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Sonia Guida, MSc.*
A Niedzwiecki, Ph.D.**

*Dr. Rath Education Services, Heerlen, NL
** Dr. Rath Research Institute, Santa Clara, CA, USA

Correspondence to
Dr. Aleksandra Niedzwiecki,
Dr. Rath Research Institute,
1260 Memorex Drive,
Santa Clara, CA 95050, USA.
Email: author@jcmnh.org

The steady increase in diabetes among children and young adults is one of the emerging health problems worldwide.

This disease, characterized by impaired glucose metabolism and abnormally high blood glucose levels, has serious negative health consequences in young organisms, many of which surface later in life.
In addition, pharmacological treatments primarily developed and tested in adult diabetics carry health risks and are associated with unanticipated side effects when administered to children.
All these concerns generate interest in developing micronutrient based approaches as safe and effective alternatives to medical drugs in both prevention and management of diabetes, especially in children.

This review outlines the scope of this health problem, highlights current therapeutic approaches to pediatric diabetes, and presents the latest findings on preventive and therapeutic potential of micronutrients and other natural compounds in controlling diabetes in children.

Introduction

Diabetes is a metabolic disorder characterized by high blood glucose levels resulting from either insufficient insulin production in the pancreas, inadequate response of the body’s cells to insulin, or both. More than 200 million people suffer from diabetes worldwide, and, according to the World Health Organization (WHO), it will become the seventh leading cause of death by 20301. Especially alarming is the growing number of children and adolescents diagnosed with this condition, which has skyrocketed within the last 20 years, prompting the journal Diabetes Care to call it an “emerging epidemic”.

Manifestation of diabetes in children

Type 1 diabetes

Type 1 diabetes (known as insulin-dependent, juvenile or childhood-onset diabetes) is characterized by deficient insulin production in the pancreas,which requires daily administration of insulin. Symptoms include frequent urination, thirst, persistent hunger, weight loss, vision changes and fatigue, all of which may occur suddenly2. Until not long ago, most children diagnosed with diabetes suffered from the type 1 form of the disease. Its incidence and prevalence had varied depending on the geographical region (Figure 1) and it was speculated that environmental factors could contribute to these differences3.

According to these data, type 1 diabetes is widespread among children in Finland and Sardinia and rather uncommon in China, India and Venezuela. Wide variations in disease occurrence have also been noted between neighboring areas in Europe and in North America. Finland, Germany and Norway have reported annual increases of type 1 diabetes in children. Barat reports that in France currently more than one quarter of children diagnosed with type 1 diabetes are under the age of 54.

Continuing increase in type 1 diabetes incidence was also registered in the UK, where the  disease was shown to be more frequent in children than in young adults5.

In Europe, in general, the substantial increase in type 1 diabetes has been noted in  children younger than 5 years of age3.

Forecasts indicate that a doubling of new cases of type 1 diabetes in European children  younger than 5 years is predicted between 2005 and 2020, and that the incidence in  children younger than 15 years will rise by 70%6.

Figure 1. Incidence of type 1 diabetes in children aged 0-14 years, by geographical region and over time3.

Type 2 diabetes

Type 2 diabetes (also called non-insulin-dependent or adult-onset diabetes) results from the body’s ineffective response to insulin or its insufficient production. About 90% of people diagnosed with diabetes suffer from type 22. Although symptoms may be  similar to type 1 diabetes, they are often less pronounced. As a result, the disease may be diagnosed  several years after onset, once its complications have already arisen.

Until recently, this type of diabetes was seen mainly in adults, but now it is increasingly diagnosed in children2. Experts estimate that type 2 diabetes in youth has grown from less than 5 percent in 1994 to about 20 percent of all newly diagnosed cases in recent years. Currently, about 45% of diabetes cases in adolescents are attributed to type 2 diabetes7,8.

Causes of diabetes in children

Type 1 diabetes

The exact causes of type 1 diabetes are largely unknown. Since type 1 diabetes is often inherited, it was speculated that genetics may play a pivotal role in its development. In most cases it is a result of an autoimmune condition in which the immune system damages the pancreatic cells which consequently cease producing a hormone, insulin. Other anticipated causes include:

Childhood vaccinations. The U.S. Centers for Disease Control (CDC) supports scientific studies by Classen, whose research concludes that vaccines can trigger type 1 diabetes. The evaluation of type 1 diabetes cases in relation to immunizations indicate an increase in the incidence of type 1 diabetes 2-4 years following the introduction of the MMR (measles, mumps, and rubella) and pertussis vaccines. Inversely, a decrease in type 1 diabetes was observed 3-4 years after the discontinuation of pertussis and BCG (Bacillus Calmette–Guérin) vaccines9. Classen and colleagues also evaluated whether Hemophilus influenza B (HiB) vaccine can be associated with an increased risk of type 1 diabetes. About 116,000 children born in Finland (October 1st, 1985 – August 31st, 1987) were randomized to receive 4 divided doses of the HiB vaccine (PPR-D, Connaught) starting at 3 months of life, or one dose starting after 24 months of life. A control-cohort included 128,500 children born in Finland in the 24 months prior to the HiB vaccine study. The results showed that exposure to HiB immunization was associated with an increased risk of type 1 diabetes10.

Low levels of vitamin D. The association between vitamin D deficiency and type 1 diabetes was studied in 185 children (9.8 years old on average) diagnosed with this disease. The subjects included 51% Caucasian, 25% Hispanic, 4% mixed-Hispanic, 4% African American, and 16% other/mixed race. The majority of these young diabetic patients had low vitamin D levels (40% showing vitamin D insufficiency, and 18% were vitamin D deficient). The study concluded that vitamin D deficiency is common at onset of pediatric type 1 diabetes11. These findings corroborated with a metaanalysis study by Liu and colleagues, which concluded that serum vitamin D was significantly lower in children with type 1 diabetes than in healthy controls12.

Type 2 diabetes

Development of type 2 diabetes has been largely associated with a global rise of childhood obesity. Numerous data show that healthy eating and lifestyle habits are a strong defense against this disease13.

