American Diabetes Association Guide to Nutrition Therapy for Diabetes. Marion J. Franz

      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.

SUMMARY

      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