Читать книгу American Diabetes Association Guide to Nutrition Therapy for Diabetes - Marion J. Franz - Страница 5
ОглавлениеChapter 3 Micronutrients and Diabetes
Joshua J. Neumiller, PharmD, CDE, CGP, FASCP
Requirements for Micronutrients: Dietary Reference Intakes
Requirements for Micronutrients in Diabetes
Micronutrient Effects on Glucose and Insulin Homeostasis
Definition and Regulation of Supplements
Highlights Micronutrients and Diabetes
• Dietary reference intakes (DRIs) are reference values that are quantitative estimates of nutrient intakes to be used for planning and assessing diets for healthy people. DRIs consist of four reference intakes: Recommended Dietary Allowance (RDA), Estimated Average Requirement (EAR), Adequate Intake (AI), and Tolerable Upper Intake Level (UL).
• Many micronutrients are involved in carbohydrate and/or glucose metabolism as well as with insulin release and sensitivity. This information, however, is frequently extrapolated beyond what is supported by research findings, and clinical data for most micronutrients for the treatment of diabetes are inconclusive.
• Supplements are defined as any product that is intended to supplement the diet. Dietary supplements contain one or more of the following: vitamin, mineral, herb or other botanical, or amino acid. Unlike drugs, supplements do not need to undergo efficacy or safety testing before being marketed.
• Currently, there is insufficient evidence to support the routine use of supplements for the treatment of diabetes. There are, however, select groups of individuals who may benefit, such as people with poor glycemic control and/or people with a documented deficiency of a given micronutrient or vitamin. Compelling data from well-designed, long-term studies are needed before supplement products can be recommended for widespread use in people with diabetes.
Micronutrients and Diabetes
Micronutrients are vitamins and minerals that are required in small quantities for specific physiological functions. Micronutrients often function as coenzymes or cofactors essential for metabolic processes (glycolysis, lipid metabolism, amino acid metabolism, etc.) and are thus essential to sustaining life (Shils 2005). Vitamins and minerals have been studied in the prevention and treatment of both type 1 and type 2 diabetes, as well as for the treatment of diabetes complications (Mooradian 1994). “Natural” medicines, including micronutrients, are widely used by people with diabetes. Some surveys indicate that as many as 60% of people with diabetes use some form of alternative medicine (Yeh 2002). Accordingly, it is not uncommon for consumers with diabetes to ask a variety of questions about the utility of micronutrients and supplements in the management of their diabetes.
The objective of this chapter is to assist health care professionals in answering some of the questions posed by people with diabetes concerning micronutrients. This chapter, which focuses on micronutrients for the treatment of diabetes, begins with a summary of dietary intake requirements for micronutrients for people with diabetes from the book American Diabetes Association Guide to Medical Nutrition Therapy of Diabetes (Franz 1999). The chapter then reviews and updates currently available data for select micronutrients and antioxidants on carbohydrate/glucose metabolism and/or insulin activity and reviews the U.S. Food and Drug Administration (FDA) regulation processes for supplement products.
REQUIREMENTS FOR MICRONUTRIENTS: DIETARY REFERENCE INTAKES
Before addressing the role of vitamins and minerals in diabetes, it is helpful to review requirements for micronutrients and how they are determined. Vitamins and minerals are substances required in very small amounts to promote essential biochemical reactions in cells. Together, vitamins and minerals are called micronutrients. At low nutrient levels (deficiency), dependent biological functions are impaired. In contrast, high intakes can result in toxicity and decreased absorption of other micronutrients because of competitive inhibition.
Micronutrients are specific in their functions, and most cannot be made by the body or be replaced by chemically similar elements. They must come from food or supplements. Small amounts of micronutrients are needed for optimal performance, yet lack of a micronutrient for a prolonged period can result in disease seemingly disproportionate to the amount missing. For example, although only small amounts of vitamins are needed, lack of vitamin C results in scurvy, lack of adequate thiamin in beriberi, and lack of adequate niacin in pellagra.
Several factors make determining exact individual requirements for micronutrients difficult. First, metabolism and use of micronutrients are homeostatically regulated, making requirements and the effect of supplementation dependent on an individual’s nutritional status. For example, if intake of a particular micronutrient is low, absorption may be increased, and when intake is adequate, excess nutrient may be excreted in the feces and in small amounts in the urine.
Assessment of micronutrient status is difficult. It is assumed that levels of micronutrients in body fluids (plasma) reflect tissue and intracellular status and, therefore, that decreased serum levels indicate suboptimal status. However, plasma levels generally do not reflect intracellular status. Correlations between plasma levels and tissue status, especially in marginal deficiencies, are not always apparent.
Furthermore, metabolism and use of nutrients in general is highly integrated with other nutrients, hormones, and physiological factors. With excessive (or deficient) intakes of a particular micronutrient, the balance of this highly orchestrated scheme is disrupted, which leads to a cascade of effects. For example, calcium use is affected by a high protein intake, phosphorus and vitamin D intakes, and parathyroid hormone. Changes in any of these factors may affect dietary calcium requirements.
Requirements for micronutrients have been historically based on the 10th edition of Recommended Dietary Allowances (RDAs) (Food and Nutrition Board 1989). However, the RDAs, published since 1941 by the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences, are being replaced by a new approach called Dietary Reference Intakes (DRIs) (Yates 1998). The DRIs are developed by the Food and Nutrition Board in partnership with Health Canada and Canadian scientists. DRIs are reference values that are quantitative estimates of nutrient intakes to be used for planning and assessing diets for healthy people. The standards are for apparently healthy people and are not meant to be applied to those with acute or chronic disease or for the replacement of nutrient levels in previously deficient individuals. For individuals with specific needs, adjustments in the values may need to be made. They consist of four reference intakes: RDA, Adequate Intake (AI), Tolerable Upper Intake Level (UL), and Estimated Average Requirement (EAR).
The four primary uses of the DRIs are for assessing intakes of individuals, assessing intakes of population groups, planning diets for individuals, and planning diets for groups. RDAs and AIs both may be used as goals for individual intakes, whereas EARs may be used to examine the possibility of inadequacy and ULs the possibility of overconsumption for individuals. EARs are also used as guides to limit individual intake and to set goals for the mean intake of groups or of a specific population, as well as for the assessment of inadequate intakes within a group. Table 3.1 summarizes the definitions for the various reference values.
Table 3.1 Terms for Nutrient Requirements
• Adequate Intake (AI): An AI is provided instead of an RDA when sufficient scientific evidence is not available to calculate an EAR. The AI is a recommended daily intake level based on observed or experimentally determined approximations of nutrient intake by a group of healthy people that are assumed to be adequate (Yates 1998). The primary use of the AI is as a goal for the nutrient intake of individuals.
