Micronutrients and diabetes

Diabetes (diabetes mellitus) is an endocrine disorder characterized by insulin insufficiency (type 1 diabetes) or insulin resistance (type 2 diabetes) and chronically raised blood sugar levels. Vascular diseases (diabetic angiopathies) play a deciding role in the course of the disease. Diabetics are more likely to suffer a heart attack or stroke (macroangiopathy), and almost all sufferers are affected by damage to the small blood vessels (microangiopathy), the eyes (retinopathy), kidneys (nephropathy) or nerves (neuropathy). The metabolic status of diabetes sufferers is characterized by permanent oxidative stress due to impaired carbohydrate and lipidmetabolism. Early and sustained sufficient intake of antioxidant micronutrients that regulate carbohydrate metabolism is therefore particularly important in the prevention of diabetes.

B Vitamins

As coenzymes the B vitamins play a central role in carbohydrate, protein and lipid metabolism. A diabetic metabolic status is characterized by both higher requirements and increased renal elimination of B vitamins, especially when the diabetes is not well managed. Studies indicate that the majority of type 1 and type 2 diabetics have inadequate supplies of vitamin B1 and impaired thiamine metabolism (1). A tissue-specific vitamin B1 deficiency (e.g., in the kidneys) can increase the risk of vascular complications (e.g., nephropathy) (2), and ensuring sufficient provision should be a focus of therapy. Further, vitamin B1 – as well as vitamins B6 and B12 – supports nervous system functions and helps prevent diabetic neuropathies. The fat-soluble precursor of vitamin B1 (benfotiamine) is used, sometimes in combination with alpha-lipoic acid, to treat diabetic neuropathies (3). In this context an improved energy supply for axonal transport and the increased synthesis of transport proteins are under discussion as potential mechanisms involved in the regeneration of nerve cells. Moreover, benfotiamine and vitamin B6 inhibit the increased glycosylation of proteins associated with elevated blood sugar levels. In studies with patients suffering from a diabetes-related impairment of the peripheral nervous system (polyneuropathy), supplementation with benfotiamine significantly improved symptoms of pain sensation, nerve conduction velocity and vibration sensation compared to placebo (4).

A lack of folic acid and/or vitamin B12 leads to impaired metabolism of the amino acid methionine and is frequently accompanied by elevated plasma homocysteine concentrations. Elevated homocysteine levels are regarded as an independent risk factor for stroke, heart attack, dementia and macular degeneration. Compared to non-diabetics, diabetics are three to five times more likely to suffer a stroke. In addition, patients with type 2 diabetes, elevated homocysteine levels and vitamin B12 deficiency are at substantially greater risk of developing diabetic eye damage (retinopathy). This can range from visual impairment to complete blindness (5). A lack of vitamin B12 can also considerably increase the risk of developing diabetic neuropathies. In older people with elevated homocysteine levels the rate of brain atrophy was clearly slowed by regular intake of vitamins B12, B6 and folic acid (6). Regular administration of vitamin B12 is often indicated for diabetes patients being treated with metformin to prevent a medication-induced deficiency. In one study with type 2 diabetics, treatment with metformin led to a dip in cognitive performance which improved again when treatment was accompanied by supplementation with vitamin B12 and calcium (7).

In high (pharmacological) doses, vitamin B3 has a preventive effect on the manifestation or progression of type 1 diabetes where there is still adequate residual function of insulin -producing islet cells (beta cells). The vitamin inhibits the destruction and enhances regeneration of pancreatic beta cells (8). Hence beta-cell dysfunction can be reduced and insulin sensitivity and glucose utilization improved. Moreover, vitamin B3 appears to reduce the glycosylation of proteins and hemoglobin (HbA1C).

Vitamin C and E

Metabolic disorders that occur with diabetes, such as chronically elevated blood sugar levels (hyperglycemia), a disorder of lipid metabolism (raised fatty acid, triglyceride and LDL concentrations) and insulin resistance, cause increased production of reactive oxygen species (ROS), which trigger structural and functional changes to the lining of the blood vessels through activation of intracellular signaling cascades, and hence lead to the development of atherosclerotic lesions. The developing oxidative stress is inevitably linked to reduced availability of vasodilatory nitrogen monoxide and impaired functioning of the lining of the blood vessels, the endothelium. Parallel to these processes in the vessel linings, blood platelets (thrombocytes) are activated inside or on the surface of the vessels. These encourage the formation of blood clots and increase the risk of thrombosis or even a heart attack or stroke. Oxidative stress, as indicated by elevated levels of cell-damaging products of lipid peroxidation, and a raised rate of protein glycosylation play a central role in the onset of diabetic micro- and macropathies (9).