Overweight. The increase in type 2 diabetes among children and adolescents has emerged in parallel with an alarming rise in overweight and obesity among youth (Figure 2). Increase in visceral fat has been implicated in developing the insulin resistance which often precedes type 2 diabetes14. A prospective cohort study conducted between 1965 and 2007 in 5,532 American Indian children showed that diabetes incidence was higher in overweight than in normal weight children15. These results, which corroborate data obtained in other populations and countries (WHO European Region), highlight the strong involvement of body weight and dietary habits in the development of diabetes in children.

Diet and food industry. The food industry has an important role in influencing children’s diets and their dietary choices. Due to food processing methods and modern agriculture our diet has become calorie rich and micronutrient poor. In addition, most processed foods advertised are targeted at and consumed by the young population and contain large amounts of sugar (i.e. soft drinks, cereals, snacks and ready-toeat meals), increasing the risk of diabetes.

Figure 2. Overweight prevalence among U.S. children and adolescents14.

Boulton and colleagues investigated the amount of sugars in juice drinks and smoothies marketed to children sold by seven major UK supermarkets. The results showed that the sugar content in these products is unacceptably high and the study concluded that manufacturers must stop adding unnecessary sugars and calories16 as a necessary measure to reduce the prevalence of overweight, obesity and type 2 diabetes17. Especially of concern is an increasing consumption of High Fructose Corn Syrup (HFCS), which, as an inexpensive ingredient, has become the most commonly used sweetener in processed foods. Its introduction parallels a rise in obesity, diabetes, hypertension and kidney disease18,19, as the liver converts fructose into fat. It has been shown that as little as four weeks of a moderate fructose diet can increase blood cholesterol and glucose levels. Human and animal studies have shown that fructose can induce metabolic syndrome including insulin resistance, coronary microvascular disease, and oxidative stress. Interestingly these effects have not been seen in animals fed glucose or starch, which suggests that these mechanisms are not mediated by excessive caloric intake, but rather relate to fructose processing in the body20.

Physical activity. The WHO defines “physical activity” as any bodily movement involving skeletal muscles that requires energy expenditure. This differs from “exercise”, which is a physical activity that is planned and structured. Insufficient physical activity is considered one of the 10 leading risk factors for death worldwide and a key risk factor for diabetes. According to the WHO, over 80% of the world’s adolescent population has insufficient physical activity21,22.

Insufficient physical activity has also been linked to a higher risk of diabetes in children. A retrospective population-based survey in 2,720 adults (1,096 male and 1,624 female) showed that early sport practice during childhood and adolescence was associated with lower occurrence of type 2 diabetes and arterial hypertension later in adulthood23. These data are supported by a prospective longitudinal study in 8 year old children (199 subjects) and in 12 year olds (107 children). The evaluation of anthropometric data, blood tests and physical activity in this population showed that physical activity improves insulin sensitivity and over time affects the levels of C-peptide (indicator of insulin production in the pancreas)24.

Health consequences of type 1 and type 2 diabetes in children

Children develop type 2 diabetes at a later age compared to those with type 1 diabetes. Both types of diabetes can be initially asymptomatic and early diagnosis of this disease is critical for minimizing its negative health effects later in life.

Hyperglycemia. Hyperglycemia is characterized by a high level of glucose in the blood, which causes biological damage by attaching to other molecules, often proteins such as the ones that build our blood vessels or transport oxygen (hemoglobin). This glucose-triggered damage contributes to cellular dysfunction and various other complications of diabetes25.

Cardiovascular disease. Although diabetic children and adolescents with type 1 and type 2 diabetes can be asymptomatic for cardiovascular disease, the long term effects of high blood glucose levels result in detrimental health effects when they become adults. Circulatory problems and impaired blood flow can lead to blindness from clots formed in the arteries of the eyes, cause kidney failure, gangrene, heart attacks from blockages developing in the coronary arteries, and strokes from obstructing blood flow to the brain. Aglycoprotein involved in bone metabolism, Osteoprotegerin (OPG), has emerged as an independent biomarker of cardiovascular disease and is implicated in diabetes and poor glycemic control. A study in 56 children (12.1 ± 3.4 years old) with type 1 diabetes, and in 46 healthy children (11.3 ± 3.0 years old), showed that serum OPG levels were significantly elevated in children with type 1 diabetes compared to healthy controls26. In a Japanese study, approximately 10% of subjects who developed type 2 diabetes before the age of 30 had atherosclerotic vascular disease, poor glycemic control and microvascular complications, especially microalbuminuria, nephropathy, and end-stage renal disease. It has been shown that individuals with early onset type 2 diabetes have an increased tendency to develop microalbuminuria and hypertension, the known risk factors for cardiovascular disease27. In addition, abnormal lipoprotein plasma levels have been observed in children and adolescents with type 1 and 2 diabetes28,29 as well as a risk of chronic inflammation30.

Celiac disease. Most patients with type 1 diabetes have asymptomatic celiac disease or display symptoms that may be confused for diabetes. Studies in Western Europe, North America, and Australia indicate that the prevalence of celiac disease among children and adults with type 1 diabetes greatly exceeds this condition found in the general population. For these reasons all children with type 1 diabetes should be evaluated for celiac disease31.

Chronic autoimmune thyroiditis. This condition is characterized by thyroid dysfunction and the presence of thyroid specific autoantibodies in blood serum. The autoimmune thyroiditis appears to be significantly frequent among young patients with type 1 diabetes. Since 1990, Kourdonouri and collaborators have been conducting annual screenings for thyroid disease in 659 children and adolescents (54.3% were boys) with type 1 diabetes. This included testing for antibodies against thyroperoxidase (anti-TPO), thyroglobulin (anti-TG) and TSH (thyroid stimulating hormone). The study showed that all patients with significantly higher values for anti-TPO and anti-TG at the onset of type 1 diabetes remained positive during the following five years. The authors concluded that anti-TPO and TSH should be evaluated in children with type 1 diabetes at onset of this disease and that children older than 12 should be screened yearly32. These data have been confirmed by a recent study in Taiwanese children and adolescents with type 1 diabetes, which showed that autoimmune thyroid disorders were quite common among diabetics33.

Cognitive and behavioral impairment. Children and adolescents with type 1 diabetes34 (Figure 3) and type 2 diabetes often display behavioral disorders and cognitive impairment. Jabbourand colleagues investigated barriers to active lifestyles in children with type 1 diabetes. They showed that among others a loss of control of diabetes, fear of hypoglycemia, work schedule, and low fitness levels were the most important barriers that affected children’s psychological balance35. A group of researchers at the Cincinnati Children’s Hospital Medical Center assessed cognitive and behavioral performance in obese adolescents with type 2 diabetes and found they performed worse than controls36.