• Daily Value (DV): This term is used for nutrient levels on food and supplement labels. DVs are derived from RDAs (or AIs) to represent both sexes and most age-groups.
• Dietary Reference Intakes (DRIs): This is an umbrella term for a set of four reference values: EAR, RDA, AI, and UL.
• Estimated Average Requirement (EAR): The process for setting the RDA depends on being able to set the EAR. The EAR is the amount of nutrient that is estimated to meet the nutrient requirements of half the healthy individuals in a life stage and gender group (Yates 1998). When selecting the EAR, reduction of disease risk is considered, along with many other health parameters. No RDA is proposed if it is determined that an EAR cannot be set. The EAR is used to assess adequacy of intakes of population groups.
• Recommended Dietary Allowance (RDA): The RDA is the average daily dietary intake level of a nutrient that is sufficient to meet the nutrient requirement of nearly all (97–98%) healthy individuals in a particular life stage (life stage considers age and, when applicable, pregnancy or lactation) and gender group (Yates 1998). The RDA includes a generous safety factor related to a bell-shaped curve. The majority of the population actually requires only approximately two-thirds of the RDA. This is in contrast to energy requirements, which are based on average needs.
• Tolerable Upper Intake Level (UL): The UL is the highest level of nutrient intake that is likely to pose no risks or adverse health effects to almost all individuals in the general population. As intake increases above the UL, the risk of adverse effects increases. The UL is not intended to be a recommended level of intake. There is no established benefit for healthy individuals if they consume nutrient intakes above the RDA or AI (Yates 1998). The UL applies to chronic daily use. It is useful because of the increased interest in availability of fortified foods and the increased use of dietary supplements.
Adapted from Yates 1998.
REQUIREMENTS FOR MICRONUTRIENTS IN DIABETES
The literature on the micronutrient status of people with diabetes contains conflicting reports depending on the population studied and because of the uncertainties in methodologies (Mooradian 1994; Mooradian 1987). Adequately controlled studies that establish the role of trace elements in the pathogenesis of carbohydrate intolerance are not available. Although animal studies have suggested that deficiencies in many of the trace elements—including zinc, chromium, magnesium, copper, manganese, and vitamin B6—may lead to glucose intolerance, evidence for their role in the pathogenesis of glucose intolerance in humans is not definitive.
Many of the studies are done in animals in the laboratory, where diets can be manipulated easily in comparison to the diet of free-living subjects. The result of animal studies should not be extrapolated to humans without studies being performed in humans to validate the findings.
One of the problems with human studies in individuals with diabetes is that trace-metal and water-soluble vitamin urinary losses are increased during uncontrolled hyperglycemia with glycosuria; therefore, the effect of the response to micronutrients may depend on the degree of glucose tolerance. Furthermore, in some studies, the initial glucose tolerance varies from normal to glucose intolerant to diabetes. Results from all of these subjects may be combined, which would minimize the effects of a micronutrient. Furthermore, often, the effect of micronutrients on insulin secretion is biphasic. Low concentrations of the vitamin may stimulate insulin secretion, and high concentrations may have an inhibitory effect.
In human studies, the amount of the micronutrient being studied in the diet eaten is often unknown. For example, studies have reported beneficial effects of chromium on glucose and/or lipid metabolism in subjects eating varied diets with unknown chromium contents. To further confuse the role of micronutrients and diabetes, serum or tissue content of certain elements—copper, manganese, iron, and selenium—can be higher in people with diabetes than in control subjects without diabetes. On the other hand, serum ascorbic acid (vitamin C), B vitamins, and vitamin D may be lower in individuals with diabetes, whereas vitamins A and E have been reported to be normal or increased.
Regardless of the research problems, many micronutrients are intimately involved in carbohydrate and/or glucose metabolism as well as in insulin release and sensitivity. Unfortunately, this information is frequently extrapolated beyond what the research supports. The American Diabetes Association (ADA) recommends that individualized meal planning include optimization of food choices to meet RDA and DRI intakes for all micronutrients (ADA 2012).
MICRONUTRIENT EFFECTS ON GLUCOSE AND INSULIN HOMEOSTASIS
The 1999 chapter of American Diabetes Association Guide to Medical Nutrition Therapy for Diabetes concluded that data available did not justify routine supplementation of vitamins and minerals for people with diabetes. However, it was concluded that there are select groups of people who may benefit, such as patients in poor glycemic control and patients deficient in water-soluble micronutrients. An update on chromium, magnesium, vitamin D, and antioxidant supplementation in the treatment of diabetes is provided below. Table 3.2 summarizes research related to carbohydrate and/or glucose metabolism and the known effects related to the treatment of diabetes for additional selected micronutrients.
Table 3.2 Effects of Select Vitamins and Minerals on Carbohydrate and/or Glucose Metabolism or Insulin and the Effects of Supplementation on Diabetes
Chromium
The biologically active complex of elemental chromium is the glucose tolerance factor, which is a complex composed of chromium bound to two molecules of nicotinic acid and single molecules of the amino acids glutamic acid, glycine, and cysteine. Food sources of chromium include canned foods, meats, fish, brown sugar, coffee, tea, some spices, whole-wheat bread, rye bread, and brewer’s yeast. The glucose tolerance factor has a role in glucose homeostasis, with chromium deficiency in animals being associated with an increase in blood glucose, cholesterol, and triglycerides. Mechanistically, the glucose tolerance factor acts as a cofactor for insulin and may facilitate insulin–membrane receptor interaction. However, the glucose tolerance factor lowers plasma glucose only in the presence of insulin (fed state) and not in 24-h fasting animals (Truman 1977). Chromium supplements are available in several forms, with the most common forms being chromium picolinate, chromium nicotinate, chromium polynicotinate, and chromium chloride. The picolinate and nicotinate salts demonstrate better absorption and retention of chromium compared to inorganic salt forms such as chromium chloride (Lanca 2002; Kaats 1996).
As with many micronutrients, evidence is conflicting regarding the role of chromium in the treatment of diabetes. Chromium levels can be below normal in people with diabetes (Davies 1997; Morris 1985), and epidemiological studies have linked lower levels of chromium measured within toenails with an increased risk of diabetes and cardiovascular disease (Rajpathak 2004). In regard to the treatment of type 2 diabetes, several clinical studies have shown that supplementation with oral chromium picolinate improves insulin sensitivity, decreases fasting plasma glucose, and improves A1C (Anderson 1997; Lee 1994; Martin 2006; Rabinovitz 2004). Additional benefits include reductions in total cholesterol and triglyceride levels (Anderson 1997; Lee 1994) and weight reduction in type 2 diabetes patients being treated with a sulfonylurea (Martin 2006). Glycemic benefits have likewise been described with chromium supplementation in people with type 1 diabetes and corticosteroid-induced hyperglycemia (Fox 1998; Ravina 1999).