In diabetics, increased oxidative stress can be demonstrated directly after consumption of a meal (10). Concentrations in plasma of the antioxidant vitamins C and E and the intracellular ratio of ascorbic acid to its oxidized form (dehydroascorbic acid) are significantly lower in diabetics than non-diabetics. In comparison with people who have a healthy metabolism, levels of vitamin C in the plasma and cells of diabetics can be over 30% lower in some cases (11). Cellular uptake of vitamin C is enhanced by insulin and impeded by high blood sugar levels. Increasing the concentration of vitamin C leads to a decrease in the proportion of glycosylated hemoglobin (HbA1C) (12). Increasing plasma levels of vitamin C by 20 micromoles per liter (0.35 mg/dL) reduced the risk of hyperglycemia by almost a third. The antioxidant status of a diabetic can be significantly improved by targeted administration of vitamin C, which reduces protein glycosylation by competitively displacing glucose from the amino groups of proteins. In this way the vitamin prevents endothelial damage induced by glycosylated reaction products and improves endothelium function (13). Vitamin C also reduces aldose reductase and hence slows the intracellular accumulation of the sugar alcohol sorbitol, which can exacerbate damage to nerves, eyes and kidneys (14). In a randomized controlled study with type 2 diabetics, adjunctive administration of 2 x 500 mg vitamin C per day for a period of four months led to a significant decrease in insulin resistance, HbA1C values and plasma levels of total cholesterol, LDL cholesterol and triglyceride, compared with placebo (15). Further, supplementary administration of vitamin C appears to enhance the metabolic regulatory activity of the antidiabetic medication metformin (16) and to have a positive effect on complications like depression (17) and periodontitis (18) in diabetics.

As a highly effective antioxidant, vitamin E protects enzymes and hormones, as well as the polyunsaturated fatty acids of biological membranes and LDL, against oxidation by oxygen radicals. During this process vitamin E is oxidized and must be regenerated by vitamin C or flavonoids. In this way the vitamin combats the oxidative degradation of fatty acids (lipid peroxidation) and in particular the oxidative modifications of LDL that contribute to the incidence of atherosclerosis. Moreover, vitamin E lowers thrombocyte aggregation and hence the risk for thromboses, and reduces the extent of protein glycosylation (HbA1C) (19). In addition, by inhibiting enzymes the vitamin slows inflammatory processes and the proliferation of connective tissue in the blood vessels and therefore reduces the threat or advance of diabetic complications (20).

Vitamin D

Recent studies indicate that an inadequate supply of vitamin D could be involved in the onset of numerous chronic diseases like diabetes mellitus types 1 and 2 (21, 22). Study data indicate that a lack of vitamin D represents a risk factor for type 2 diabetes and for metabolic syndrome, since it increases insulin resistance and reduces insulin secretion from pancreatic beta cells (23). Higher blood vitamin D levels could be linked to lower blood sugar readings. In this context a reduction in the pro-inflammatory tumor necrosis factor alpha, a signaling substance (cytokine), in the immune system appears to play an important part. In one randomized controlled study with insulin-resistant women having a mean blood vitamin D concentration lower than 10 ng/mL, daily administration of 4000 IU for six months led to a significant improvement in insulin sensitivity and a reduction in insulin resistance (24). Insulin resistance was optimized with vitamin D values around 32 to 48 ng/mL (80 to 120 nmol/L). It thus appears that patients with a distinct vitamin D deficiency benefit especially from supplementation with vitamin D.

A sufficient intake of vitamin D also seems to have a positive influence on the mortality risk for patients having type 2 diabetes as an element of a metabolic syndrome: In a study of patients with metabolic syndrome, a vitamin D status over 30 nanograms per milliliter was associated with a 75% reduction in total mortality and a 66% reduction in mortality from cardiovascular diseases(e.g., cardiac insufficiency) as compared to patients with severe vitamin D deficiency (under 10 ng/mL) (25). Supplementary intakes of vitamin D seem to lead to an improvement in lipid metabolism in type 2 diabetes sufferers, especially in combination with physical exercise (26).

Experimental research produced evidence that vitamin D can help prevent the destruction of insulin-producing pancreatic beta cells and thus combat the onset of type 1 diabetes (27). It is assumed that this is due primarily to the immunomodulatory action of the vitamin via T-helper cells and to the reduction of pro-inflammatory cytokines.

Omega-3 fatty acids

Apart from hypertension, elevated triglyceride levels (hypertriglyceridemia), which are regarded as an indicator for insulin resistance, are the most important risk factor for myocardial infarction. In some studies elevated blood levels of omega-3 fatty acids were found to be associated with increased sensitivity to insulin (28) and reduced resistance to insulin (29). The long-chain, polyunsaturated omega-3 fatty acids appear to possess lipid-lowering, antithrombotic and endothelium-protective properties (30). Diabetes sufferers could therefore especially benefit from omega-3 fatty acids for the prevention of diabetic micro- and macroangiopathies. Further, a supplementary intake of omega-3 fatty acids appears to improve the composition of essential fatty acids in the cell membrane and myelin sheath of nerve cells and hence combat the onset of diabetic neuropathy (31). A meta-analysis showed that a supplementary intake of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can significantly raise the concentration of adiponectin in the blood (32). Adiponectin is an important hormone that controls metabolic processes such as blood sugar regulation and the containment of inflammatory processes in the body.