Diabetic nephropathy. Diabetic nephropathy is defined as an abnormal urinary albumin excretion (macroalbuminuria). Suh and colleagues found that early stages of nephropathy in pediatric patients with type 1 diabetes can be detected by urinary tubular damage and inflammatory markers37. A study in 56 patients with type 1 diabetes (mean age 13.1) and 49 healthy controls (mean age 12.8) evaluated serum NGAL (Neutrophil Gelatinase-Associated Lipocalin) and cystatin C (nephelometry), in addition to standard blood chemistry and urinary albumin excretion, at enrollment and after 12-15 months. The researchers suggested that NGAL and cystatin C, which are the markers of renal injury, may be used as supplementary tests to the urine albumin excretion for early detection of renal dysfunction in children38. Between 2002 and 2013, the annual prevalence of diabetic nephropathy in pediatric patients with diabetes increased from 1.16 to 3.44% for all cases and was highest in patients aged 12 to 18 years of age39,40.

Figure 3. Short and long term behavioral and cognitive reported alterations following type 1 diabetes mellitus onset in children and adolescents according to type 1 diabetes mellitus duration34.

Diabetic neuropathy. Nerve damage represents the major complication in type 1 diabetes classified as polyneuropathy, focal neuropathy and autonomic neuropathy. The latter seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as unawareness of hypoglycemia and cardiovascular dysfunction41.

Diabetic retinopathy. Diabetic retinopathy is caused by damage to the blood vessels of the tissue at the back of the eye (retina), which at its early stages does not cause symptoms. A retrospective study of 143 children aged 12 or younger concluded that retinopathy screening should start at this young age42.

Juvenile arthritis. Juvenile arthritis is caused by inflammation of the joints. It has been shown that juvenile arthritis and diabetes end-points were considerably larger in pediatric patients with type 1 diabetes than in the general population43.

Pediatric osteoporosis. Pediatric osteoporosis is characterized by low bone mass density (BMD). While in adults low BMD is generally due to net bone loss after its peak accrual, in children it can result from loss of bone or, more commonly, impaired bone mineralization. Endocrine disorders, such as diabetes can lead to pediatric osteoporosis44.

Periodontal disease. Periodontal diseases are bacterial infections of the tissues surrounding and supporting the teeth. Gingivitis, an inflammation of the soft tissues only, can progress to periodontitis, where destruction of the connective tissue attachment and alveolar bone can eventually lead to tooth loss. Periodontal destruction in diabetes can start early in life and become more prominent as children become adolescents45. Xavier et al. evaluated 168 children (13 +/- 3.5 years old) with type 1 diabetes for plaque index (PI), sites with bleeding on probing (BOP), probing depth (PD) and clinical attachment level (CAL) in all occlusion of permanent teeth. Gingivitis was diagnosed in 20.8% children and 5.9% children had periodontitis. The authors concluded that periodontal problems in this young population were significantly associated with the duration of type 1 diabetes and poor glycemic control46.

Skin problems. Diabetes can affect every part of the body, including the skin. In fact, skin problems are sometimes the first sign of diabetes. Some of them, such as bacterial infections, fungal infections, and itching can affect anyone, but people with diabetes are more prone to them. Skin problems that develop mostly or exclusively in people with diabetes include diabetic dermopathy, necrobiosis lipoidicadiabeticorum, diabetic blisters, and eruptive xanthomatosis47.

Digestive tract infections: Studies have shown frequent yeast-like fungi infections (e.g. Candida albicans) in the digestive tract of children with type 1 diabetes48, which is resistant to conventional antifungal treatment49 (Figure 4).

Diagnosis and conventional treatments of diabetes in children

Children are diagnosed with diabetes when blood plasma glucose values at fasting are at or above 126 mg/dl. Another blood test (called HbA1) measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. This test reflects an average blood sugar level for the past two to three months. An A1C level of 6.5 percent or higher on two separate tests indicates diabetes. In order to distinguish type 1 and type 2 diabetes, a child can also get a C-peptide test or autoantibodies test, which detects the presence of specific antibodies (ZnT8Ab), characteristic for only type 1 diabetes.

Conventional treatments

Insulin and metformin
The U.S. Food and Drug Administration (FDA)50 has only approved the use of metformin and insulin in children (FDA). Insulin is administered in children with type 1 diabetes, while insulin together with metformin can be prescribed to children with type 1 and type 2 diabetes.

Figure 4. Comparison of Candida albicans strains susceptible, intermediate, and resistant to the six tested antifungal drugs in children with type 1 diabetes mellitus (A) and healthy control subjects (B)49.

Insulin. The first option in the treatment of type 1 diabetes is a hormone, insulin, which regulates serum glucose by increasing its uptake into muscle and adipose tissue and decreases glucose production in the liver. The following insulin products are indicated for the use in children: Aspart, Glulisine, Lispro, Detemir, and Glargine51.

The administration of insulin is not risk-free as it is associated with a risk of hypoglycemia, peripheral hyperinsulinemia, headache, and weight gain. A recent Italian study which investigated the effects of Detemir in 15 pre-pubertal children with type 1 diabetes showed that this treatment was associated with an abnormal body weight not related to pubertal growth52.

The delivery of insulin not by injection, but by a pump, is often encouraged in children and adolescents. Pumps deliver insulin 24 hours a day through a catheter placed under the skin.This is more convenient for a patient and allows for better control of blood sugar. However, there were reports of pump-related adverse events in children 1–12 years old. From January 1, 1996, through December 31, 2009, a total of 21,769 reports were collected for all ages. Of these, 1,774 were for children aged 1–12 years and more than half resulted in serious outcomes (Table 1). Children were hospitalized for hyperglycemia or hypoglycemia and deaths of five patients were reported53.

Table 1. Summary of FDA insulin pump adverse event reports for ages 1-12 years, January 1, 1996, through December 31, 200953.

Metformin. Metformin, a drug classified as a biguanide, is the first option in the treatment of type 2 diabetes in pediatrics. It works by reducing glucose production and activating glucose uptake in peripheral tissues. The administration of metformin can cause various side effects, such as decreased appetite, diarrhea, muscle pain, and gastrointestinal problems54.

