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.

Summary Points

  • 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.

Alpha-Lipoic Acid

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.

Chromium

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.

Magnesium

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.

Vitamin D

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.

Zinc

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

Conclusions

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.

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