Integrative Medical Management of Diabetes and Other Chronic Diseases
-On Essential Metals, Toxic Metals and Diabetes
Richard Z. Cheng, M.D., Ph.D.
Type 2 diabetes (T2DM) is a worldwide major epidemic, affecting hundreds of millions of people worldwide. The world’s most populous country, China, has an estimated 110 million diabetic patients in 2017, according to a World Health Organization’s 2016 estimate, or about 10% of China’s population[1]. A 2017 US CDC report estimates the number of diabetes in the United States at ~ 10% of the US population, or ~ 30 million diabetic patients. There are an estimated ~ 84 million pre-diabetic patients, 1 in every 4 persons in US today. Combined, there are currently more than 100 million people in the United States with diabetes or pre-diabetes. By 2050, the total diabetes population will triple, accounting for one-third of the US population. Without intervention, pre-diabetic patients generally develop clinical diabetes within 5 years [2].
Diabetes is a major epidemic, causing huge health and economic burden to all human beings. Comprehensive management of diabetes is urgent. The comprehensive management of diabetes must be a joint effort among the governments, the business sector, the private sector, and the medical and pharmaceutical industry and consumers. Otherwise, diabetes will bring heavy, unsustainable health and financial burden to individuals, families, society, and governments.
Low-carb/ketogenic diet for diabetes management has been received increasing attention worldwide in the past few years among the general public and some healthcare providers. There are more and more clinical studies on low-carb/ketogenic diet demonstrating its effectiveness and utility for the treatment of diabetes, which is the first and foremost step in the treatment of diabetes. The clinical application of low-carb/ketogenic diet for the treatment of diabetes is most definitely a milestone towards the ideal diabetic management, but we shouldn’t stop at low carb/ketogenic diet alone. Those who expect the low-carb/ketogenic diet to be a panacea that can solve all the problems of diabetes may be disappointed down the road.
Like most other chronic diseases, T2DM is also a disease of multiple causes including a variety of exogenous factors (diabetogens), such as excessive sugar in the diet, toxic metals overload, environmental chemical toxins, etc., plus unhealthy lifestyle habits (poor sleep hygiene, stress, lack of exercise, unhealthy diet and poor nutrition). Working together, these extrinsic and intrinsic factors, if without prompt and proper intervention, will lead to a series of metabolic disturbances and wreak havoc to our health.
This is the first of a series of articles attempting to systematically analyze various factors implicated in diabetes including a final Integrative Medical Intervention Proposal for the prevention and treatment of T2DM.
Environmental pollution (metal and chemical pollutants) and T2DM
Proper functioning of human body requires some metals [3]. Some metals (such as magnesium) exist in large amounts and are called macro nutrients [4]. Macro nutrients are nutrients that require at least 100 mg of each in the daily diet [5]. In contrast, some metals such as copper (Cu), zinc (Zn), iron (Fe) and manganese (Mn), chromium (Cr), etc. exist normally in less than 100 parts per million (ppm), so they are properly called trace elements or micro nutrients [6]. Various metals such as magnesium, zinc, chromium, iron, manganese, and copper are considered essential for normal human health [3,7]. Metals are involved in various physiological processes, such as the repair groups of many proteins, water balance, and cofactors of various enzymes, etc. [8]. Several metals are used as metalloproteinases/metalloenzymes as part of proteins/enzymes [9]. Such metal-free repair group proteins cannot perform their physiological functions [10]. Normalizing the content of various metals in the body is a prerequisite for its normal function [11]. Metals contract or relax muscles and transmit impulses through nerves. Most metals exist as soluble salts that regulate the composition of biological fluids. The proper metabolic function of trace elements depends on their normal levels in various body tissues [12]. Drs. Khan and Awan has an excellent review article on this topic [7].
However, the worldwide industrial and agricultural revolutions over the past century and rapid economic development, especially in China over the past three to four decades, have also brought environmental pollution, including various toxic metals and chemicals. These environmental toxins contaminate our food, water, air, and everything we come into contact with in our daily lives. They are an important cause of chronic diseases today. For everyone, especially healthcare professionals, identifying, testing, and taking steps to prevent these toxins from getting into our body, remove them from our body, or to reduce their impact on our health is critical.
Essential metals and their physiological effects
A growing body of evidence exists and shows that these metals are essential for maintaining normal human physiology. These metal imbalances are closely related to diabetes and its complications. If the imbalance of these metals is not corrected, diabetes and other chronic diseases will ensue.