Metformin together with insulin has also been used in the treatment of type 1 diabetes. In a study in 140 overweight adolescents with type 1 diabetes the use of metformin as an adjunct to insulin did not improve glycemic control and led to an increased risk of gastrointestinal adverse events55. Another study investigated the prevalence of chronic diarrhea in 861 patients with type 1 and type 2 diabetes taking metformin. The authors concluded that chronic diarrhea is often associated with diabetes and the most common cause of non-diabetic diarrhea is metformin56.

Other conventional therapies
Although the FDA has only approved metformin and insulin in diabetic children and adolescents, some physicians recommend the use of drugs which have been approved for adults57. These often lack clinical evidence of their efficacy in a pediatric population, which makes young patients prone to unexpected health risks51. A short review of these treatment options is presented below:

Thiazolidinediones(TZDs). This class of drugs, which has not been approved in children, works by increasing insulin sensitivity in the cells. Wen and colleagues examined the potentially inappropriate prescription of TZDs in different groups of patients, including young people under 18 years of age. Data collected from Taiwan’s National Health Insurance data set from 2001 to 2006 showed that inappropriate prescription of TZDs actually increased from 9.41% in 2001 to 12.50% in 200658. The use of TZDs decreased after a black-box warning was issued in 2007 for a drug, rosiglitazone, highlighting its cardiovascular risks59.

Recently, the short-term use of rosiglitazone was evaluated in a pilot study in 21 obese adolescents (13 to 18 years old) with impaired glucose tolerance. The study found that 58% of patients treated with rosiglitazone returned to normal glucose tolerance, compared to 44% of patients taking placebo. Although few adverse events surfaced during this treatment, the authors concluded that, given the cardiovascular concerns with rosiglitazone in adults and the small pool of data on its use in children, it would be premature to recommend rosiglitazone in children60.

Sulfonylureas. Sulfonylureas promote insulin secretion by acting on pancreatic β cells60. They are not labeled for pediatric use and data on their use in children are limited.

The University Group Diabetes Program clinical trial has reported an association between the administration of the sulfonylurea drug, tolbutamide, and increased cardiovascular mortality. This provided the basis for the FDA warning about “increased risk of cardiovascular mortality” for this and other oral sulfonylurea hypoglycemic drugs61.

Amylin analog (Pramlintide). It is a synthetic analog of human amylin, a hormone that acts together with insulin to delay gastric emptying and inhibit release of glucagon, a hormone that raises the level of glucose in the blood. According to the FDA this drug has not been sufficiently studied in children but some doctors apply it off-label. Clinical evidence on the use of pramlintide in children is limited to type 1 diabetes and to small studies enrolling only 8 to 13 patients. In one of the studies, 10 adolescents 13 to 17 years of age were randomized to active treatment with 15 mcg of pramlintide before meals (titrated to 30 mcg if tolerated) or to control for 28 days. This preliminary study led to improvements in HbA1c, body weight, and insulin dose in adolescents with type 1 diabetes. However, the package insert for this drug contains a black box warning regarding risk of severe hypoglycemia in type 1 diabetes. The most common adverse events include hypoglycemia, nausea, headache, anorexia, and abdominal pain60.

Other drugs, such as Incretin based therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists as well as Meglitinides and Alpha glucosidase inhibitors were not approved for use in children60.

Differences in metabolizing drugs in children and adults

Limited data are available on age-related drug metabolism and behavior, especially in the pediatric population which encompasses wide age ranges, from the neonates (up to 1 month) to adolescents (12-16 years). Most diabetic drugs prescribed for children have been tested only in adults and their dosage is adjusted to the child´s body weight. This, however, does not reflect profound changes in body’s composition, physiology and biochemistry occurring in a growing organism, all of which have a profound impact on drug absorption, bioavailability and metabolism as well as their physiological effects. Therefore, use of these drugs in pediatrics carry unexpected health risks, some of which may surface later in life. There are several factors that affect absorption and metabolism of pharmaceutical drugs in children.

Hepatic function. The liver plays an important role in drug metabolism and its function changes at different stages of human development. As such, there are differences in metabolizing drugs in children, adults, and the elderly. Most oral drugs, which are chemical substances not known to the body, undergo a specific metabolic detoxification route in the liver. After they are absorbed in the gastrointestinal tract they do not immediately reach systemic circulation, but enter the liver for so called first-pass metabolism. There, they are processed and modified in a chain of metabolic reactions rendering drugs less toxic so they can enter the blood circulation to be distributed and delivered to the target tissue. Infants have impaired first-pass metabolism of drugs62, which makes drugs more bioavailable and not properly processed, resulting in an increased risk of drug-induced side effects.

An important enzyme system involved in drug metabolism and detoxification involves cytochromes P-450 (CYP450). This metabolic activity varies with age as supported by Hines´ investigation on ontogeny of human hepatic cytochromes P450. He measured six key cytochromes P450 in 240 human liver samples, representing ages from 8 weeks gestation to 18 years. The results showed a wide range of age-related variations in enzyme activities for each cytochrome group, which indicates different ability of our body from infancy through adolescence in processing drugs and other toxins63.

Pancreatic function. The pancreas is composed of two functional components: the “exocrine pancreas” which is built by the cells that produce enzymes, and the “endocrine pancreas” where the islets of Langerhans produce the hormones insulin and glucagon involved in glucose homeostasis. Unlike the liver, the “exocrine pancreas” has been considered to make insignificant contribution to drug metabolism and detoxification, therefore, it is seldom identified as a target organ of xenobiotic toxicity64. For these reasons little information is available for the enzymatic pattern of the pancreas65. However, it is known that infants have decreased pancreatic exocrine function, which matures by the first year62. Such physiological evolution makes infants more susceptible to druginduced side effects and pancreas impairment. When the exocrine pancreas becomes a target organ of xenobiotic toxicity, serious clinical implications can affect pancreatic cells64.

Gastric function. Gastric pH and its emptying time vary with age. Premature infants have impaired gastric acid production until after 32 weeks of gestational age. This allows orally administered acid-labile drugs that may not be absorbed intact in the mature individual to have greater bioavailability in premature and very young infants62.

