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The Role of Micronutrients in Managing Diabetes

The Role of Micronutrients in Managing Diabetes

In Brief With the exceptions of for prevention of birth defects and for prevention of bone disease, currently there is no evidence of benefit from or supplementation in diabetic patients without underlying deficiencies. Given the recent revelations about antioxidant , it is prudent to refrain from using , , or in excess of the Dietary Reference Intakes.

The Role of in Managing

Although medical therapy MINERALS is a cornerstone of the management People with uncontrolled hypergly- Joe M. Chehade, MD, Mae Sheikh- of diabetes, several areas of uncer- cemia, especially those on chronic Ali, MD, and Arshag D. Mooradian, tainty in the dietary guidelines still diuretic therapy, are prone to develop 1 MD exist. The degree of uncertainty is deficiencies in some minerals, notably especially high in the area of assess- , , and .2,3 ing status and the role Deficiencies of certain minerals such of micronutrients in the pathogenesis as potassium, magnesium, and possi- of diabetes and its complications.2,3 bly zinc and may predispose Laboratory methods available for one to carbohydrate intolerance. measuring the status of most micro- The need for potassium or mag- are still unsatisfactory. nesium replacement is easily accepted In the early 1990s, the Food because the effects of overt potassium and Nutrition Board revised the or magnesium deficiency, especially Recommended Dietary Allowance on the cardiovascular system and (RDA) system, and a new set of nutri- skeletal muscles, are profound and ent reference values was born: Dietery readily detectable. The deficiency Reference Intakes (DRIs). There are state of potassium and magnesium is four types of DRIs: Estimated Average relatively easy to detect based on low Requirement (EAR), RDA, Adequate serum levels. The consequences of zinc Intake (AI), and Tolerable Upper and chromium deficiency are slow to Intake Level (UL). emerge, and the need for supplemen- tation is more difficult to ascertain.1–3 There has been considerable subjec- tivity in assigning DRI values for many Chromium micronutrients. In addition, the lack Several small studies have found that of evidence showing that antioxidant chromium supplementation improves vitamins result in any beneficial health intolerance, gestational dia- outcomes despite the overwhelming betes, and corticosteroid-induced evidence of increased oxidative load in diabetes.6–8 Two randomized, pla- diabetes has left health care providers cebo-controlled studies in Chinese with a significant degree of confusion subjects with diabetes have shown that about whether micronutrient supple- chromium supplementation has ben- mentation should be recommended for eficial effects on glycemic control.9,10 people with diabetes.4,5 Unfortunately, chromium status was This article reviews the status of evi- not evaluated in these studies at base- dence for select minerals and vitamins line or after supplementation. in diabetes care and the advantages Other well-designed studies have or disadvantages of supplementation failed to demonstrate any significant of the diet with micronutrients and benefit of chromium supplementation herbal extracts. in people with diabetes6 and have not 214 Diabetes Spectrum Volume 22, Number 4, 2009 shown any benefit in reducing body dations for adequate daily intake of may cause selenosis, affect- From Research to Practice / Diabetes and CAM Therapies weight.11 The earlier studies used are 200 IU for children and ing the , skin, nails, and hair.19 In chromium chloride preparation. More adults ≤ 50 years of age, 400 IU for addition, two recent studies examin- recent studies have used chromium adults 51–70 years of age, and 600 IU ing the relationship between serum picolinate, which has better bioavail- for adults ≥ 71 years of age. People liv- selenium levels and the prevalence of ability. The dose and formulations of ing in northern latitudes often require diabetes among U.S. adults found that chromium used are important variables higher amounts (at least 800 IU).15 high serum selenium levels were posi- in the outcomes of the clinical