By William C. Haas III, MD, MBA
Integrative Medicine Fellow, Department of Family and Community Medicine, University of Arizona, Tucson
Dr. Haas reports no financial relationships relevant to this field of study.
- Type 2 diabetes is associated with a number of micronutrient deficiencies.
- Zinc is supported with the best evidence for improving glycemic control among type 2 diabetics.
- Recommendations for micronutrient supplementation among diabetics is largely limited by a paucity of high-quality studies.
Type 2 diabetes mellitus (T2DM), characterized by peripheral insulin resistance and pancreatic ß-cell dysfunction, represents a worldwide public health concern, as more than 400 million people are expected to be affected by the year 2030.1 Despite advances in the treatment for T2DM (long-acting insulins, GLP-1 agonists, DPP-4 inhibitors, etc.), achieving optimal glycemic control remains a challenge, partly as a result of non-adherence to complex medication regimens. Now more than ever, uncovering new insights for the prevention and management of T2DM is essential for improving outcomes and providing patient-centered care.
Regardless of whether medical providers are aware, diabetic patients frequently experiment with integrative modalities. In fact, according to one study, patients with T2DM are 1.6 times more likely to try complementary and alternative therapies as compared to non-diabetics.2 Moreover, among the various modalities reported, botanical remedies and micronutrient supplements consistently rank at the top of several surveys.3,4
Part one of this two-part review will focus on the role of micronutrients in the prevention and management of T2DM. Micronutrients, including vitamins and minerals, are required for many functions in the body, including glucose metabolism, insulin activity, and prevention of tissue oxidation.5 Unfortunately, chronic hyperglycemia has been shown to reduce the levels of various micronutrients in the body,6 which further disturbs glucose regulation and potentially worsens diabetic complications.7 Over the past few decades, researchers have examined the effects of supplementing these micronutrient deficiencies, and some of the most commonly encountered supplements in clinical practice are reviewed below.
A potent lipophilic antioxidant, alpha-lipoic acid (ALA) is a naturally occurring compound found in trace amounts in organ meats and vegetables. Unlike the other supplements reviewed, ALA is used primarily for the treatment of painful diabetic neuropathy. Its mechanism for improving neuropathic pain may be related to an improvement of nerve blood flow as well as a reduction in oxidative stress.8
ALA has been extensively studied in both intravenous (IV) and oral forms. Initial investigations, including the original ALADIN (Alpha-Lipoic Acid in Diabetic Neuropathy) and SYDNEY (Symptomatic Diabetic Neuropathy Trial) trials, focused on treating diabetic neuropathy with IV ALA. Both studies found that 600 mg of IV ALA daily significantly improved symptom severity as compared with placebo when used for periods of 2-3 weeks.9,10 These studies prompted additional investigations focusing on the use of oral ALA. The SYNDEY 2 trial compared three different doses of oral ALA (600 mg, 1200 mg, and 1800 mg daily) against placebo. After 5 weeks, all three doses outperformed placebo with near equal improvements in total symptom scores across the different doses.11 Unlike the SYDNEY 2 trial, the ALADIN 3 trial did not find a statistically significant difference between placebo and 1800 mg of oral ALA daily, although the results trended toward improvement.12 Recently, results of a 4-year, multicenter, randomized, double-blind trial of 600 mg of oral ALA daily found clinically meaningful improvements in neuropathy and a prevention in the progression of neuropathic impairments.13
Overall, studies support both IV and oral ALA for the treatment of diabetic neuropathy. Oral ALA is clearly the easiest and most accessible form for patients to use, with 600 mg per day being the ideal dose when balancing cost and potential side effects. At doses > 1200 mg daily, patients have been noted to experience nausea, vomiting, and/or vertigo. The most commonly reported adverse events include heart rate and rhythm abnormalities.13 The cost for a 1-month supply at 600 mg daily ranges between $25-40. Of note, the R isomer of ALA may be more effectively utilized in the body compared to other formulations and should be considered when making recommendations to patients. Additionally, patients should be advised not to confuse this supplement with alpha-linolenic acid, which is also abbreviated as ALA.