Gut function. As with the skin area, the absorptive surface area of the gut is relatively greater in the infant than in the adult. The immature gut also exhibits permeability to large molecular species, including intact proteins that are not absorbed by the mature gut. Gastric emptying and gut transit time may be prolonged in premature and ill newborns. On the other hand, healthy infants may have transit times shorter than those for adults62.

Micronutrients and diabetes

Micronutrients, which include vitamins, minerals and other natural compounds, play an essential role in human nutrition in supporting optimum growth and development and sustaining life. Although they are required in much smaller amounts than proteins, carbohydrates and fats, they enable our body to convert food to bioenergy, facilitate synthesis of enzymes and hormones, build cellular compounds, and sustain all physiological functions. Micronutrient deficiencies, especially long-term, are associated with severe health consequences and even death66.

Micronutrients, essential for healthy cellular metabolism, including proper processing of drugs and toxins, are safe at a wide dosage ranges. Although a “healthy” diet can theoretically provide adequate amounts of nutrients, in reality many people fail to meet the required levels. The risk of developing micronutrient deficiencies is higher in pathological conditions, such as diabetes, due to high demands for micronutrients in response to the body’s metabolic changes as well as to anti-diabetic drug therapies. The role and effectiveness of micronutrients in various aspects of diabetes have been evaluated in numerous in vitro and in vivo studies. In addition, some natural compounds were subjected to clinical trials. Unfortunately, there are not many clinical and scientific studies evaluating the role of micronutrients in prevention and management of diabetes in children, although several of these natural compounds have been used in managing diabetes in the young.

The requirements for micronutrients vary depending on our age, but also genetics, lifestyle, dietary patterns, various pathologies, and environmental factors. Current official guidelines, such as the Recommended Dietary Allowance (RDA), provide information on quantities of individual nutrients required to maintain health in already healthy individuals. The Adequate Intake (AI) is used when scientific evidence is insufficient to develop an RDA. The Tolerable Upper Intake Level (UL) has been developed to indicate the level of nutrient intake which should pose no adverse health effects in almost all individuals in the general population (National Institutes of Health, NIH). However, these guidelines refer to intake of nutrients as individual compounds and for many people the recommended doses are not adequate to maintain optimum health. Unfortunately, the mutual interactions of micronutrients, their absorption and bioavailability when taken as complexes have not been well investigated. Most vitamins and other micronutrients are taken in forms of random mixtures and with different diets, therefore their final metabolic effects are largely a matter of chance and can’t be effectively controlled. The need to address these and other important aspects in micronutrient supplementation has been advocated by the Dr. Rath Research Institute, whose scientific research has contributed to a better understanding of nutrient interactions and synergy in various aspects of health67.

Metabolic effects of select vitamins in diabetes

Vitamins are natural organic compounds that are not produced by the organism, with a few exceptions, such as vitamins D and K. Vitamin D is produced by the body through the action of the sun, and vitamin K is made in small amounts by gut bacteria. Thus, vitamins must be necessarily obtained in the diet. They have diverse chemical structures and cellular functions and are categorized as water-soluble and fat-soluble vitamins.

Vitamin A
Vitamin A includes fat-soluble retinoids such as retinol, retinal, and retinyl esters. It is found in fruits and vegetables in the form of precursors, known as carotenoids, which are converted in the body into vitamin A according to its needs. Vitamin A is important in supporting immune function, vision process, reproduction, and takes part in cellular communication. Vitamin A-rich sources include liver and fish oils, also milk and eggs. Carotenoids are abundant in leafy green, orange and yellow vegetables, tomato products, fruits and some vegetable oils68.

Based on the fact that diabetes is associated with a compromised antioxidant status in the body, supplementation with antioxidants, such as vitamin A, should play an important role in diabetes. However, most research supporting vitamin A benefits in diabetes derives from in vitro or animal studies, with almost no clinical studies conducted in diabetic patients.

The study using type 2 diabetic BALB/c mice demonstrated a considerable improvement in total antioxidant potential, glycemic control, and a therapeutic effect against pancreatic beta cell degeneration with vitamin A supplementation69. It has also been demonstrated that vitamin A can regulate insulin release70 and is essential for the maintenance of pancreatic β-cell functions71. Dietary vitamin A deprivation itself can induce hyperglycemia and lower insulin secretion in mice, while its supplementation restores glycemic control, normal islet size distribution, and endocrine profiles, among others. The authors of this study suggested that vitamin A is important in people with diabetes71.

Vitamin B12
Vitamin B12 (cobalamin) is a water-soluble vitamin that plays a fundamental role in DNA synthesis, proper red blood cell formation, and neurological functions. It is naturally found in animal products, including fish, meat, poultry, eggs, and milk72.

Several cross-sectional studies and many case reports have documented a widespread deficiency of vitamin B12 in type 2 diabetes patients. In addition, patients with type 1 diabetes-associated pernicious anemia are also frequently deficient in this vitamin73.

A recent study in obese adolescents with pre-diabetes and/or clinical features of insulin resistance showed low or borderline vitamin B12 status74. In addition, treatment with metformin and concomitant use of proton pump inhibitors/histamine H2-antagonists have been associated with higher risk of developing B12 deficiency in patients with type 2 diabetes75.

An earlier investigation determining serum vitamin B12 levels in patients with type 2 diabetes taking metformin for 5 years or longer has shown vitamin B12 deficiency and its borderline deficiency in 8.6% and 26% of patients respectively76. A study by Dekelbab & Kakkannat carried out in 90 children (7-18 years old) showed that obese children are more likely to have vitamin B12 deficiency whether treated with metformin or not77.

Vitamin C
Vitamin C is a water-soluble vitamin and one of the most important micronutrients not produced in the human body. It is an essential cofactor of numerous enzymes and a potent antioxidant. Best sources of vitamin C are fruits and vegetables, including citrus fruits, tomatoes, peppers, kiwifruit, broccoli, strawberries, and Brussels sprouts. It is not naturally present in grains78.