trials. (vitamin D3) is pre- tively associated with the prevalence of Given the current body of evidence, ferred for replacement because it has a diabetes,22 that selenium supplementa- chromium supplementation in any longer half-life,17 and its measurement tion did not prevent type 2 diabetes, formulation available cannot be rec- in serum levels is less likely to be fraught and that it may increase the risk for ommended as a tool for weight loss or with uncertainties. However, high-dose the disease.23 Thus, the indiscriminant diabetes management.12 formulations of cholecalciferol are not use of selenium supplements should be readily available, and therefore plant- discouraged until more randomized, Zinc derived (vitamin D2) is controlled trials examine their effects People with uncontrolled diabetes more commonly prescribed. on human health. have increased zinc losses in the urine. Serum 25-hydroxy vitamin D lev- Ordinarily, these losses are counter- els should be measured after 3 months VITAMINS balanced by enhanced zinc absorption of supplementation. If serum levels of in the gut.2,3 However, it is conceivable 25-hydroxy vitamin D are not nor- Vitamin A, Carotenoids, and that the latter compensatory mecha- malized at that time, then work up Retinoids nism may not be sufficient to prevent for , particularly gluten Vitamin A is essential for normal zinc deficiency in some people. enteropathy, should be considered. vision and for an effective function- Small studies in older subjects with ing of the immune system.2,3 Because diabetes have suggested some benefit Vanadium of its role in cell differentiation, it in healing skin ulcerations with zinc Vanadium has a significant effect on may have a role in the emergence and supplementation.2,3,13 Reliable labora- glucose . However, clinical propagation of neoplastic disease. tory techniques to measure zinc status studies have failed to show evidence of A number of carotenoids, especially are not clinically available, and clini- efficacy of vanadium in diabetes beta-carotenoids, are considered to be cal trials with zinc supplementation and have found that there is potential pro-vitamins because of their ability in diabetic subjects are very small and for toxicity.18 New organo-vanadium to convert to vitamin A in the liver. have yielded inconsistent results. A compounds with higher potency and Retinoids derive from natural vitamin recent observational study reported less toxicity are under investigation as A products and have some properties a significant inverse association of a potential treatment of diabetes.18 similar to carotenoids. dietary intakes and serum levels of There is no evidence that people zinc and selenium with gestational Selenium with diabetes are at risk of vitamin A diabetes.14 These observations merit Selenium is an important component deficiency, and therefore there is no additional confirmatory studies. of selenoproteins, which are implicated reason to recommend vitamin A in If one suspects zinc deficiency, in modulating oxidative stress and reg- amounts beyond the DRIs.2,3 Indeed, especially in high-risk patients such ulating hormone activity.19 In excess vitamin A consumption may as those with prolonged glycosuria five trials (four with high risk of bias), have deleterious effects on health. and diuretic therapy, one can consider selenium seemed to show significant These adverse effects include increased supplementation of zinc sulfate, 220 beneficial effect on gastrointestinal risk of liver fibrosis, increased inci- mg three times daily. This should be occurrence.20 dence of lung cancer (especially in initiated for no more than 3 months There are also some supportive smokers and in those exposed to because prolonged zinc supplemen- data to suggest that selenium may asbestos), increased risk of osteopo- tation may inhibit absorption prevent . However, rosis, and increased incidence of birth and adversely affect lipid profiles.2,3,13 a recent randomized, placebo-con- defects when vitamin A in excess of trolled trial in 35,533 men given 200 10,000 IU per day is taken before Calcium µg per day of L-selenomethionine or the seventh week of gestation.24–29 A Recent studies have shown that cal- matched