Originally discovered in brewer’s yeast, chromium is a trace element commonly found in its trivalent form. It is believed to be necessary for both glucose and lipid metabolism.14,15 Severe chromium deficiency has been reported to cause reversible insulin resistance and diabetes.16 Through its action with glucose tolerance factor, chromium increases insulin receptors, improves insulin binding, and enhances beta cell sensitivity.17
Chromium is a widely marketed and commonly purchased supplement for improving glycemic control,18 yet the evidence is split at best. One of the initial studies on chromium yielded an impressive 1.0% hemoglobin A1c lowering effect after supplementing diabetics with 200 mg of chromium picolinate daily for 4 months.19 Ten years later, a meta-analysis, which included 14 randomized, controlled trials, reported that chromium significantly improved hemoglobin A1c levels (-0.6%; 95% confidence interval [CI], -0.9% to -0.2%) among type 2 diabetics.20 Unfortunately, a closer look of this meta-analysis revealed that the positive effect was driven primarily by the aforementioned study, which has been criticized for its poor methodological quality, including inadequate blinding as well as concerns for detection and selection bias.21 Further clouding the picture, other more recent meta-analyses reached different conclusions regarding chromium’s positive effect on glycemic control.22,23
Despite the mixed evidence for chromium in the management of T2DM, the majority of researchers agree that the existing evidence is low in quality. The conservative recommendation would be to dissuade diabetic patients from spending money on this supplement at this time. Patients who insist on using chromium should be advised to avoid doses > 1200 mcg/day, given reports of renal failure.24,25 Other more common side effects include abdominal discomfort and bloating.
Despite being the fourth most abundant mineral in the body, magnesium is frequently consumed in inadequate amounts.26 Unfortunately, inadequate dietary intake of magnesium has been linked to various disease states, including diabetes mellitus.27 Research further suggests that hypomagnesemia among diabetics may contribute to worse glycemic control as well as an increase in retinopathy, nephropathy, and foot ulcers when compared to those with normal magnesium levels.28
With regards to supplementation, evidence suggests that higher intakes of magnesium may decrease the risk of T2DM, but improvements in glycemic control are not validated. In a 15-year prospective cohort study involving nearly 2000 patients, increased magnesium intake was noted to be a significant protective factor against the development of T2DM.29 These findings were further supported by another meta-analysis of 13 prospective studies, and the association was not modified by geographic region, follow-up length, or gender.30 Shifting focus to glycemic control, a meta-analysis of nine randomized, double-blind, controlled trials found that although magnesium supplementation potentially lowered fasting glucose levels, no significant decrease in hemoglobin A1c levels were seen.31 Another meta-analysis of seven cohort studies concluded that magnesium supplementation for the reduction of glucose levels is inconsistent.32
Ultimately, adequate magnesium intake is likely a protective factor against the development of T2DM; however, current evidence does not support supplementation for the treatment of diabetes. The most prudent recommendation for patients with limited resources would be to skip magnesium supplements all together and consume a variety of magnesium-containing foods (leafy green vegetables, nuts, fish, chocolate) given their overall health benefits. For patients desiring to supplement beyond food sources, dosing typically starts at 100 mg daily, working up toward 300-600 mg daily, keeping in mind that higher doses may cause diarrhea.
Best known for its role in calcium metabolism and bone growth, vitamin D is a fat-soluble vitamin that acts as a hormone at various sites in the body.33 In fact, several studies over the past decade have reported associations between vitamin D deficiency and many extra-skeletal diseases, including T2DM.34,35 With regard to glucose homeostasis, vitamin D is believed to regulate insulin receptor expression as well as stimulate insulin release from pancreatic B-cells.36,37
Despite the striking prevalence of vitamin D deficiency among type 2 diabetics, evidence does not support supplementation at this time.38 Several randomized, controlled trials and meta-analyses have shown that neither short-term nor long-term vitamin D supplementation improves glycemic control.39,40,41,42 Unfortunately, this lack of efficacy leaves clinicians stuck when facing evidence that vitamin D deficiency increases both all-cause and cardiovascular mortality among type 2 diabetics.43 Fortunately, one meta-analysis has found that taking 500 IU of vitamin D per day decreased the risk of developing diabetes by 13% when compared to intake below 200 IU/day.44
Recommendations for vitamin D supplementation among type 2 diabetics could eventually change as several variables remain unknown (optimal dosing, duration of therapy, etc). However, until clarity develops, diabetics should not routinely supplement with vitamin D for the expressed purpose of improving glycemic control. For those patients with other indications, supplementation should include 800-1000 IU daily, and target a serum 25-hydroxyvitamin D level between 30-50 ng/mL. Keep in mind that although vitamin D is largely considered safe, prolonged high-dose supplementation (50,000 IU/day), in rare circumstances, can lead to hypercalcemia.