Vitamin C plays a special role in diabetes due to its structural similarity to sugar (glucose) and the use of common intracellular transporters, GLUT1 and GLUT3, by both compounds. As a consequence, elevated glucose levels promote vitamin C deficiency inside the cells by competing with vitamin C for its intracellular entry. This has particularly detrimental consequences for the cardiovascular system in diabetic patients. High glucose related vitamin C deficiency inside the blood vessel wall cells impairs collagen production, thereby compromising vascular integrity and accelerating atherosclerosis as well as microvascular dysfunctions in different organs in diabetic patients (Figure 5)25. Moreover, it has been shown that insufficient ascorbate levels in red blood cells in diabetes promote rigidity of these cells, thereby contributing to microvascular angiopathy79. In addition to impaired intracellular transport, inadequate vitamin C status in diabetic patients is prompted by higher urinary losses of this vitamin and increased metabolic turnover, all contributing to increased dietary requirements for vitamin C in diabetic patients.

Most clinical aspects of vitamin C in diabetes have been evaluated in adults80,81 and confirm compromised vitamin C status, including low vitamin C levels in type 2 diabetic patients with more severe diabetic nephropathy82. A study in 84 patients with type 2 diabetes receiving different doses of vitamin C for six weeks showed that its intake at a level of 1,000 mg a day may be beneficial in decreasing blood glucose and lipid levels, thus reducing the risk of vascular complications83. A recent study with 2,025 children aged 9-10 years investigated the relationship between vitamin C blood levels, fruit and vegetable intakes and insulin resistance. Based on a 24h dietary recall it was found that lower plasma vitamin C levels were associated with insulin resistance in these young individuals84.

Figure 5. Vitamin C Supplementation is an essential measure for diabetic patients in preventing cardiovascular disease25.

Vitamin D
Vitamin D is a fat-soluble vitamin mostly known for facilitating calcium absorption. However this vitamin also affects cell growth, inflammation and various neuromuscular and immune functions. The best sources are fatty fish (salmon, tuna, and mackerel) and fish liver oils. Small amounts of vitamin D are found in beef liver, cheese, and egg yolks85.

The majority of epidemiological studies have demonstrated an association between low vitamin D and insulin resistance and/or type 2 diabetes mellitus. Also, the study in young patients with type 1 diabetes showed that over 95% of them had insufficient (20-30 ng/mL) or deficient (86. The association between vitamin D levels (25(OH)D) and HbA1c was confirmed in 197 diabetic children and adolescents with type 1 diabetes, showing a high prevalence of low vitamin D status in association with type 1 diabetes87. Treatment of 53 pediatric type 1 diabetes patients with vitamin D3 for three months demonstrated better glycemic control and a statistically significant reduction in HbA1C88.

Vitamin D deficiency has been also associated with diabetic peripheral neuropathy89. In the pediatric populationits prevalence ranges from 7% to 54% depending on the diagnostic criteria used, but vitamin D subclinical manifestations occur in about 57% children and adolescents with type 1 diabetes41. In addition, a study of 517 children and adolescents with type 1 diabetes showed that vitamin D deficiency can double the risk of developing retinopathy90.

Vitamin K
Vitamin K is a generic name for a family of quinone compounds such asphylloquinone (vitamin K1) and a series of menaquinones (vitamin K2). Vitamin K functions as a coenzyme for vitamin K-dependent carboxylase, required for the synthesis of proteins involved in hemostasis and bone metabolism and other physiological functions. Best sources of vitamin K1 include vegetables, especially green leafy vegetables, vegetable oils, and some fruits. Meat, dairy foods and eggs contain low levels of vitamin K1, but modest amounts of vitamin K291.

It was reported that vitamin K supplementation has beneficial effects in improving insulin sensitivity92. Both animal and human studies have suggested that a beneficial function of vitamin K in insulin sensitivity and glucose tolerance may be mediated by its regulation of cytokines secreted by adipose tissue, its anti-inflammatory properties and lipid-lowering effects93. In a 3 year randomized, double-blind, placebo controlled trial of 355 patients, vitamin K significantly improved insulin sensitivity in men with diabetes by interfering with pancreatic β-cell proliferation, insulin sensitivity, production of adiponectin, and glucose tolerance94. Vitamin K effects were not evaluated in diabetic pediatric population.

Metabolic effects of minerals in various aspects of diabetes

Chromium
Chromium, required in trace amounts in humans, is known to enhance the action of insulin. Chromium is widely distributed in food, but only in small quantities (less than 2 mcg per serving). Good sources include meat and wholegrain products, some fruits, vegetables, and spices95.

The evaluation of chromium levels in plasma, erythrocytes and urine in 47 children diagnosed with type 1 diabetes and 118 non-diabetic controls showed a negative chromium balance in diabetic subjects, suggesting that chromium supplementation together with insulin may be necessary96. A recent study from Harvard Medical School showed that the odds of having type 2 diabetes were lower in adults who, in the previous 30 days, had consumed supplements containing chromium97. However, chromium supplementation in pediatric diabetic patients has not been evaluated.

Iron
Iron is an essential element in almost all living organisms. It is needed in oxygen transport (as a component of hemoglobin), bioenergy production (electron transport) and normal cellular functions. Dietary iron is available in two main forms: heme and non-heme. Meat, seafood and poultry contain both heme and non-heme iron. Plants such as nuts, beans, vegetables and fortified grain products are the sources of non-heme iron98.

Anemia can occur in diabetic children and may contribute to various complications of the disease, such as cognitive impairment. In 100 children with type 1 diabetes (age 6-17 years), red blood cells, hemoglobin, glycosylated hemoglobin, hematocrit, red blood cell volume, the molar mass of hemoglobin in red blood cells, mean corpuscular hemoglobin in red blood cells, and iron concentrations in serum were measured. The results showed that in the group of children with type 1 diabetes, a significantly lower concentration of three ferric parameters affected non-verbal intelligence. The authors concluded that the prevalence of reduced ferric parameters justifies preventive measures to reduce the risk of anemia in diabetic children99.

Magnesium
Magnesium is an abundant mineral in the body and a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions, including protein synthesis, muscle and nerve function, blood glucose control, and regulation of blood pressure. It is required for bioenergy production, oxidative phosphorylation, and glycolysis. Magnesium also plays a role in nerve impulse conduction, muscle contraction, and normal heart rhythm. Good sources include green leafy vegetables (i.e. spinach), legumes, nuts, seeds, and whole grains100.

Over the past decades, hypomagnesemia (serum magnesium 101, and also that subjects with poor glycemic control had low magnesium levels102,103,104. Magnesium supplementation or its increased intake can be important in prevention of type 2 diabetes in obese children105.

