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

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