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

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