Selenium
Selenium, a trace element, is a constituent of more than two dozen seleno-proteins that play critical roles in thyroid hormone metabolism, DNA synthesis, reproduction, protection from oxidative damage and infections. Its best sources are seafood and organ meats, others include muscle meats, cereals and other grains and dairy products106.

Evaluation of oxidant status and micronutrient levels in 35 children with type 1 diabetes and 26 healthy children showed that selenium and zinc levels were significantly lower in diabetic subjects than in controls and inversely correlated with HbA1C levels. Diabetic children also had lower levels of glutathione peroxidase, which requires selenium for its activity. This study concluded that supplementation of these minerals can be beneficial in controlling diabetes and preventing its complications107.

Zinc
Zinc is an essential mineral required for the catalytic activity of approximately 100 enzymes involved in immune function, protein synthesis, wound healing, DNA synthesis, and cell division. Zinc also supports normal growth and development during pregnancy, childhood and adolescence and is required for proper sense of taste and smell. Oysters contain more zinc per serving than any other food, but red meat, poultry, beans, nuts, certain types of seafood (such as crab and lobster), whole grains, fortified breakfast cereals, and dairy products are also good sources108.

Zinc is essential for the normal processing and storage of insulin and might enhance glucose cellular intake by modulating insulin signaling pathways109. The first comprehensive systematic review and meta-analysis on the effects of zinc supplementation in patients with diabetes, involving three studies on type 1 diabetes and 22 studies on type 2 diabetes, demonstrated that zinc supplementation has beneficial effects on glycemic control and healthy lipid parameters110.

Reports in the literature on the zinc status of children and adolescents with type 1 diabetes mellitus are limited and contain contradictory results. Some investigators have shown decreased serum zinc concentrations in subjects with diabetes111,112, while in earlier studies its elevated levels were observed as compared to non-diabetic controls113. A few studies observed no changes in zinc status114,115. However, a recent study involving 88 children with type 1 diabetes and 76 healthy controls concluded that while there was no difference in zinc levels between these groups, there was a significant difference between zinc levels and insulin dose/BMI in diabetics101. A study involving 17 children with insulin-dependent diabetes indicated a secondary zinc deficiency in these children that could increase a risk of stunted growth 116. It appears that zinc supplementation is beneficial in controlling diabetes in children.

Metabolic effects of phytobiologicals in diabetes

Phytobiologicals (also called phytochemicals) include a large group of plant-derived compounds, which include phenolic acids, flavonoids, stilbenes/lignanes, and many others117. They are widely present in fruits, vegetables, beans, cereals and plant-based beverages such as tea and wine117. Their higher intake has been associated with many positive effects on diabetes118,119,120,121,122, but the effects of individual phytobiological compounds in children have not been thoroughly evaluated. Most information regarding efficacy of these secondary plant metabolites in the prevention and management of diabetes has been based on laboratory studies or on reports of their intake in adults.

Cinnamon. Cinnamon is a common spice obtained from the inner bark of Cinnamonum trees. Cinnamon extract is an insulin sensitizer, protects mesangial cells, decreases inflammatory markers, and lowers glucose, lipids, and blood pressure in patients with type 2 diabetes123.

The effects of cinnamon intake as an adjunct to a suffonylurea drug (glibenclamide) in 25 adult patients with type 2 diabetes showed that those taking cinnamon had reduced fasting blood glucose levels, less glycosylated HbA1c, and improve doxidative stress markers compared to a placebo124. Also, the efficacy of polyphenol–rich cinnamon extracts in lowering blood glucose levels and ameliorating oxidative stress was demonstrated in 15 volunteers with elevated fasting blood glucose125.

Curcumin. Curcumin, the main component of the Indian spice turmeric, has been used in traditional medicine to improve diabetes and its comorbidities. Its supplementation has been linked to improved insulin resistance through activation of the insulin receptor and related metabolic pathways126. Recently, Weisberg and collaborators showed that dietary intake of curcumin was associated with increased insulin production and prevention of hyperglycemia127. Curcumin binds directly to GLUT1 receptors, thereby inhibiting glucose transport. In intestinal epithelial cells this would likely result in reduced absorption of dietary glucose and a hypoglycemic effect128. Animal studies indicate that curcumin can help in alleviating heart microvascular diabetic complications129. It can benefit in diabetic nephropathy by inhibiting renal lipid accumulation and decreasing oxidative stress through AMPK and Nrf2 signaling pathway130. Its value has also been shown in diabetes induced periodontal disease131. Curcumin supplementation has not been evaluated in children.

Green tea extract. Epigallocatechin gallate (EGCG) is an antioxidant compound present in green tea. Epidemiological studies have demonstrated correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. EGCG can oppose endothelial dysfunction and ameliorate metabolic insulin resistance132. Green tea polyphenols were beneficial in various aspects of diabetes in adults133,134, but have not been investigated in pediatric diabetes.

Quercetin. Quercetin is an antioxidant widely distributed in plants and, together with its glycosides, exerts anti-diabetic properties by interfering with insulin signaling in peripheral target tissues. Quercetin positively affects glucose metabolism in the liver and skeletal muscle135, and is able to reduce blood glucose levels by stimulating insulin release136 and insulin sensitivity137. No studies were done in the pediatric population.

Resveratrol. Resveratrol is a polyphenol whose anti-diabetic potential has been confirmed in several studies. Its benefits include increased cerebral vasodilator responsiveness in the cerebral arteries138, as well as anti-inflammatory and hepato-protective effects139. Resveratrol may also be considered as a therapeutic option to prevent diabetic retinopathy140. No clinical studies are available in the pediatric population.

Coenzyme Q10 and diabetes

Coenzyme Q10 (CoQ10), also known as ubiquinone, is an antioxidant and essential component in the synthesis of adenosine triphosphate (ATP) in the mitochondrial bioenergy cycle. CoQ10 is synthesized internally but the ability to produce this nutrient decreases with age. Fish, meats and whole grains all have small amounts of CoQ10, but not enough to significantly boost its levels in the body141.

There is a growing body of evidence suggesting that mitochondrial dysfunction secondary to oxidative stress plays a critical role in the pathogenesis of type 2 diabetes. It was found that administration of CoQ10 could ameliorate cell apoptosis induced by high glucose and increase mitochondrial membrane potential, as well as reduce oxidative stress. These findings provide a potential treatment strategy targeting dysfunctional endothelial progenitor cells in diabetic patients142.

