prospective study suggested a protective effect of higher plasma selenium concentrations on the later occurrence of disturbed blood sugar regulation in men (58).
Increasing evidence suggests a crucial role for magnesium in insulin action and sensitivity: an adequate magnesium status may be useful in improving insulin resistance and hence for preventing type 2 diabetes (59). Some studies indicated a beneficial effect of magnesium supplementation on reversing insulin resistance in non- diabetic subjects with low magnesium status (60). A more recent randomized controlled trial indicated that oral magnesium supplementation may improve insulin sensitivity even in non- diabetic subjects with normal magnesium status, emphasizing the need for an early optimization of magnesium intake to prevent insulin resistance and subsequently type 2 diabetes (61).