placebo did not show any recent meta-analysis of the experimen- cium and vitamin D are not only favorable effect on the incidence of tal data suggested that beta-carotene required for skeletal health but also prostate cancer.21 In the same trial, in combination with vitamin A and may have a role in immune modula- 400 IU per day of vitamin E either vitamin E significantly increased mor- tion and pancreatic insulin secretion alone or in combination with selenium tality.20 Increased yellowing of the skin and action.15,16 The recommended also did not prevent prostate cancer.21 and belching were nonserious adverse daily intake varies according to age of The potential cancer-preventive effect effects of excess beta-carotene.20 the subject and, in females, the meno- of selenium should be tested in ade- pausal state. At the present time, there quately conducted randomized trials. Select is no reason to recommend higher cal- Selenium deficiency may occur in Folate and folic acid are forms of a cium and vitamin D intake for people geographical areas where the agricul- water-soluble B vitamin designated as with diabetes compared to an age- tural soil is depleted of selenium. In vitamin B9. Folate occurs naturally matched cohort of nondiabetic people. these populations, selenium prevention in food, and folic acid is the synthetic The Institute of Medicine recommen- should be pursued. However, excess form of this vitamin. Diabetes Spectrum Volume 22, Number 4, 2009 215 Deficiency results in a macro- convulsants that are known to increase Vitamin E () cytic and elevated levels of folate catabolism.2,3 Vitamin E is also a potent antioxidant. . Plasma homocysteine The role of vitamins B1, B6, and In experimental studies, vitamin E concentration in type 2 diabetes cor- B12 in the treatment of diabetic neu- supplementation in excess of DRIs was relates with age, creatinine, folate, ropathy has not been established and capable of reducing LDL oxidation and but not with diabe- cannot be recommended as a standard and stabilized platelet membranes.3 tes-related variables such as duration, or routine therapeutic option.1–3 Observational studies have suggested current degree of control, or presence Vitamin B3 is made up of that vitamin E supplements may con- 30 of complications. Folic acid might (nicotinic acid) and its amide. In a fer cardioprotective effects.5 However, also have favorable effects on cogni- study of newly diagnosed subjects interventional trials including those 13 tion in older adults. The realization with type 1 diabetes,35 that have enrolled a large number of that folate has a pivotal role in pre- 41 was found to preserve β-cell mass. people with diabetes have not sup- venting birth defects has prompted However, the number of subjects ported the use of vitamin E to reduce folate fortification of and grain 5 enrolled in this study was small, and cardiovascular risk. A recent meta- products in the United States.1 the clinical utility of nicotinamide in analysis of the experimental data has Because of the association between suggested that vitamin E supplements this population is not established. elevated serum homocysteine levels may actually increase mortality.40 and cardiovascular disease (CVD), Vitamin C (Ascorbic Acid) People with diabetes generally there has been increasing interest in Ascorbic acid has potent antioxidant do not have vitamin E deficiency. folate supplementation to lower homo- activity. However, under certain Indeed, the plasma and platelet con- cysteine. However, interventional experimental conditions, it can also be tent of vitamin E may be increased in trials with folate and and 2,3 a pro-oxidant.4 Although the evidence diabetes. Although consumption in B12 supplementation have failed to is not conclusive, people with diabe- the range of 1,000 IU of vitamin E is prevent cardiovascular events despite considered relatively safe, there has 31,32 tes may have depleted tissue stores of lowering homocysteine levels. In a been some concern associated with vitamin C. The tissue uptake of dehy- study of 5,442 women who were U.S. this practice.40 Progression of retinitis health professionals > 42 years of age droascorbate can be prevented by high 36 pigmentosa