An essential mineral in the human body, zinc is responsible for numerous enzymatic and cellular processes in addition to functioning as an antioxidant and anti-inflammatory agent.45,46,47 With regards to glucose metabolism, research has demonstrated that zinc plays an important role in the synthesis, storage, and release of insulin.48,49,50 Zinc deficiency is relatively common among diabetic patients, and evidence supports both a cause and effect association — deficiency increases diabetes risk and diabetes impairs zinc metabolism.51,52,53
The research on zinc supplementation among diabetics has focused primarily on glucose control, with an isolated study evaluating diabetic peripheral neuropathy. With regard to glucose control, two separate meta-analyses found that zinc supplementation decreased hemoglobin A1c by approximately 0.6%.54,55 Although several of the studies analyzed included zinc in combination with other vitamins and minerals, a secondary analysis of zinc therapy alone demonstrated similar beneficial effects on glycemic control.55 Naturally, the question of prevention arose, given the reported zinc deficiency among many diabetics; however, a Cochrane review in 2015 concluded that the current evidence does not support zinc supplementation for the prevention of T2DM.56 Finally, when looking at diabetic complications, specifically peripheral neuropathy, supplementation with 660 mg of zinc sulfate daily for 6 weeks improved motor nerve conduction velocities compared to placebo in a small, randomized, double-blind trial.57 Unfortunately, follow-up studies on zinc for diabetic neuropathy have been limited.
Ultimately, zinc may be a reasonable supplement to consider for improving glycemic control in type 2 diabetics, keeping in mind that this recommendation is largely based on two meta-analyses with a great deal of heterogeneity. The dose and formulation most commonly tested for glycemic control was 30 mg of zinc sulfate per day. Zinc is generally well-tolerated, aside from reports of nausea, vomiting, and metallic taste. Of note, several cases of copper deficiency have been associated with high-dose zinc supplementation.58
Mounting evidence confirms that type 2 diabetics are deficient in several vitamins and minerals; however, the manner in which these deficiencies influence the progression of type 2 diabetes is not always clear. Given the growing interest of micronutrient supplements among patients with T2DM, researchers have expanded their study in the field. The current evidence most strongly supports the use of zinc for improving glycemic control with positive but mixed evidence for chromium. Magnesium may be best suited for preventing T2DM, but as with vitamin D, it probably does not play a role in the active management of diabetes. With this said, there is always a role for finding these nutrients, when possible, in food sources as part of an overall healthy diet. Finally, ALA offers promise to patients suffering from peripheral neuropathy. Despite these general conclusions, clinicians should bear in mind that the overall quality of existing evidence remains limited due to a significant amount of heterogeneity among the patient populations and supplements studied. As diabetic patients continue to seek out additional treatment options, it will remain important to monitor the evolving research.
- Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care 2011;34:1249-1257.
- Garrow D, Egede LE. Association between complementary and alternative medicine use, preventive care practices, and use of conventional medical services among adults with diabetes. Diabetes Care 2006;29:15-19.
- Egede LE, et al. The prevalence and pattern of complementary and alternative medicine use in individuals with diabetes. Diabetes Care 2002;25:324-329
- Yeh GY, et al. Complementary and alternative medicine use among patients with diabetes mellitus: Results of a national survey. Am J Pub Health 2002;92:1648-1652.
- O’Connell BS. Select vitamins and minerals in the management of diabetes. Diabetes Spectrum 2001;14:133-148
- Mooradian AD, et al. Selected vitamins and minerals in diabetes. Diabetes Care 1994;17:464-479.
- Vincent AM, et al. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004;25:612-628.
- Papanas N, Zeigler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother 2014;15:2721-2731.
- Ziegler D, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38:1425-1433.
- Ametov AS, et al. SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: The SYDNEY trial. Diabetes Care 2003;26:770-776.
- Ziegler D, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial. Diabetes Care 2006;29:2365-2370.
- Ziegler D, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care 1999;22:1296-1301.
- Zeigler D, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 trial. Diabetes Care 2011;34:2054-2060.
- Schwarz K, Mertz W. Chromium(III) and the glucose tolerance factor. Arch Biochem Biophys 1959;85:292-295.
- Cefalu WT, Hu FB. Role of chromium in human health and in diabetes. Diabetes Care 2004;27:2741-2751.
- Freund H, Atamian S, Fischer JE. Chromium deficiency during total parenteral nutrition. JAMA 1979;241:496-498.
- Vincent JB. The biochemistry of chromium. J Nutr 2000;130:715-718.
- Nutrition Business Journal. NBJ’s Supplement Business Report 2003. San Diego, CA: Penton Media Inc; 2003.
- Anderson RA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 1997;46:1786-1791.
- Balk EM, et al. Effect of chromium supplementation on glucose metabolism and lipids: A systematic review of randomized controlled trials. Diabetes Care 2007;30:2154-2163.
- Landman G, et al. Chromium does not belong in the diabetes treatment arsenal: Current evidence and future perspectives. World J Diabetes 2014;15:160-164.
- Siksomboon N, et al. Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes. J Clin Pharm Ther 2014;39:292-306.