Despite the promising findings described above, other studies have not demonstrated benefits with chromium supplementation (Abraham 1992; Althius 2002; Kleefstra 2006; Uusitupa 1983; Wise 1978). Even in studies that have shown benefit, the extrapolation of study findings to all people with diabetes is questionable. It has been speculated that chromium supplementation may be primarily beneficial in individuals with poor nutritional status or low chromium levels as opposed to all people with diabetes. For example, one of the largest studies performed that demonstrated clinical benefit was performed in China, where poor nutritional status is more likely, potentially accounting for the clinical benefit observed (Anderson 1997; Kleefstra 2006). Of note, a systematic review on the effect of chromium supplementation on glucose metabolism and lipids concluded that larger effects were more commonly observed in poor-quality studies and that evidence is limited by poor study quality, and heterogeneity in methodology and results (Balk 2007). Table 3.3 provides a summary of select clinical chromium supplementation studies (including results of English language randomized controlled trials [RCTs] including ≥10 human subjects with diabetes in each study arm).
Table 3.3 Select Clinical Evidence Available for Chromium Supplementation as a Treatment for Diabetes
Confounding the interpretation of chromium supplementation studies is the lack of an accurate and reliable measurement of chromium status, thus making chromium deficiency and characterization of study populations based on chromium status difficult to demonstrate (Guerrero-Romero 2005). Whereas chromium supplementation is generally considered safe, it must also be considered that high doses of chromium have been associated with chromosomal damage, psychiatric disturbances, rhabdomyolysis, and renal and hepatic toxicity in some cases (Guerrero-Romero 2005). On the basis of currently available evidence and considerations of potential toxicity with long-term use, current opinion states that chromium supplements can be considered for short-term use in patients suspected of having a chromium deficiency, based on dietary history (Cefalu 2004). Because of inconclusive clinical evidence, however, the use of routine chromium supplementation in people with diabetes is controversial (Cefalu 2004). After reviewing the evidence, the ADA concluded that benefit from chromium supplementation in individuals with diabetes or obesity has not been clearly demonstrated and therefore cannot be recommended (ADA 2008).
Magnesium
Magnesium is a divalent cation that is intimately involved in numerous important biological reactions that take place within the body. Magnesium is a cofactor for over 300 metabolic reactions in the body, including protein synthesis, adenylate cyclase synthesis, cellular energy production and storage, preservation of cellular electrolyte composition, cell growth and reproduction, DNA and RNA synthesis, and stabilization of mitochondrial membranes (Volpe 2008). Magnesium is unevenly distributed in the body, with ~50–60% residing in the skeleton, nearly 50% present in muscle and soft tissues, and only ~1% present in the extracellular compartment, such as serum or interstitial body fluids. Serum magnesium measures only 0.3% of total body magnesium and does not provide a sensitive index of magnesium deficiency.
Low levels of magnesium have been associated with a variety of illnesses, including hypertension, cardiac arrhythmias, congestive heart failure, retinopathy, and insulin resistance (McNair 1978; Paolisso 1990; Resnick 1989; Shattock 1987; Whelton 1989; Yajnik 1984). Of note, magnesium has been shown to play a significant role in glucose and insulin metabolism (Barbagallo 2003; Paolisso 1997). Likewise, decreased magnesium intake has been correlated to an increased risk of type 2 diabetes and metabolic syndrome (Dong 2011; Guerrero-Romero 2002; He 2006; Murakami 2005). Poorly controlled diabetes has been shown to lead to enhanced osmotic diuresis and increased urinary loss of magnesium (de Leeuw 2004), and severe hyperglycemia can decrease tubular reabsorption of magnesium, resulting in lower magnesium levels due to increased excretion (Barbagallo 2003). Additional research indicates that physiological stressors (such as type 2 diabetes) may act to deplete magnesium within the body, which, in turn, may impair normal metabolism and exacerbate the disease state (Bohl 2002).
Research to date indicates that low magnesium blood levels may play a role in insulin resistance (He 2006; Song 2004). Insulin is known to be involved in the shift of magnesium intracellularly. Likewise, intracellular magnesium is likely involved in the regulation of insulin activity on oxidative glucose metabolism. This result is evidenced by the finding that low intracellular magnesium leads to disorders in tyrosine kinase activity at the insulin receptor level, resulting in decreased insulin sensitivity and insulin-mediated glucose uptake (Barbagallo 2003).
So what role does magnesium supplementation have in the treatment of diabetes? Hypomagnesemia occurs in an estimated 25–38% of people with type 2 diabetes and is more common in individuals with poorly controlled diabetes (de Lordes Lima 1998). Evidence from clinical studies evaluating magnesium supplementation in people with type 2 diabetes or insulin resistance has been conflicting. Some clinical studies suggest that magnesium supplementation is effective in decreasing fasting blood glucose levels and improving measures of insulin sensitivity (Rodriguez-Moran 2003; Yokota 2004; Paolisso 1992; Guerrero-Romero 2004). In contrast, other studies have reported no effect of magnesium supplementation on insulin or glucose levels (de Lordes Lima 1998; de Valk 1998; Eibl 1995; Gullestad 1994; Paolisso 1994). The discrepancies in data could be due to a variety of factors, including differences in magnesium salts or doses used, differences in magnesium status in study participants at baseline, or differences in study methodologies used. Please see a summary of select clinical studies (including results of English language RCTs including ≥10 human subjects with diabetes in each study arm) in Table 3.4.
Table 3.4 Select Clinical Evidence Available for Magnesium Supplementation as a Treatment for Diabetes
Vitamin D
Epidemiological research indicates that people with low vitamin D levels have a significantly higher risk of type 2 diabetes than individuals with higher levels (Martins 2007; Pittas 2007). Animal studies have shown that vitamin D deficiency inhibits pancreatic insulin secretion (Nyomba 1986), and the pancreatic b-cell expresses vitamin D receptors (Bland 2004). In turn, vitamin D has been posited as a potential therapeutic agent in both the prevention and treatment of type 1 and type 2 diabetes (Mathieu 2005).
Vitamin D deficiency has been associated with higher risks for metabolic syndrome and type 2 diabetes (Chiu 2004; Scragg 2008; Scragg 2004), and current evidence indicates that vitamin D treatment improves glucose tolerance and insulin resistance (Parekh 2010; von Hurst 2010). Of note, the National Health and Nutrition Examination Survey showed an inverse relationship between serum 25-hydroxyvitamin D and the incidence of type 2 diabetes and insulin resistance (Ford 2005; Scragg 2004).