and increased incidence of with either a history of CVD or three ambient glucose levels. hemorrhagic have been linked or more coronary risk factors, daily The rationale for use of vitamin C to excessive consumption of vitamin intake of a combination pill of 2.5 mg in the diabetic population is based on E.40 Consumption in excess of DRIs of folic acid, 50 mg of vitamin B6, and its potential effects on reducing athero- is not recommended. If an individual 1 mg of vitamin B12 did not reduce sclerotic plaque formation, preventing chooses to use supplements, the dose cardiovascular events after microangiopathy, improving vascular should be limited to < 400 IU/day. 7.3 years of treatment and follow- integrity, and aiding in wound heal- up despite significant homocysteine ing.2,3,13 However, supplementation OTHER MICRONUTRIENTS lowering.31 Similarly, combined folic with vitamin C in interventional tri- acid, vitamin B6, and vitamin B12 als has not reduced the risk of cancer Herbal Preparations treatment had no significant effect on or cardiovascular disease.37–40 In the Some herbal preparations have been overall risk of total invasive cancer or Women’s Antioxidant Cardiovascular shown to have modest short-term 42 breast cancer among women.33 Study, supplementation with vitamin beneficial effects on glycemia. Well- The combination of folic acid, C (500 mg of ascorbic acid daily), vita- designed, randomized, controlled hydrochloride, and min E (600 IU of alpha- trials in small numbers of subjects may have pro- have shown some benefits of Coccinia every other day), or beta-carotene (50 42 tective effects against age-related mg every other day) offered no benefits indica and American . Other supplements that may have favorable macular degeneration (AMD). In the in the primary prevention of total can- effects on glycemic control include Women’s Antioxidant and Folic Acid cer incidence or cancer mortality.37 Gymnema sylvestre, Aloe vera, Cardiovascular Study, participants Consumption of vitamin C in were randomly assigned to receive a Momordica charantia, and Nopal.42 amounts > 1 g/day can cause some combination of folic acid (2.5 mg/day), Some may have favorable effects on abdominal bloating and osmotic pyridoxine hydrochloride (50 mg/day), body weight. However, in a review of diarrhea.13 There is no reason to rec- and cyanocobalamin (1 mg/day) or the available literature, the evidence for placebo. A total of 5,205 of these ommend vitamin C intake in excess any role of herbal products in reducing women did not have a diagnosis of of the DRIs. Smokers must consume body weight was not convincing, and AMD at baseline and were included larger amounts of ascorbic acid to the authors concluded that none of the in this analysis. The results indicated reach comparable plasma levels of supplements reviewed can be recom- that daily supplementation with folic nonsmokers, most likely because of mended for over-the-counter use.43 acid, pyridoxine, and cyanocobalamin an increased turnover.3 People with Commercially available prod- may reduce the risk of AMD.34 diabetes can achieve adequate intake ucts vary in their active ingredients. There are no health concerns with of vitamin C through consumption of In addition, some preparations have folate supplementation except for five daily servings of fruits and vegeta- been found to surreptitiously include aggravating bles. In individuals who are incapable pharmaceutical agents that cause and occasionally causing seizures in of getting sufficient amounts from hypoglycemia. Herbal preparations people with epilepsy and marginal dietary sources, supplementation of also have the potential to interact folate status who are receiving anti- ascorbic acid is reasonable.2,3,13 with other medications. Therefore, it 216 Diabetes Spectrum Volume 22, Number 4, 2009 is important for health care providers benefit on decreasing the incidence of of the DRIs. Tables listing the DRIs From Research to Practice / Diabetes and CAM Therapies to be aware when their patients with major cardiovascular events.47 In con- have been published and are available diabetes are using these products. trast, vitamin E was associated with an online.49 increased risk of hemorrhagic .47 