Micronutrients and diabetes mellitus

Diabetes mellitus is a chronic disorder of blood sugar metabolism with temporary or permanent increase in blood glucose levels. Diabetics have a significantly increased risk for serious comorbidities and complications and, consequently, mortality. The World Health Organization estimates that the number of deaths due to diabetes will double by 2030. The causes of this are the general population growth and increase in age, an unhealthy diet, obesity and a sedentary lifestyle.

Type 1 diabetes is caused by an insulin deficiency due to destruction of the insulin-producing cells (beta cells) in the pancreas. The cause of this cell destruction is still unclear; a combination of hereditary predisposition, environmental factors (e.g., viral infections) and a malfunction of the immune system is suspected. Only about 10 percent of diabetes cases in the world are due to type 1. These are dependent on a replacement of the missing insulin by injection. With type 1 diabetes, weight loss, nausea, frequent urination, faster and deeper breathing, changes in the acid-base balance of the body, and the development of a diabetic coma with loss of consciousness occur within weeks without prompt treatment. Its highest incidence is in children between the ages of 11 and 13.

Type 2 diabetes results from cells in specific organs becoming less responsive to insulin (insulin resistance). Due to blocked insulin receptors on the cell membranes, glucose cannot or can only partially be taken up by the cells, meaning that an excess of it remains in the blood. Insulin resistance is not always associated with the development of type 2 diabetes. Why the disease ultimately develops and how far a genetic influence is decisive is not yet clear. The onset of type 2 diabetes is mostly gradual and may initially be completely symptom-free. General symptoms such as increased thirst, malaise, increased susceptibility to infection, itching, fatigue and dizziness are often misinterpreted. By this time damage could already have been done to the heart, kidneys, eyes or nerves, for example. In particular, comorbidities and complications affect the well being of patients. Type 2 diabetes, which 90 percent of all diabetics have, usually only becomes apparent for the first time after age 40, but more and more young people are becoming affected. Causal factors include an imbalanced, high-fat diet, obesity and physical inactivity.

Diabetes during pregnancy usually causes no symptoms and can therefore be easily overlooked. Nevertheless, it must be treated it as it could lead to complications with the pregnancy.

According to the World Health Organization (WHO), currently about 220 million people worldwide are affected by diabetes mellitus (1). The costs of the disease put considerable strain on health systems: According to the International Diabetes Federation (IDF), the cost for the treatment of diabetes globally in 2010 was about $376 billion (11.6 percent of total health spending). The IDF predicts that these costs will increase by 2030 to $490 billion (2).

These contribute to the occurrence of strokes, heart attacks and vascular disease. Besides smoking and physical inactivity, diabetes mellitus – particularly in combination with other risk factors (hypertension, disorders of fat metabolism) – contributes to such occurrences. With circulatory disorders of the minor blood vessels (macroangiopathy), a distinction is made – depending on where the disease occurs – between retinopathy (eye) and nephropathy (kidney). Diabetic retinopathy is a chronic ischemia of the retina induced by diabetes mellitus that can reduce vision and sometimes lead to blindness. The nephropathy is a change in the renal vessels caused by diabetes mellitus, leading to a deterioration of renal function.

In addition, diabetes mellitus can cause various nerve disorders (neuropathies). Peripheral neuropathy is a nerve-related disorder of the temperature and pain receptors in the extremities (usually in both feet). Autonomic neuropathy is a failure of the nerves that innervate the internal organs (e.g., gastrointestinal tract, heart, bladder). Diabetic neuropathies affect some 50 percent of patients.

The focus is on maintaining a normal body weight or, for obese people, achieving a weight reduction, increasing physical activity as well as avoiding nicotine and alcohol.

A balanced diet that meets the following requirements is of crucial importance (3):

• low in fat (no more than 10 percent of the total intake)
• rich in complex carbohydrates, which lead to a slow increase in blood sugar levels (e.g., carbohydrates from vegetables and pulses – a total of about 40 to 60 percent of the total supply amount)
• contain an adequate amount of protein (10 to 20 percent of the total amount of energy)
• contain sufficient micronutrients – for example, vitamins C and E and several carotenoids act as antioxidants. They can thus contribute to prevention of typical diabetic consequential damage (circulatory disorders of the coronary arteries, of the legs, eyes, etc.). These nutrients are abundant in fresh fruits and vegetables.

Lifestyle-change programs for type 2 diabetes prevention – including increased exercise and change in
diet – have shown a promising effect on the reduction of the overall incidence of type 2 diabetes and its complications. Also, increased intakes of certain micronutrients have been reported to reduce the risk of developing diabetes (see below). It seems reasonable, therefore, to suggest that the two preventive approaches for type 2 diabetes may be combined into a single successful intervention program.

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 oxidative and 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).

Most patients with diabetes die of complications from blood clots in the vessels altered by atherosclerosis, mostly from heart attacks or strokes. Diabetes mellitus is an independent risk factor for these complications that already exists in a very early stage of the metabolic disorder. Diabetics are prone to blood clots (due to increased reactivity of platelets and reduced dissolution of blood clots) and to an accelerated development of atherosclerosis of the coronary vessels. For the earliest possible prevention of vascular complications, in addition to the measures against hyperglycemia, elevated blood pressure, elevated blood lipids and blood clot formation, an adequate supply of micronutrients is important.

To date, only a few studies have examined the effectiveness of micronutrients in the prevention and treatment of circulatory disorders of the major arteries (macroangiopathy) and small vessels (microangiopathy) in the eyes and kidneys of diabetic patients. In one study it was shown that high blood levels of homocysteine – a risk factor for macroangiopathy and microangiopathy – promotes the stiffening of arteries (a precursor of atherosclerosis) in diabetic patients (62). These high homocysteine levels correlated with low levels of vitamin B12 and folic acid in the blood. High homocysteine levels also appeared to promote damage to peripheral nerves of diabetics, causing diabetic foot, for example (63).

As for the impairment of kidney function in diabetics, it was shown in a study that an increased supply of omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid from the diet in type 1 diabetics could have a positive effect on the severity of renal dysfunction (64). Carotenoids functioning as antioxidants also appear to be beneficial for the renal health of diabetics (65).

Numerous studies have demonstrated the high relevance of antioxidant micronutrients such as vitamins C and E, carotenoids and coenzyme Q10, in the regulation of blood flow, blood pressure and blood clotting in healthy subjects, high-risk groups and cardiovascular patients (see also Topic of the Month, March 2011). The ability to maintain a normal vascular tone through the reduction of vascular oxidative stress could be part of the positive effect of vitamins in the prevention of cardiovascular diseases. In a recent randomized controlled study, it was shown that regular intake of a combination of antioxidant micronutrients could contribute to an increase in the elasticity of major and minor arteries and an improvement in glucose and fat metabolism in patients with multiple cardiovascular risk factors (e.g., hypertension and diabetes) (66).

Similarly, there is evidence that micronutrients may play a role in the prevention of possible complications of diabetes during pregnancy or a pregnancy combined with a pre-existing diabetic condition. The preventive effect of an adequate supply of antioxidants and folic acid are under discussion in relation to fetus malformations (67, 68). Secondly, low blood levels of vitamin B12 during a diabetic pregnancy and the risk of permanent diabetes have been linked (69).

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