Ultimately, current evidence does not definitively show that daily vitamin D supplementation is effective in the treatment or prevention of type 1 or type 2 diabetes (Mitri 2011; Pittas 2007; Takiishi 2010). A review of vitamin D and type 2 diabetes included eight observational cohort studies and 11 RCTs. In three small underpowered trials (n = 32–62) in individuals with type 2 diabetes, there was no effect of vitamin D supplementation on glycemic outcomes (Mitri 2011). Although preclinical data and observational studies are suggestive of a benefit of vitamin D supplementation in people with diabetes, large prospective, randomized, placebo-controlled trials that measure blood 25-hydroxyvitamin D concentration and clinically relevant glycemic outcomes are needed. Indeed, a great deal of research is currently underway concerning the role of vitamin D in the treatment and prevention of diabetes; however, at the time of this publication, results from large, prospective, randomized trials were not available. The use of vitamin D in deficient individuals is well founded, particularly in regard to bone health. The Institute of Medicine (IOM) concluded in its 2010 report (IOM 2010) that the evidence for a benefit of vitamin D in bone health is compelling, but that for other conditions such as cancer and cardiovascular disease, the evidence is inconclusive and insufficient to drive specific nutritional requirements for vitamin D intake. Table 3.5 provides a summary of DRI recommendations for vitamin D supplementation per the 2010 IOM recommendations (IOM 2010). For a more detailed discussion of vitamin D supplementation for the treatment and prevention of diabetes, please refer to the reviews by Takiishi and Mitri and colleagues (Mitri 2011; Takiishi 2010).
Table 3.5 Current DRIs for Vitamin D
Antioxidants
The 1999 chapter concluded that while there is no justification for the routine supplementation of vitamins and minerals for people with diabetes, antioxidant supplements, such as vitamin E, may be proven to play a role in preventing oxidative damage to tissues and may be recommended for use in the future. Oxidative stress has been implicated in contributing to the pathogenesis of a variety of conditions including coronary artery disease, cancer, and the onset and progression of diabetes and its complications (Sheikh-Ali 2011). Oxidative stress results from free radical production. Free radicals are toxic compounds generated in the process of normal metabolism that contain one or more unpaired electrons. Unpaired electrons have a strong affinity for electrons from other molecules. Because of their reactive nature, free radicals can initiate a chain of oxidative events leading to toxic cellular damage. Antioxidants are compounds that are able to neutralize free radicals. In people with diabetes, depletion of cellular antioxidant defense systems occurs, and the disease is associated with an increase in the production of free radicals. Glucose has been shown to promote oxidative stress in endothelial cell cultures, where elevated ambient dextrose concentrations increased superoxide production (Horani 2004), with elevated plasma glucose levels correlating with superoxide production and increased oxidation of LDLs (Ceriello 2003). For a detailed discussion of the role of oxidative stress in diabetes, refer to the review by Sheikh-Ali and colleagues (Sheikh-Ali 2011).
While a variety of antioxidants are used by people with diabetes, some of the most common products used include vitamin E, vitamin C, and b-carotene. Table 3.6 summarizes research related to carbohydrate and/or glucose metabolism and/or inflammation and the known effects related to the treatment of diabetes for selected antioxidants. Interestingly, while there exists a great deal of empiric evidence that supplementation with antioxidant vitamins is beneficial in people with diabetes, intervention trials with antioxidants in this population have thus far failed to demonstrate clinical benefit. The Physician’s Health Study II, for example, showed that 400 IU vitamin E every other day and 500 mg vitamin C daily conveyed no benefit in regard to decreasing the incidence of major cardiovascular events, with vitamin E actually being associated with an increased risk of hemorrhagic stroke (Stampfer 1993). In another trial, vitamin E dosed at 600 mg every other day did not protect a cohort of healthy women from myocardial infarction, stroke, or cancer (Yochum 2000). Interestingly, a meta-analysis of 68 randomized trials concluded that treatment with vitamin A, vitamin E, and b-carotene may actually place people at an increased risk of mortality (Qiao 1999).
Table 3.6 Effects of Select Antioxidants on Carbohydrate and/or Glucose Metabolism or Insulin and the Effects of Supplementation on Diabetes
Another popular antioxidant supplement used by people with diabetes is a-lipoic acid. Doses of 600–1,800 mg of oral and 500–1,000 mg of intravenous a-lipoic acid have been shown to improve insulin resistance and glucose effectiveness after 4 weeks and 1–10 days of administration, respectively (Jacob 1996; Jacob 1999; Konrad 1999). Endogenous a-lipoic acid acts as a coenzyme involved in carbohydrate metabolism (Beitner 2003). Perhaps most notably, a-lipoic acid at doses ranging from 600 to 1,200 mg/day appears to improve the symptoms of peripheral neuropathy such as numbness, burning, and pain in the extremities (Ziegler 1999; Reljanovic 1999; Ziegler 1995; Ruhnau 1999; Ametov 2003; Ziegler 2004). Experimental models suggest that a-lipoic acid increases neuronal glucose uptake and blood flow, improves neuronal conduction velocity, and increases the amount of reduced glutathione available within neurons (Kishi 1999; Nagamatsu 1995).
Overall, the contrast between strong experimental evidence of the increased oxidative load in diabetes and its contribution to the pathogenesis of the disease and the lack of clinical benefit shown in clinical trials to date is curious. This “antioxidant paradox,” as coined by Sheikh-Ali and colleagues (Sheikh-Ali 2011), is certainly unexpected and cannot be presently explained. Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised by the ADA because of lack of evidence of efficacy and concern related to long-term safety (ADA 2012).
DEFINITION AND REGULATION OF SUPPLEMENTS
The FDA defines a dietary supplement as any product (other than tobacco) that is intended to supplement the diet. Dietary supplements contain one or more of the following: vitamin, mineral, herb or other botanical, amino acid, or other dietary substance (which could include phytochemicals, concentrates, metabolites, extracts, or combinations of any of the above) (Dietary Supplement Health and Education Act [DSHEA] 1994). Medical foods are exempt from this definition and are defined as foods used under medical supervision and intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Examples are enteral and parental products (DSHEA 1994).
Dietary supplements, although often sold as foods, are used more like drugs. However, unlike drugs, they do not have to be proven effective before being marketed. A drug is formally defined as a substance used as (or in the preparation of) a medication, and the FDA has clear premarket jurisdiction over these substances. Supplements are designed to cure deficiencies, but do not further improve normal status unless proven to be useful as therapeutic agents. If they are to be used as therapeutic agents, their efficacy should be proven by the same standards required for drugs.