Iron (Fe): Ferritin is the major storage form of iron. Ferritin is often higher in patients with diabetes and other chronic diseases, suggesting excess iron load. Serum ferritin levels may be a surrogate marker to predict the development of diabetes.
Iron is an important metal essential for the synthesis of hemoglobin and myoglobin. Iron, like zinc and vitamin C, is also required for the synthesis of elastin and collagen [13]. In the blood, a small portion of serum iron is transported into cells by glycoproteins (called transferrin) [14]. Ferritin is a way of storing free iron in human tissues. Ferritin levels are often increased in newly diagnosed diabetic patients [15,16]. Compared with non-diabetics, patients with diabetes have higher ferritin levels. Recently, it has been reported that the higher the serum ferritin, the more iron deposition in the tissue, which increases linearly with the duration of diabetes [17]. Elevated serum ferritin is considered an indicator of iron overload and can cause hemochromatosis in severe cases [18]. Multiple studies have shown an association between hemochromatosis and type 2 diabetes [19–21]. High iron levels are a major contributor of intracellular oxidative stress, oxidize various biomolecules, such as nucleic acids, proteins, and lipids, which may promote the development of T2DM by reducing insulin secretion from pancreatic beta cells and increasing insulin resistance [22–26]. Studies have shown a strong relationship between serum ferritin levels and insulin resistance in pre-diabetes [27,28]. In addition to elevated glucose, serum ferritin levels may be a surrogate marker of diabetes to predict the onset of disease [29,30].
Magnesium (Mg): Patients with diabetes, gestational diabetes are usually low in magnesium. Magnesium deficiency plays an important role in the development of insulin resistance and diabetes.
Magnesium is one of the most abundant macro nutrients and is essential for proper health. The activity of more than 300 enzymes requires magnesium, and these enzymes have a variety of important physiological functions in the human body [31,32]. Magnesium-containing enzymes are involved in glucose homeostasis, neurotransmission, and DNA and RNA synthesis [33]. Magnesium plays an important role in regulating insulin secretion from β islet cells and improves insulin binding of insulin receptors [34,35]. Magnesium deficiency has been shown to lead to a decrease in insulin-mediated glucose uptake [31,36]. On the other hand, magnesium supplementation can prevent insulin resistance and reduce the development of diabetes [37]. Some studies report that compared with healthy controls, patients with diabetes have lower levels of magnesium in the serum and increased excretion of magnesium in the urine [36]. Studies have shown that oral magnesium supplements can lower blood sugar, blood pressure, and triglycerides [37]. Magnesium deficiency is a major factor in the development and worsening of diabetes. Low magnesium appears to be one of the direct causes of insulin resistance [38].
A large PREVEND study in the Netherlands this year (2019) studied 5,747 subjects who were initially non-diabetic. After 11 years of follow-up, authors concluded that low plasma magnesium levels were independently associated with a higher risk of diabetes in women [39]. A recent study involving 14,353 participants with a follow-up of over a 29-year showed that extremely low serum magnesium concentrations in American adults were significantly associated with an increased risk of all-cause mortality [40]. Long-term magnesium deficiency significantly promotes insulin resistance, and continuous magnesium supplementation significantly increases serum and intracellular magnesium concentrations. Magnesium supplementation appears to improve insulin-mediated cellular glucose uptake and improve insulin resistance [41–44]. A 10-year study of 13,525 Japanese showed that high magnesium intake reduces the risk of diabetes [45]. After a 28-year comprehensive analysis of more than 200,000 people in 3 cohorts, researchers showed that higher magnesium intake reduces the risk of diabetes, especially when combined with a low-carb diet [46 ].
In patients with diabetes, high magnesium intake and high serum magnesium reduce the risk of coronary heart disease [47]. In animal studies, magnesium seems to not only reduce insulin resistance, but also increase insulin receptors and glucose transporters, which are hallmarks of diabetes [48–50]. In many diabetic patients, there is a vicious cycle of low magnesium leading to insulin resistance and insulin resistance leading to magnesium deficiency [34,51]. A double-blind randomized trial showed that magnesium has been shown to improve the ability of β-cells to secrete insulin as needed in non-diabetic populations [52]. Low magnesium levels can inhibit insulin secretion in non-diabetics [53]. Diabetics with low magnesium levels tend to develop faster and have more complications [54].