- Bailey CH. Improved meta-analytic methods show no effect of chromium supplementation on fasting glucose. Bill Trace Elem Res 2014;157:1-8.
- Wasser WG, et al. Chronic renal failure after ingestion of over-the-counter chromium picolinate. Ann Intern Med 1997;126:410.
- Ceruli J, et al. Chromium picolinate toxicity. Ann Pharmacother 1998;32:428-431.
- Ford ES, Mokdad AH. Dietary magnesium intake in a national sample of U.S. adults. J Nutr 2003;133:2879-2882.
- Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys 2007;458:40-47.
- Dasgupta A, et al. Hypomagnesemia in type 2 diabetes mellitus. Indian J Endocrinol Metab 2012;16:1000-1003.
- Hata A, et al. Magnesium intake decreases type 2 diabetes risk through the improvement of insulin resistance and inflammation: The Hisayama Study. Diabet Med 2013;30:1487-1494.
- Dong J, et al. Magnesium intake and risk of type 2 diabetes: Meta-analysis of prospective cohort studies. Diabetes Care 2011;34:2116-2122.
- Song Y, et al. Effects of oral magnesium supplementation on gylcaemic control in Type 2 diabetes: A meta-analysis of randomized double-blind controlled trials. Diabet Med 2006;23:1050-1056.
- Guerrero-Romero F, Rodriquez-Moran M. Oral magnesium supplementation: An adjuvant alternative to facing the worldwide challenge of type 2 diabetes? Cir Cir 2014;82:282-289.
- Allgrove J. Physiology of calcium, phosphate, magnesium and vitamin D. Endocr Dev 2015;28:7-32.
- Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009;94:26-34.
- Holick M. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
- Maestro B, et al. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 2000;47:383-391.
- Borissova AM, et al. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 2003;57:258-261.
- Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81:353-373.
- Al-Sofiani M, et al. Effect of vitamin D supplementation on glucose control and inflammatory response in type II diabetes: A double blind, randomized clinical trial. Int J Endocrinol Metab 2015;13:e22604.
- Krul-Poel U, et al. Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes (SUNNY Trial): A randomized placebo-controlled trial. Diabetes Care 2015;38:1420-1426.
- George PS, et al. Effect of vitamin D supplementation on glycaemic control and insulin resistance: A systematic review and meta-analysis. Diabet Med 2012;29:e142-150.
- Haroon N, et al. Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes: A systematic review of interventional studies. J Diabetes Metab Disord 2015;14:3.
- Joergensen C, et al. Vitamin D levels and mortality in type 2 diabetes. Diabetes Care 2010;33:2238-2243.
- Mitri J, et al. Vitamin D and type 2 diabetes: A systematic review. Eur J Clin Nutr 2011;65:1005-1015.
- Maret W. Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr 2103;4: 82-91.
- Cruz KJ, et al. Antioxidant role of zinc in diabetes mellitus. World J Diabetes 2015;6:333-337.
- Bonaventura P, et al. Zinc and its role in immunity and inflammation. Autoimmun Rev 2015;14:277-285.
- Chimienti F. Zinc, pancreatic islet cell function and diabetes: New insights into an old story. Nutr Res Rev 2013;26:1-11.
- Rossetti L, et al. Insulinomimetic properties of trace elements and characterization of their in vivo mode of action. Diabetes 1990;39:1243-1250.
- Huang L. Zinc and its transporters, pancreatic ß-cells, and insulin metabolism. Vitam Horm 2014;95:365-390.
- Chen H, Tan C. Prediction of type-2 diabetes based on several element levels in blood and chemometrics. Biol Trace Elem Res 2012;147:67-74.
- Garg VK, et al. Hypozincemia in diabetes mellitus. J Assoc Physicians India 1994;42:720-721.
- Saharia GK, Goswami RK. Evaluation of serum zinc status and glycated hemoglobin of type 2 diabetes mellitus patients in a tertiary care hospital of assam. J Lab Physicians 2013;5:30-33.
- Capdor J, et al. Zinc and glycemic control: A meta-analysis of randomized placebo controlled supplementation trials in humans. J Trace Elem Med Biol 2013;27:137-142.
- Jayawardena R, et al. Effects of zinc supplementation on diabetess mellitus: A systematic review and meta-analysis. Diabetol Metab Syndr 2012;4:13.
- El Dib R, et al. Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. Cochrane Database Syst Rev 2015;5:CD005525.
- Gupta R, et al. Oral zinc therapy in diabetic neuropathy. J Assoc Physicians India 1998;46:939-942.
- Willis MS, et al. Zinc-induced copper deficiency: A report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005;123:125-131.