Although the FDA is responsible for ensuring that supplements are safe for human consumption, the FDA cannot intervene until damage or harm is documented. Under the Nutrition Labeling and Education Act of 1990, it was proposed that supplements should be required to meet the same requirements as conventional foods to qualify for a health claim and that they should follow the same labeling requirements. However, a Dietary Supplement Act, Title II of Prescription Drug User Free Act of 1992, prohibited the FDA from taking action against supplements for unauthorized health claims until December 1993 (FDA 1993a; FDA 1993b). Finally, in October 1994, Congress passed the Dietary Supplement Health and Education Act (DSHEA 1994), a compromise between the supplement industry and the original intent of the Nutrition Labeling and Education Act of 1990.
There are several key provisions of DSHEA. This act allows supplements to bypass the premarket FDA regulations for drugs or food additives. Supplement manufacturers or companies that sell supplements do not have to prove their products are effective or safe before they go to market. Instead, the burden of proof for an unsafe supplement is placed on the FDA. The FDA can intervene only after an illness or injury occurs. After complaints are received, the FDA is required to prove that the supplement causes harm when taken “as directed” on the label before a product can be restricted. Herbal remedies also may be sold without any knowledge of their mechanism of action (Angell 1998).
Supplements must have the same type of nutritional labeling found on foods, and they cannot carry claims that mention a specific disease unless the claims are backed by scientific evidence. Labels on vitamins, minerals, herbs, amino acids, and other supplements are allowed to make claims about maintaining a healthy body. To protect consumers, the law requires that supplement packages let shoppers know that these types of claims “have not been evaluated by the Food and Drug Administration” and are “not intended to diagnose, cure, or prevent any disease.” The law also prohibits point-of-sale information, such as an article or book chapter supporting a dietary supplement claim, without prior FDA review.
Finally, the standards used to prepare and package supplements are left up to the company. Therefore, the product’s purity or the amount of the active ingredients in a supplement cannot be certain, even from one package to the next of the same product. DSHEA included the recommendation that good manufacturing practices be used in the development of supplements; however, this protocol is not enforced by the FDA. Good manufacturing practices include a host of activities that are important for manufacturing a product that is free of defects and can include the following: quality assurance surrounding the use of raw materials, strict recordkeeping guidelines, high standards for cleanliness and safety, employment of qualified personnel, in-house testing and production and process controls, and guidelines regarding storage and distribution of products. Patients would be well advised to seek supplements manufactured by reputable companies that follow good manufacturing practices. People should be counseled to purchase products that have been independently evaluated and contain the United States Pharmacopeial Convention (USP), ConsumerLab (CL), or Natural Products Association seal of approval.
Until reliable studies document the therapeutic benefit of pharmacological dosages of vitamins and minerals, the prudent approach is to supplement with micronutrients only when a specific deficiency status is documented (Chehade 2009). Patients should be educated about the toxicity of mega-doses of micronutrients and be counseled regarding acquiring daily vitamin and mineral requirements by means of a balanced, healthful eating pattern.
People with poorly controlled diabetes are susceptible to several micronutrient deficiencies (Franz 2002). The first step in identifying a deficiency is an evaluation of the nutritional state, including the individual’s food and eating habits, food preferences, and overall health status. Healthy adults can receive all the necessary nutrients from foods, but certain high-risk groups, such as growing and developing children and youths, women during pregnancy and lactation, individuals eating <1,200 kcal/day, elderly individuals (especially people with low socioeconomic status), patients in intensive care units or long-term nursing facilities, and total vegetarians, may benefit from an appropriate vitamin-mineral supplement.
On the basis of current evidence, there is presently no justification for routine supplementation of vitamins and minerals for people with diabetes (Chehade 2009). However, there are select groups of people who may benefit, such as patients with diabetes in poor glycemic control, who are more likely to have deficiencies in magnesium, zinc, vitamin D, and water-soluble vitamins. While vitamin and mineral supplements should not be substituted for a healthful eating pattern, there is likely no harm in taking a multivitamin supplement with dose levels no higher than 100% of the RDA. Doses above that do not convey extra protection, but they do increase the risk of toxic side effects. Furthermore, it is likely that the response to supplements is determined by nutritional state, so people with micronutrient deficiencies will likely respond favorably.
Micronutrients are intimately involved in the metabolism of carbohydrates and other nutrients and with the body’s use of glucose and insulin. However, without well-designed clinical trials to prove efficacy, the benefit of pharmacological doses of supplements is unknown, and findings from small clinical and animal studies is frequently extrapolated to clinical practice. Presently, there is no evidence of benefit from vitamin or mineral supplementation in people with diabetes without underlying evidence of a deficiency.