One of the major differences Alpha- In addition, neither vitamin E nor vita- between the recent DRI reports and Alpha-lipoic acid (LA) is a naturally min C supplementation reduced the the previous RDAs is the creation of a occurring dithiol micronutrient with risk of prostate or total cancer.40 In UL. The UL is different from excessive potent antioxidant properties.44 LA the Women’s Health Study,48 vitamin intake and toxicities. Intake levels at scavenges free radicals, chelates transi- E supplements (600 mg every other the upper UL should be interpreted tion metal ions, and increases cytosolic day) did not protect healthy women as a “warning flag” but not as toxic glutathione and vitamin C levels. It against heart attacks, strokes, or can- levels. ULs could not be established has an essential role as a for cer. A meta-analysis of 68 randomized for , thiamin, , mitochondrial bioenergetic . trials with 232,606 participants con- vitamin B12, , bio- The potential beneficial effects cluded that treatment with vitamin tin, or carotenoids. In the absence of of LA on both prevention and treat- A, vitamin E, and beta-carotene may ULs, extra caution may be warranted ment of diabetes have been shown in well increase mortality.40 On the other in consuming levels above RDA or AI multiple studies. LA has been proven hand, the possible effects of vitamin recommendations. to have a role in preventing β-cell C and selenium on mortality require 40 destruction and enhancing insulin additional study. References sensitivity. Unfortunately, the improve- The discrepancy among the 1 ment in insulin sensitivity after oral results of interventional trials with Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeister LA, administration of LA is < 20% of the antioxidant vitamins and the known Hoogwerf B, Mayer-Davis E, Mooradian improvement seen after intravenous increased oxidative load and its con- AD, Purnell JQ, Wheeler M: Evidence-based administration.44 This limits the clini- sequences in diabetes are unexpected nutrition principles and recommendations cal utility of this compound. and cannot be readily explained at the for the treatment and prevention of diabetes The antioxidant effects of LA and related complications. Diabetes Care present time. 25:148–198, 2002 may also be helpful in slowing the development of diabetic neuropa- CONCLUSIONS AND 2Mooradian AD, Failla M, Hoogwerf B, 44 Maryniuk M, Wylie-Rosett J: Selected vita- thy. Although the role of long-term RECOMMENDATIONS mins and minerals in diabetes. Diabetes Care supplementation is less clear, there is People with poorly controlled diabetes 17:464–479, 1994 evidence to suggest that oral LA at a are susceptible to multiple micronu- 3 1–4 Mooradian AD: Micronutrients in diabe- dose of 600–1,800 mg/daily may be trient deficiencies. Some of these tes mellitus. In Drugs, Diet, and Disease. beneficial in the treatment of diabetic micronutrients have potent antioxi- Vol. 2. Ioannides C, Flatt PR, Eds. Hemel peripheral neuropathy and cardiovas- dant activity. It is not known whether Hempstead, U.K., Ellis Horwood, 1999, p. cular autonomic neuropathy.44 the ingestion of antioxidant vitamins 183–200. could delay or perhaps reverse the oxi- 4Mooradian AD: Antioxidants and diabetes. MICRONUTRIENTS AS dative damage. Nestle Nutr Workshop Ser Clin Perform ANTIOXIDANTS People with diabetes should be Programme 11:107–122, 2006 Several micronutrients have potent educated about the importance of 5Hasanain B, Mooradian AD: Antioxidant antioxidant properties. These include vitamins and their influence in diabetes mel- acquiring daily vitamin and min- litus. Curr Diabetes Rep 2:448–456, 2002 carotenoids, vitamins E and C, sele- eral requirements from natural food 6 nium, and some of the B vitamins, sources. In select groups such as the Cefalu WT, Hu FB: Role of chromium in human health and in diabetes. Diabetes Care notably folate, pyridoxine, and elderly, pregnant or lactating women, 27:2741–2751, 2004 cyanocobalamin. strict vegetarians, or those on calorie- 7Ryan GJ, Wanko NS, Redman AR, Cook Diabetes, especially when poorly restricted diets, supplementation with CB: Chromium as adjunctive treatment controlled, is associated with increased a