Coenzyme Q10

Aerobic energy metabolism depends on an adequate supply of coenzyme Q10. Blood levels of coenzyme Q10 are frequently lower than normal in type 2 diabetics (33). For example, patients with diabetic disease of the myocardium (cardiomyopathy) may have low serum levels. In patients with diabetic retinopathy the ratio of reduced to oxidized coenzyme Q10 is substantially lower – a sign of increased oxidative stress (34). Coenzyme Q10 concentrations in the pancreas fall with increasing age. In studies, targeted administration of coenzyme Q10 to diabetes sufferers have optimized the energy balance of the heart, increased the protection of lipoproteins against oxidation, reduced lipid peroxidation and improved vascular endothelium function (35, 36). Clinical studies also indicated that coenzyme Q10 could lower diastolic and systolic blood pressure in type 2 diabetics (37).

Magnesium

An insufficient concentration of intracellular magnesium is viewed as a major cause of the onset of insulin resistance. Magnesium appears to be able to improve glycemic control via a positive influence on the activity of the insulin receptor and signal conduction (38). In diabetics, magnesium status is often unsatisfactory due to increased renal elimination (39). This in turn leads to poor glucose utilization, increased insulin resistance, higher blood glucose and HbA1C levels and progression of diabetic complications (40). Further, treatment with frequently used antidiabetic medication (e.g., metformin) and diuretics can often lower magnesium concentrations in the blood (41). When magnesium levels are low, a rise in the concentration of C-reactive protein (CRP) – an important risk factor for vascular complications like thrombosis and heart attack – can be observed (42).

One extensive epidemiological study showed that the risk for both diabetes mellitus type 2 and for metabolic syndrome as a diabetes precursor rises as magnesium intake falls. According to a meta-analysis the risk for diabetes was reduced by 15% per 100 mg of additional magnesium intake (43). A more recent meta-analysis reported an approximately 60% lower risk for diabetes in study participants with the highest dietary and supplementary magnesium intakes compared to subjects with the lowest intakes (44). According to one new study, the preventive effect of an adequate magnesium intake for type 2 diabetes appears to vary depending on genetic variations and ethnic origin (45). Magnesium (Mg2+) is taken up via ion channels that are coded by genes for which the different single nucleotide polymorphisms are known. These ion -channel-related gene variants can significantly influence the body’s magnesium status and its glucose metabolism, and are associated with the risk of developing type 2 diabetes. A sufficient intake of magnesium could partially compensate for the magnesium deficiency caused by these genetic mutations.

A poor magnesium status is frequently observed in diabetes sufferers with diabetic retinopathy as well as in patients with diabetic polyneuropathy; in studies, a supplementary intake of magnesium was found to bring about a significant improvement (46). Supplementation with magnesium was also effective in diabetic patients with inadequate magnesium values and newly diagnosed depression: the symptoms of depression improved to the same extent as with antidepressant treatment (47).

Trace elements

Zinc is an important element of insulin structure; it has a stabilizing effect and protects against oxidative damage. Zinc deficiency can lead to decreased synthesis of insulin receptors and to a decline in glucose tolerance and insulin sensitivity (48). Moreover, an insufficient intake of zinc could promote the incidence of atherosclerotic vascular changes and its consequences for diabetics (e.g., coronary heart disease) (49). As a rule, zinc status is poorer in type 1 and type 2 diabetics compared to non-diabetics. Zinc elimination is increased two- to threefold and zinc absorption is diminished (50). Apart from this, medication administered to lower blood pressure (ACE inhibitors) can increase renal zinc loss in diabetics (51). Since a key enzyme of folic acid metabolism is zinc-dependent, zinc deficiency can also worsen folic acid status. A meta-analysis of several studies showed that a supplementary intake of zinc can bring about a significant lowering of fasting glucose values and a slight reduction in the concentrations of glycosylated hemoglobin (HbA1C) (52).

Chromium supports the activity of insulin and sensitizes the pancreatic beta cells, promoting the expression of insulin. Chromium deficiency can lead to reduced glucose tolerance and disordered glucose utilization (53). Studies showed that supplementation with chromium (III) could bring about an improvement in glucose and/or lipid metabolism, in particular in diabetes sufferers with insufficient chromium intake (54). A meta-analysis of numerous clinical studies with type-2 diabetes patients revealed that supplementary administration of chromium (III) improved HbA1C values and fasting blood sugar, as well as lipid metabolic status (55).

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