Bibliography
Abraham AS, Brooks BA, Eylath U: The effects of chromium supplementation on serum glucose and lipids in patients with and without non-insulin dependent diabetes. Metabolism 41:768–771, 1992
Althius MD, Jordon NE, Ludington EA, Wittes JT: Glucose and insulin responses to dietary chromium supplements: a meta-analysis. Am J Clin Nutr 76:148–155, 2002
American Diabetes Association: Nutrition recommendations and interventions for diabetes (Position Statement). Diabetes Care 31 (Suppl. 1):S61–S78, 2008
American Diabetes Association: Standards of medical care in diabetes: 2012. Diabetes Care 35 (Suppl. 1):S11–S63, 2012
Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samiqullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group: The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 26:770–776, 2003
Anderson RA, Cheng N, Bryden NA, Polansky MM, Cheng N, Chi J, Feng J: Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46:1786–1791, 1997
Angell M, Kassirer JP: Alternative medicine-the risks of untested and unregulated remedies. N Engl J Med 339:839–841, 1998
Arquilla ER, Packer S, Tarmas W, Miyamoto S: The effect of zinc on insulin metabolism. Endocrinology 103:1440–1449, 1978
Balk EM, Tatsioni A, Lichtensetin AH, Lau J, Pittas AG: Effect of chromium supplementation on glucose metabolism and lipids. Diabetes Care 30:2154–2163, 2007
Barbagallo M, Dominguez LJ, Galioto A, Ferlisi A, Cani C, Malfa L, Pineo A, Busardo A, Paolisso G: Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med 24:39–52, 2003
Beitner H: Randomized, placebo controlled, double-blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoaging of facial skin. Br J Dermatol 149:841–849, 2003
Bland R, Markovic D, Hills CE, Hughes SV: Expression of 25-hydroxyvitamin D3-1 alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol 121:89–90, 2004
Blostein-Fujii A, DiSilvestro RA, Frid D, Katz C, Malarkey W: Short-term zinc supplementation in women with non-insulin dependent diabetes mellitus: effects on plasma 5'-nucleotidase activities, insulin-like growth factor I concentrations, and lipoprotein oxidation rates in vitro. Am J Clin Nutr 66:639–642, 1997
Boden G, Chen X, Ruiz J, van Rossum GD, Turco S: Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin dependent diabetes mellitus. Metabolism 45:1130–1135, 1996
Bohl CH, Volpe SL: Magnesium and exercise. Crit Rev Food Sci Nutr 42:533–563, 2002
Bond JS, Failla ML, Unger DF: Elevated manganese concentration and arginase activity in livers of streptozotocin-induced diabetic rats. J Biol Chem 258:8004–8009, 1983
Cefalu WT, Hu FB: Role of chromium in human health and in diabetes. Diabetes Care 27:2741–2751, 2004
Ceriello A: The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications. Diabetologia 46 (Suppl. 1):M9–M16, 2003
Chehade JM, Sheikh-Ali M, Mooradian AD: The role of micronutrients in managing diabetes. Diabetes Spectrum 22:214–218, 2009
Chiu KC, Chu A, Go VL, Saad MF: Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79:820–825, 2004
Cohen N, Halberstam M, Schilmovich P, Chang CJ, Shamoon H, Rosetti L: Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin dependent diabetes mellitus. J Clin Invest 95:2501–2509, 1995
Davies S, Howard JM, Hunnisett A, Howard M: Age-related decreases in chromium levels in 51,665 hair, sweat, and serum samples from 40,872 patients: implications for the prevention of cardiovascular disease and type II diabetes mellitus. Metabolism 46:469–473, 1997
de Leeuw I, Engelen W, De Block C, Van Gaal L: Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1DM). Magnes Res 17:109–114, 2004
de Lordes Lima M, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Cangucu V: The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care 21:682–686, 1998
de Valk HW, Verkaaik R, Van Rijn HJ, Geerdink RA, Struyvenberg A: Oral magnesium supplementation in insulin-requiring type 2 diabetic patients. Diabet Med 15:503–507, 1998
Dietary Supplement Health and Education Act of 1994 (DSHEA). Public Law 103-417
Dong J-Y, Xun P, He K, Qin L-Q: Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes Care 34:2116–2122, 2011
Eibl NL, Kopp HP, Nowak HR, Schnack CJ, Hopmeier PG, Schernthaner G: Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy. Diabetes Care 18:188–192, 1995
Elliott RB, Pilcher CC, Fergusson DM, Stewart AW: A population based strategy to prevent insulin-dependent diabetes using nicotinamide. J Pediatr Endocrinol Metab 9:501–509, 1996
Erlinger TP, Guallar E, Miller ER, Stolzenberg-Solomon R, Appel LJ: Relationship between systemic markers of inflammation and serum beta-carotene levels. Arch Intern Med 161:1903–1908, 2001
European Nicotinamide Diabetes Intervention Trial Group: European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomized controlled trial of intervention before the onset of diabetes. Lancet 363:925–931, 2004
Everson GJ, Shrader RE: Abnormal glucose tolerance in manganese deficient guinea pigs. J Nutr 94:89–94, 1968
Failla ML, Kiser RA: Hepatic and renal metabolism of copper and zinc in the diabetic rat. Am J Physiol 244:E115–E121, 1983
Food and Drug Administration: Food labeling: mandatory status of nutrition labeling and nutrient content, revision, format for nutrition label. Federal Register 58:2151, 1993a
Food and Drug Administration: Regulation of dietary supplements. Federal Register 58:33692, 1993b
Food and Nutrition Board, Institute of Medicine, National Academy of Sciences: Recommended Dietary Allowances. 10th ed. Washington, DC, National Academies Press, 1989
Ford ES, Ajani UA, McGuire LC, Liu S: Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 28:1228–1230, 2005
Fox GN, Sabovic Z: Chromium picolinate supplementation for diabetes mellitus. J Fam Pract 46:83–86, 1998
Franz MJ: 2002 Diabetes nutrition recommendations: grading the evidence. Diabetes Educ 28:756–766, 2002
Franz MJ: Micronutrients and diabetes. In American Diabetes Association Guide to Medical Nutrition Therapy for Diabetes. Franz MJ, Bantle JP, Eds. Alexandria, VA, American Diabetes Association, 1999, p. 165–191
Garg A, Grundy SM: Nicotinic acid as therapy for dyslipidemia in noninsulin-dependent diabetes. JAMA 264:723–726, 1990
Goldfine A, Simonson D, Folli F, Patti ME, Kahn R: Metabolic effects of sodium metavanadate in humans with insulin-dependent and non-insulin dependent diabetes mellitus in vivo and in vitro studies. J Clin Endocrinol Metab 80:3311–3320, 1995
Guerrero-Romero F, Rodriquez-Moran M: Complementary therapies for diabetes: the case for chromium, magnesium, and antioxidants. Arch Med Res 36:250–257, 2005
Guerrero-Romero F, Rodriguez-Moran M: Low serum magnesium levels and metabolic syndrome. Acta Diabetol 39:209–213, 2002
Guerrero-Romero F, Tamez-Perez HE, Gonzalez-Gonzalez G, Salinas-Martinez AM, Montes-Villarreal J, Trevino-Ortiz JH, Rodriguez-Moran M: Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance: a double-blind placebo-controlled randomized trial. Diabetes Metab 30:253–258, 2004