preparation is advis- for type 2 diabetes. Ann Pharmacother accumulation of oxidative end prod- able.1 However, vitamin and mineral 37:876–885, 2003 45,46 ucts. The increased oxidative stress supplementation in pharmacological 8Althuis MD, Jordan NE, Ludington EA, in diabetes is the result of excess glyce- doses should be viewed as thera- Wittes JT: Glucose and insulin responses to mia and depletion of the antioxidant peutic intervention and, just as with dietary chromium supplements: a meta-analy- defense system.4 Because increased medications, should be subjected to sis. Am J Clin Nutr 76:148–155, 2002 oxidative stress has been implicated placebo-controlled trials to demon- 9Cheng N, Zhu X, Shi H, Wu W, Chi J, in the increased risk of cardiovascu- strate safety and efficacy. Cheng J, Anderson RA: Follow-up survey of people in China with type 2 diabetes mellitus lar disease and cancer, the association At the present time, there is no consuming supplemental chromium. J Trace between consumption of antioxidant evidence of benefit from vitamin or Elements Exp Res 12:55–60, 1999 vitamins and minerals and reduced mineral supplementation in people 10Anderson RA, Cheng N, Bryden NA, CVD risk is understandable. However, with diabetes who do not have under- Polansky MM, Cheng N, Chi J, Feng J: measurements of individual antioxi- lying deficiencies. Exceptions include Elevated intakes of supplemental chromium dant vitamins have not consistently folate for prevention of birth defects improve glucose and insulin variables in individuals with type 2 diabetes. 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Cappuccio, FP, Ceriello A, Reid ME: Effects 35Visalli N, Cavallo MG, Signore A, Baroni JAMA 300:2123–2133, 2008 of long-term selenium supplementation on the MG, Buzzetti R, Fioriti E, Mesturino C, 48Lee IM, Cook NR, Gaziano JM, Gordon incidence of type 2 diabetes: a randomized Fiori R, Lucentini L, Matteoli MC, Crinò D, Ridker PM, Manson JE, Hennekens CH, trial. Ann Intern Med 147:217–223, 2007 A, Corbi S, Spera S, Teodonio C, Paci F, Buring JE: Vitamin E in the primary preven- Amoretti R, Pisano L, Suraci C, Multari G, 24Lee IM, Cook NR, Manson JE, Buring tion of cardiovascular disease and cancer: Sulli N, Cervoni M, De Mattia G, Faldetta JE, Hennekens CH: Beta-carotene supple- the Women’s Health Study: a randomized MR, Boscherini B, Pozzilli P. A multi-centre mentation and incidence of cancer and controlled trial. JAMA 294:56–65, 2005 randomized trial of two different doses of cardiovascular disease: the Women’s Health nicotinamide in patients with recent-onset 49Institute of Medicine Food and Nutrition Study. J Natl Cancer Inst 91:2102–2106, 1999 type 1 diabetes (the IMDIAB VI). Diabetes Board: DRI tables. Available online from 25Hennekens CH, Buring JE, Manson JE, Metab Res Rev 15:181–185, 1999 http://fnic.nal.usda.gov/nal_display/index. Stampfer M, Rosner B, Cook NR, Belanger php?info_center=4&tax_level=3&tax_ 36Mooradian AD: Effect of ascorbate and C, LaMotte F, Gaziano JM, Ridker PM, subject=256&topic_id=1342&level3_ dehydroascorbate on tissue uptake of glucose. Willett W, Peto R: Lack of effect of long- id=5140 Diabetes 36:1001–1004, 1987 term supplementation with beta carotene on the incidence of malignant eoplasms 37Lin J, Cook NR, Albert C, Zaharris E, and cardiovascular disease. N Engl J Med Gaziano JM, Van Denburgh M, Buring JE, Joe M. Chehade, MD, is Associate 334:1145–1149, 1996 Manson JE: Vitamins C and E and beta Professor, Mae Sheikh-Ali, MD, is carotene supplementation and cancer risk: a 26Omenn GS, Goodman GE, Thornquist randomized controlled trial. J Natl Cancer Assistant Professor, and Arshag D. MD, Balmes J, Cullen MR, Glass A, Keogh Inst 101:14–23, 2009 Mooradian, MD, is Professor in the JP, Meyskens FL Jr, Valanis B, Williams JH Jr, Barnhart S, Cherniack MG, Brodkin CA, 38Cook NR, Albert CM, Gaziano JM, Department of Medicine, University Hammar S. Risk factors for lung cancer and Zaharris E, MacFadyen J, Danielson E, of Florida College of Medicine in for intervention effects in CARET: the Beta Buring JE, Manson JE: A randomized Jacksonville, Fla. 218 Diabetes Spectrum Volume 22, Number 4, 2009

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