Women with gestational diabetes also show low magnesium compared to normal or non-pregnant women [55]. Magnesium and vitamin E supplementation can significantly improve glycemic control and lipid levels in women with gestational diabetes [56].
Manganese (Mn)
Manganese acts as a cofactor in a variety of enzymes, including those related to bone marrow production and the metabolism of carbohydrates, proteins and fats [57]. This is essential for the proper use of choline, thiamine, biotin, vitamin C and vitamin E. Manganese as an enzyme cofactor is also involved in mitochondrial glycoprotein synthesis [58]. When deficient in manganese, the activity of these enzymes is impaired, leading to abnormal cartilage production [59]. Manganese is also a cofactor for pyruvate carboxylase, which plays a role in converting various non-carbohydrates to glucose through gluconeogenesis. In short, manganese is required for normal insulin synthesis, its secretion and manganese imbalance is implicated in the development of diabetes [3]. A study by Forte et al. found a manganese deficiency in patients with type 2 diabetes [60].
Copper (Cu)
Copper is another essential mineral that has multiple biological functions. It is required for the catalytic activity of superoxide dismutase (SOD), and it is involved in protecting cells from superoxide radicals [61]. Copper imbalance is associated with disruption of normal high-density lipoprotein (HDL) and low-density lipoprotein (LDL) balances [62]. Copper also activates the cytochrome oxidase involved in the mitochondrial electron transport chain [63]. In the absence of copper, cytochrome oxidase reduces its activity, which may cause mitochondrial deformation in metabolically active tissues (such as pancreatic acinar cells, liver cells, etc.) [64,65] Existing studies have shown that copper deficiency is one of the causes of the development of cardiovascular disease [66]. Other reports suggest that copper also helps prevent arthritis-related inflammation and epilepsy [67]. Disturbances in copper levels are associated with abnormalities related to the metabolic pathways of diabetes and its complications [3,68]. Copper and zinc metals play a role in protecting human tissues from oxidative damage [69,70].
Zinc (Zn)
Zinc is an essential trace element and is involved in multiple biochemical pathways such as transcription, translation, cell division, and apoptosis [71]. More than 300 enzymes require zinc for their catalytic activity. Removal of zinc from the catalytic site results in the loss of various enzyme activities [72]. About 70% of zinc binds to albumin, and any pathological changes in albumin will affect zinc levels in serum [73]. Zinc malabsorption can cause various types of diseases, including skin, gastrointestinal, neurological, and immune disorders [74].
Chromium (Cr)
The biological activity of chromium depends on its valence and the chemical complexes it forms [12,75]. The trivalent form of chromium has high biological activity and is required for optimal glucose uptake by cells [75,76]. Chromium regulates insulin and blood glucose levels by upregulating glucose transporter (GLUT4) transport in muscle cells to stimulate insulin signaling pathways and metabolism [77]. Chromium deficiency can lead to elevated blood sugar levels and, if persisted for long periods, can lead to the development of diabetes [78]. Some reports suggest that chromium supplements can lower blood sugar levels in patients with diabetes [79]. Prolonged hyperglycemia increases urinary excretion of chromium [3,60].
The relationship between toxic metals and health, chronic diseases, and especially diabetes
When lead, arsenic, zinc, cadmium, mercury and nickel exceed the normal levels, they are powerful oxidants, which can promote the development of chronic diseases including diabetes and even cancer [80].
The toxic metals lead (Pb), nickel (Ni), cadmium (Cd), and arsenic (As) enter the body and deposit in the tissue and are not degradable. As a result, these metals often remain in the tissues for long periods of time, and the problems they cause are often difficult to eliminate. Human tissues can tolerate a certain level of metals. Exceeding this threshold limit can cause tissue damage due to metal toxicity. Some toxic metals, including nickel and arsenic, have been shown to be carcinogens [81–83].
Lead (Pb)
Some toxic metals (including lead) in biological samples (ie, plasma and urine) of diabetic individuals are reported to be higher than non-diabetic individuals [84]. Lead is harmful to most organs of the human body and interferes with metabolism and cellular function [85]. Studies have shown a linear relationship between blood lead levels and renal insufficiency in age-related diseases. This may be due to frequent exposure to environmental lead [86]. Studies have shown that exposure to lead can severely affect the antioxidant pathway [83]. Existing evidence suggests that metal-induced toxicity may cause disturbances in the antioxidant mechanisms in living tissues. As a result, reactive oxygen species (ROS) are produced. This imbalance of antioxidants can lead to peroxidative degradation of proteins, nucleic acids and lipids. The oxidative attack of ROS on cellular components has been implicated in the pathogenesis of several human diseases, including diabetes [87,88]. In fact, most, if not all, chronic diseases are associated with elevated oxidative stress.