Gullestad L, Jacobsen T, Dolva LO: Effect of magnesium treatment on glycemic control and metabolic parameters in NIDDM patients. Diabetes Care 17:460–461, 1994
Halberstam M, Cohen N, Shlimovich P, Rossetti L, Shamoon H: Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not obese nondiabetic subjects. Diabetes 45:659–666, 1996
Hallbook T, Lanner E: Serum-zinc and healing of venous leg ulcers. Lancet 2:780–782, 1972
He K, Liu K, Daviglus ML, Morris SJ, Loria CM, Van Horn L, Jacobs DR, Savage PJ: Magnesium intake and incidence of metabolic syndrome among young adults. Circulation 113:1675–1682, 2006
Head KA: Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev 11:294–329, 2006
Horani MH, Haas MJ, Mooradian AD: Rapid adaptive down regulation of oxidative burst induced by high dextrose in human umbilical vein endothelial cells. Diabetes Res Clin Pract 66:7–12, 2004
Institute of Medicine Food and Nutrition Board: Dietary Reference Intakes for Calcium, Phosphorous, Magnesium, Vitamin D, and Fluoride. Washington, DC, National Academies Press, 2010
Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ: Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 104:284–288, 1996
Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K: Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 27:309–314, 1999
Jiang Q, Christen S, Shigenaga MK, Ames BN: Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 74:714–722, 2001
Kaats GR, Blum K, Fisher JA, Adelman JA: Effects of chromium picolinate supplementation on body composition: a randomized, double-masked, placebo-controlled study. Cur Ther Res 57:747–756, 1996
Kaplan WE, Abourizk NN: Diabetic peripheral neuropathies affecting the lower extremity. J Am Podiatry Assoc 71:356–362, 1981
Kinlaw WB, Levine AS, Morley HE, Silvis SE, McClain CJ: Abnormal zinc metabolism in type II diabetes mellitus. Am J Med 75:273–277, 1983
Kishi Y, Schmelzer JD, Yao JK, Zollman PJ, Nickander KK, Tritschler HJ, Low PA: Alpha-lipoic acid: effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy. Diabetes 48:2045–2051, 1999
Kleefstra N, Houweling ST, Jansman FG, Groenier KH, Gans RO, Meyboom-de Jong B, Bakker SJ, Bilo HJ: Chromium treatment has no effect in patients with poorly controlled, insulin-treated type 2 diabetes in an obese Western population: a randomized, double-blind, placebo-controlled trial. Diabetes Care 29:521–525, 2006
Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH: Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 22:280–287, 1999
Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL: AHA Science Advisory: Antioxidant vitamin supplements and cardiovascular disease. Circulation 110:637–641, 2004
Lanca S, Alves A, Vieira AL, Barata J, de Freitas J, de Carvalho A: Chromium-induced toxic hepatitis. 13:518–520, 2002
Lau AL, Failla ML: Urinary excretion of zinc, copper and iron in the streptozotocin-diabetic rat. J Nutr 114:224–233, 1984
Lee NA, Reasner CA: Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM. Diabetes Care 17:1449–1452, 1994
Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, Bosch J, Dagenais G, Mann JFE, Gerstein H, on behalf of the Health Outcomes Prevention (HOPE) Investigators: Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes. Diabetes Care 25:1919–1927, 2002
Martin J, Wang ZQ, Zhang XH, Wachtel D, Volaufova J, Matthews DE, Cefalu WT: Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care 29:1826–1832, 2006
Martin Mateo MC, Bustamante J, Gonzalez Cantalapiedra MA: Serum zinc, copper and insulin in diabetes mellitus. Biomedicine 29:56–58, 1978
Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, Felsenfeld A, Levine B, Mehrotra R, Norris K: Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 167:1159–1165, 2007
Mathieu C, Gysemans C, Giulietti A, Bouillon R: Vitamin D and diabetes. Diabetologia 48:1247–1257, 2005
McNair P, Christiansen C, Madsbad S, Lauritzen E, Faber O, Binder C, Transbol I: Hypomagnesemia, a risk factor in diabetic retinopathy. Diabetes 27:1075–1077, 1978
Mitri J, Muraru MD, Pittas AG: Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr 65:1005–1015, 2011
Molnar GD, Berge KG, Rosevear JW, McGuckin WF, Achor RP: The effect of nicotinic acid in diabetes mellitus. Metabolism 13:181–189, 1964
Montonen J, Knekt P, Jarvinen R, Reunanen A: Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care 27:362–366, 2004
Mooradian AD, Faila M, Hoogwerf B, Isaac R, Maryniuk M, Wylie-Rosett J: Selected vitamins and minerals in diabetes mellitus (Technical Review). Diabetes Care 17:464–479, 1994
Mooradian AD, Morley JE: Micronutrient status in diabetes mellitus. Am J Clin Nutr 45:877–895, 1987
Morris BW, Kemp GJ, Hardisty CA: Plasma chromium and chromium excretion in diabetes. Clin Chem 31:334–335, 1985
Murakami K, Okubo H, Sasaki S: Effect of dietary factors on incidence of type 2 diabetes: a systematic review of cohort studies. J Nutr Sci Vitaminol 51:292–310, 2005
Nagamatsu M, Nickander KK, Schmelzer JD, Rava A, Wittrock DA, Tritschler H, Low PA: Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 18:1160–1167, 1995
Niewoehner CB, Allen JI, Boosalis M, Levine AS, Morley JE: The role of zinc supplementation in type II diabetes mellitus. Am J Med 81:63–68, 1986
Nyomba BL, Auwerx J, Bormans V, Peeters TL, Pelemans W, Reynaert J, Bouillon R, Vantrappen G, De Moor P: Pancreatic secretion in man with subclinical vitamin D deficiency. Diabetologia 29:34–38, 1986
Omenn GS: Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health 19:73–99, 1998
Paolisso G, Barbagallo M: Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Am J Hypertens 10:346–355, 1997
Paolisso G, Scheen A, Cozzolino D, Di Maro G, Varricchio M, D’Onofrio F, Lefebvre PJ: Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients. J Clin Endocrinol Metab 78:1510–1514, 1994
Paolisso G, Scheen A, D’Onofrio E, Lefebvre P: Magnesium and glucose homeostasis. Diabetologia 33:511–514, 1990
Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, D’Onofrio F: Daily magnesium supplements improve glucose handling in elderly subjects. Am J Clin Nutr 55:1161–1167, 1992
Parekh D, Sarathi V, Shivane VK, Bandgar TR, Menon PS, Shah NS: Pilot study to evaluate the effect of short-term improvement in vitamin D status on glucose tolerance in patients with type 2 diabetes. Endocr Pract 16:600–608, 2010
Pittas AG, Lau J, Hu FB, Dawson-Hughes B: The role of vitamin D and calcium in type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029, 2007
Polo V, Saibene A, Pontiroli AE: Nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas. Acta Diabetol 35:61–64, 1998
Pozzilli P, Browne PD, Kolb H: Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM: the Nicotinamide Trialists. Diabetes Care 19:1357–1363, 1996