Menke and colleagues measured CoQ10 concentrations in plasma and blood cells, and redox status, in children with type 1 diabetes and healthy children. The study found that the level of plasma CoQ10 in children with type 1 diabetes was higher compared to that of healthy children. The authors suggested that in children with poorly controlled diabetes, an increase in antioxidant CoQ10 and intracellular redox capacity may represent self-protection of the body during the development of oxidative stress143.

Role of fiber in diabetes

Dietary fiber comprises the edible parts of plants that cannot be digested or absorbed in the small intestine and pass into the large intestine intact. It is often categorized based on its solubility into soluble and insoluble fiber present in different proportions in fiber-containing foods.

Rich sources of soluble fiber include oats, barley, fruits, vegetables and pulses (beans, lentils, chickpeas), while insoluble fiber is found in wholegrain cereals and breads.

Soluble fiber can slow digestion and absorption of carbohydrates and hence lower the rise in blood glucose that follows a meal (postprandial) and insulin response. This can help people with diabetes in controlling their blood glucose levels. In addition, fiber may contribute to weight control by delaying the gastric emptying of ingested foods into the small intestine, thereby creating a sensation of fullness. It can interfere with the absorption of dietary fat and cholesterol, as well as with the entero-hepatic recirculation of cholesterol and bile acids, which may result in reduced blood cholesterol levels144.

The data consistently confirm positive effects of dietary fiber on lowering risk of diabetes and its symptoms in general145. However, there are not many studies evaluating its effect in children. A randomized clinical trial examining longitudinally the association of dietary fiber intake with multiple indicators of glycemic control in youth with type 1 diabetes concluded that glycemic control may be improved by increasing intake of high-fiber, low glycemic-index, carbohydrate-containing foods146. This was in agreement with the results of an earlier study conducted in type 2 diabetic children which showed that psyllium intake decreased postprandial glucose147. Also, a study in Latino children showed that children without symptoms of metabolic syndrome had higher soluble fiber intake148, but others found no association149. The differences may relate to quality and type of fiber intake.

Micronutrient synergy and its application in young organisms with diabetes

Biological effects of micronutrients largely depend on mutual interactions and cooperation with other natural components in numerous complex cellular metabolic pathways. The new approach in dietary supplementation developed at the Dr. Rath Research Institute and introduced as “micronutrient synergy” allows for application of specific combinations of micronutrients in a controlled way. Synergy allows for expanded metabolic efficacy of micronutrients by simultaneously targeting several cellular mechanisms associated with various pathologies and enhanced efficacy with lower doses of individual components. Micronutrient synergy presents a new strategy in developing effective natural approaches against various human pathologies, including diabetes.

An in vivo study conducted in young mice with diabetes showed that a specific micronutrient synergy was superior to a diabetes drug, metformin, in regulating blood sugar levels and other aspects of diabetes150. Diabetes was induced in these young mice by feeding them a fructose-rich diet, which indicates its relevance to the effects of high fructose consumption in youth and adolescence. Fructose-induced protein damage was evaluated by measuring serum levels of fructosamine, a marker of protein damage in diabetes. The results showed that dietary intake of the synergistic micronutrient complex reduced serum fructosamine by about 4%, while metformin caused its 15.9% increase (Figure 6). In addition, insulin blood levels in mice in the micronutrient supplemented group were restored to normal values, while the metformin group had reduced insulin. In addition, micronutrient supplementation showed to be beneficial in reducing the risk of cardiovascular disease in these animals by lowering blood pressure, total cholesterol, and counteracting other negative effects of fructose150. These results indicate that synergistically interacting micronutrient composition results in more comprehensive anti-diabetic effects than individual compounds.

Figure 6. Comparative effects of metformin and diabetic nutrient mixture on fructosamine levels in fructose-fed mice. The DNM group demonstrated significantly lower fructosamine concentration (3.94% decrease) than the control (fructose-only fed) group, whereas the MET- treated group showed a 15.9% increase in fructosamine compared to the control. A t-test performed between the DNM group vs the fructose alone group and ANOVA for all groups yielded p<0.05150.

Conclusions

Evaluation of research, clinical and therapeutic approaches to diabetes in children and young adults indicates the need for intensifying research efforts to address unique aspects of this disease in this age group. In particular, specific attention should be placed on the benefits of vitamins, minerals, phytochemicals, and other natural compounds as safe and effective measures in prevention and management of diabetes in children. Health efficacy of these micronutrients has already been indicated in various clinical and scientific studies and supported by their practical application in a form of dietary supplementation. The major limiting factor in accepting therapeutic efficacy of natural approaches in diabetes as well as many other health problems is a lack of financial interest in advancing access to natural therapies, which do not generate exuberant profit margins like pharmaceutical approaches. Therefore, governmental support of this research direction is warranted.

Scientific and clinical support for the effectiveness of natural therapies against diabetes will also encourage and intensify further research interest in this globally growing health threat.

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Figure 1. Incidence of type 1 diabetes in children aged 0-14 years, by geographical region and over time3

Figure 2. Overweight prevalence among U.S. children and adolescents14

Figure 3. Short and long term behavioral and cognitive reported alterations following type 1 diabetes mellitus onset in children and adolescents according to type 1 diabetes mellitus duration34

Figure 4. Comparison of Candida albicans strains susceptible, intermediate, and resistant to the six tested antifungal drugs in children with type 1 diabetes mellitus (A) and healthy control subjects (B)49

Table 1. Summary of FDA insulin pump adverse event reports for ages 1-12 years, January 1, 1996, through December 31, 200953

Figure 5. Vitamin C Supplementation is an essential measure for diabetic patients in preventing cardiovascular disease25

Figure 6. Comparative effects of metformin and diabetic nutrient mixture on fructosamine levels in fructose-fed mice. The DNM group demonstrated significantly lower fructosamine concentration (3.94% decrease) than the control (fructose-only fed) group, whereas the MET- treated group showed a 15.9% increase in fructosamine compared to the control. A t-test performed between the DNM group vs the fructose alone group and ANOVA for all groups yielded p<0.05150

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Diabetes in Children and the Role of Micronutrients

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