Cadmium (Cd)
Cadmium is a heavy metal that is widely found in air, water, and soil. The increase in cadmium in water is absorbed by plants, animals and humans [84]. Regular exposure to cadmium can lead to its excessive accumulation in the kidneys, leading to kidney damage and kidney diseases [87]. In addition, high levels of cadmium can reduce calcium absorption, and severely cause bone and kidney damage, known as “Itai-Itai Disease” (Itai is Japanese for Painful) , caused by widespread cadmium poisoning was first discovered in Japan [89]. It has also been reported that cadmium may down-regulate glucose transporter 4 (GLUT4) transport through insulin and enhance the induction of pancreatic β-cell destruction in diabetes [80].
Arsenic (As)
Arsenic is a naturally occurring lethal metalloid, mainly used in copper alloys and lead batteries. It is also commonly found in the production of pesticides, herbicides and pesticides. Arsenic is a Group I carcinogen by WHO [80,90–92]. The underground water pollution of arsenic is seriously threatening human beings worldwide [81,84,93]. Arsenic is widely recognized as a carcinogen and a strong oxidant that can damage neurons, liver, cardiovascular, subcutaneous and renal organ systems. Chronic arsenic overdose is the most common epidemic in the world, as is diabetes [94].
Regular exposure to arsenic has been linked to a variety of diseases, including certain types of cancer and diabetes. Studies have shown that glucose metabolism is disrupted due to changes in cell signal transduction, and subsequent translocation of GLUT4 to the membrane may be arrested. Some studies have shown that arsenic is associated with β-cell dysfunction [14,75].
Arsenic is mainly found in underground mineral compounds. It is especially common in the Himalayas. In Bangladesh, with a population of 167 million, more than 100 million people suffer from acute arsenic poisoning, accounting for 2 of every 3 people in this Southeast Asian country! As a result of mining and coal burning, arsenic is released into the atmosphere and surface water on which we live, polluting our living environment. Arsenic, lead, mercury and cadmium accumulate in rice. But arsenic is particularly problematic in rice because arsenic is present in water and soil all over the world, and rice grows in water for a long time. Rice contains vitamins, minerals, and carbohydrates, but rice also has something nasty: pollution of metals, especially inorganic arsenic (arsenic). Rice is a major source of inorganic arsenic contamination in the human diet [93]. Rice absorbs 10-20 times more arsenic than other crops. The arsenic content is highest in rice husks, so brown rice has a higher arsenic content [93]. In the past few decades, China’s rapid economic development has also paid a huge price: environmental pollution, especially cadmium, arsenic, lead, and antimony [95].
65% of Chinese people eat rice as their staple food. Of the causes of arsenic excess in Chinese, 60% are thought to be related to arsenic contamination in rice [93]. Half of the world’s population eats rice every day.
About 4% of the 300 million people in the United States have arsenic in public drinking water that exceeds the US Environmental Protection Agency’s (EPA) standard (10ug/L) [96]. The actual number may be well over 4%, as there are many (close to half) water sources in the United States that have not been tested. Globally, it is estimated that superficial groundwater affecting 400 million people has high levels of inorganic arsenic [94]. Seafood, rice, mushrooms, and poultry are the main sources of arsenic in food.
Nickel (Ni)
Nickel is a ferromagnetic element and is mainly used in Ni-Cd batteries. Most people are exposed to nickel in different ways, such as drinking water, air, and eating foods contaminated with nickel [97]. The kidney has been observed to be the main organ of nickel accumulation and therefore the cause of renal insufficiency [98]. Forte et al. found that the nickel content in the blood of patients with type 2 diabetes was significantly higher than that in the normal control group [60].
In short, the researchers analyzed various biological fluids such as serum/plasma, hair, urine, etc. in order to understand changes in metal metabolism in various diseases including diabetes. Among these biological samples, urine is unique because it is easily accessible and non-invasively sampled. In some previously published studies, researchers have shown that the amount of metal in urine corresponds to the amount of metal in their serum [1,14]. Previous studies have shown a link between toxic metals and essential trace metals [78].