Pozzilli P, Visalli N, Cavallo MG, Signore A, Baroni MG, Buzzetti R, Fioriti E, Mesturino C, Fiori R, Romiti A, Giovannini C, Lucentini L, Matteoli MC, Crino A, Teodonio C, Paci F, Amoretti R, Pisano L, Suraci C, Multari G, Suppa M, Sulli N, De Mattia G, Faldetta MR: Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes. Eur J Endocrinol 137:234–239, 1997
Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, Boccuni ML, Fava D, Gragnoli C, Andreani D: Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 38:848–852, 1995
Qiao LY, Goldberg JL, Russell JC, Sun XJ: Identification of enhanced serine kinase activity in insulin resistance. J Biol Chem 274:10625–10632, 1999
Rabbani N, Alam SS, Riaz S, Larkin JR, Akhtar MW, Shafi T, Thornalley PJ: High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomized, double-blind placebo-controlled pilot study. Diabetologia 52:201–212, 2009
Rabinovitz H, Friedensohn A, Leibovitz A, Gabay G, Rocas C, Habot B: Effect of chromium supplementation on blood glucose and lipid levels in type 2 diabetes mellitus elderly patients. Int J Vitam Nutr Res 74:178–182, 2004
Rajpathak S, Rimm EB, Li T, Morris JS, Stampfer MJ, Willett WC, Hu FB: Lower toenail chromium in men with diabetes and cardiovascular disease compared with healthy men. Diabetes Care 27:2211–2216, 2004
Rao RH, Vigg BL, Jaya Rao KS: Failure of pyridoxine to improve glucose tolerance in diabetics. J Clin Endocrinol Metab 50:198–200, 1980
Ravina A, Slezak L, Mirsky N, Bryden NA, Anderson RA: Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium. Diabet Med 16:164–167, 1999
Reljanovic M, Reichel G, Rett K, Lobisch M, Shuette K, Moller W, Tritschler HJ, Mehnert H: Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II): Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res 31:171–179, 1999
Resnick LM: Hypertension and abnormal glucose homeostasis: possible role of divalent ion metabolism. Am J Med 87 (Suppl. 6A):17–22, 1989
Rodriguez-Moran M, Guerrero-Romero F: Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 26:1147–1152, 2003
Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schutte K, Nehrdich D, Tritschler HJ, Mehnert H, Ziegler D: Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 16:1040–1043, 1999
Saito N, Kimura M, Kuchiba A, Itokawa Y: Blood thiamine levels in outpatients with diabetes mellitus. J Nutr Sci Vitaminol 33:421–430, 1987
Scragg R: Vitamin D and type 2 diabetes: are we ready for a prevention trial? Diabetes 57:2565–2566, 2008
Scragg R, Sowers M, Bell C: Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 27:2813–2818, 2004
Shattock MJ, Hearse DJ, Fry CH: The ionic basis of the anti-ischemic and anti-arrhythmic properties of magnesium in the heart. J Am Coll Nutr 6:27–33, 1987
Sheikh-Ali M, Chehade JM, Mooradian AD: The antioxidant paradox in diabetes mellitus. Am J Ther 18:266–278, 2011
Shils ME, Olson JA, Shike M, Ross AC, Caballero B, Cousins RJ (Eds.): Modern Nutrition in Health and Disease. 10th ed. Philadelphia, PA, Lippincott, 2005
Simon JA, Hudes ES: Serum ascorbic acid and gallbladder disease prevalence among US adults. Arch Intern Med 160:931–936, 2000
Solomon LR, Cohen K: Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus. Diabetes 38:881–886, 1989
Song Y, Manson JE, Buring JE, Liu S: Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care 27:59–65, 2004
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 328:1444–1449, 1993
Takiishi T, Gysemans C, Bouillon R, Mathieu C: Vitamin D and diabetes. Endocrinol Metab Clin North Am 39:419–446, 2010
Thurman J, Mooradian AD: Vitamin supplementation therapy in the elderly. Drugs Aging 11:433–449, 1997
Truman RW, Doisy RJ: Metabolic effects of the glucose tolerance factor (GTF) in normal and genetically diabetic mice. Diabetes 26:820–826, 1977
Uusitupa MI, Kumpulainen JT, Voutilainen E, Hersio K, Sarlund H, Pyorala KP, Koivistoinen PE, Lehto JT: Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics. Am J Clin Nutr 38:404–410, 1983
Visalli N, Cavallo MG, Signore A, Baroni MG, Buzzetti R, Fioriti E, Mesturino C, Fiori R, Lucentini L, Matteoli MC, Crino A, Corbi S, Spera S, Teodonio C, Paci F, Amoretti R, Pisano L, Suraci C, Multari G, Sulli N, Cervoni M, De Mattia G, Faldetta MR, Boscherini B, Pozzilli P: A multi-centre randomized trial of two different doses of nicotinamide in patients with recent-onset type 1 diabetes (the IMDIAB VI). Diabetes Metab Res Rev 15:181–185, 1999
Volpe SL: Magnesium, the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus. Crit Rev Food Sci Nutr 48:293–300, 2008
Von Hurst PR, Sonehouse W, Coad J: Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient: a randomized, placebo-controlled trial. Br J Nutr 103:549–555, 2010
Walter RM, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL: Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care 14:1050–1056, 1991
Whelton PK, Klag MJ: Magnesium and blood pressure: review of the epidemiologic and clinical trial experience. Am J Cardiol 63:26G–30G, 1989
Wise A: Chromium supplementation and diabetes. JAMA 240:2045–2046, 1978
Yajnik CS, Smith RF, Hockaday TDR, Ward NI: Fasting plasma magnesium concentrations and glucose disposal in diabetes. Br Med J 288:1032–1034, 1984
Yates AA, Schlicker SA, Suitor CW: Dietary reference intakes: the new basis for recommendations for calcium and related nutrients, B vitamins, and choline. J Am Diet Assoc 98:699–706, 1998
Yeh GY, Eisenberg DM, Davis RB, Phillips RS: Use of complementary and alternative medicine among persons with diabetes mellitus: results of a national survey. Am J Public Health 92:1648–1652, 2002
Yochum LA, Folsom AR, Kushi LH: Intake of antioxidant vitamins and risk of death from stroke in postmenopausal women. Am J Clin Nutr 72:476–483, 2000
Yokota K, Kato M, Lister F, Li H, Hayakawa T, Kikuta T, Kageyama S, Tajima N: Clinical efficacy of magnesium supplementation in patients with type 2 diabetes. J Am Coll Nutr 23:506S–509S, 2004
Ziegler D, Hanefeld M, Ruhnau K, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month, multicenter, randomized, controlled trial (ALADIN III Study). Diabetes Care 22:1296–1301, 1999
Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA: Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid: a 3-week multicenter randomized controlled trial (ALADIN Study). Diabetologia 38:1425–1433, 1995
Ziegler D, Low PA, Litchy WJ, Boulton AJM, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schutte K, Dick PJ: Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 Trial. Diabetes Care 34:2054–2060, 2011
Ziegler D, Nowak H, Kempler P Vargha P, Low PA: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 21:114–121, 2004
Joshua J. Neumiller, PharmD, CDE, CGP, FASCP, is an Assistant Professor of Pharmacotherapy in the College of Pharmacy, Washington State University, and co-owner of Pharmacy Advocates, LLC, Spokane, WA.
