Selenium and glucose metabolism

Recently, I did a search of the Medline database on the subject of selenium supplementation and its effect or non-effect on glucose metabolism, insulin resistance, glycemic control, etc.  I limited my search to reports of data from randomized, controlled trials.

Altogether, the Medline search yielded 48 hits.  Reading through the abstracts of the 48 journal articles, I was able to eliminate 30 references from consideration.  These 30 eliminated studies were studies that included all of my search terms but did not actually measure the effect of an intervention with selenium on some aspect of glucose metabolism.

18 good selenium supplementation studies
I was left with 18 good intervention studies that met my search criteria.  I read these studies and separated them into three distinct categories related to the effect of selenium supplementation on glucose metabolism and insulin sensitivity:

• Beneficial effect of selenium supplementation (n=6)
• No effect of selenium supplementation (n=9)
• Not beneficial effect of selenium supplementation (n=3)

Selenium supplementation beneficial for glucose metabolism
The six studies showing beneficial effects of selenium supplementation on glucose metabolism and/or insulin sensitivity enrolled a combined 402 patients.  All six studies were conducted on Iranian patients.

Basically, these six studies showed the following health benefits associated with the selenium supplementation:

• decreased plasma glucose levels
• decreased serum insulin levels
• decreased plasma HOMA-B levels
• decreased plasma HOMA-IR levels

Note:  The HOMA (homeostasis model assessment) measurements are based on plasma levels of fasting glucose and insulin.  HOMA scores have been validated for quantifying insulin resistance [Song].

Selenium supplementation with no effect on glucose metabolism
The nine studies showing no effect of selenium supplementation – neither positive nor negative – on glucose metabolism enrolled a total of 8568 patients, all of them study participants in the United Kingdom, the United States, or France.

In these nine studies, selenium supplementation was not associated with any significant changes:

• in plasma or serum glucose levels
• in insulin sensitivity measures
• in bio-markers of insulin resistance

Selenium supplementation with non-beneficial effect on glucose metabolism
The three studies that showed an undesirable effect of selenium supplementation on glucose metabolism enrolled a total of 1315 patients and study participants.  The patients in two of the studies (n = 113) were of Iranian origin.  The participants in the third study (n=1202) lived in the United States.

• One Iranian study (n=60) reported increased insulin resistance [Hosseinzadeh].
• The other Iranian study (n=53) reported increased fasting plasma glucose [Faghihi].
• The big American study (n=1202) was the post-hoc study by Dr. Saverio Stranges of the data from the Nutritional Prevention of Cancer (NPC) study.

The NPC study data show a strong association between daily supplementation with 200 micrograms of a high-selenium yeast preparation and significant reductions in total cancer mortality, total cancer incidence, and prostate cancer incidence [Clark].

Dr. Stranges reported finding an “exposure-response gradient” across tertiles of baseline plasma selenium concentrations.  He reported an increased risk for type 2 diabetes in the highest tertile only, the tertile with a baseline plasma selenium level greater than 121.6 micrograms per liter.

As limitations to his study, Dr. Stranges did note that diabetes was a secondary outcome in the NPC trial and that the diagnoses of diabetes were self-reported [Stranges].

U-shaped curve in the selenium-glucose metabolism relationship?
The relationship between selenium and glucose metabolism is clearly a complex one.  Professor Rayman, University of Surrey, Guildford, United Kingdom, has suggested that there may be a U-shaped relationship between the levels of certain selenoproteins and glucose metabolism or insulin resistance [Rayman].

In that case, it might be that both low levels of selenium and high levels of selenium over a longer period could have harmful effects.

The protective range for plasma selenium status seems to be 120-170 micrograms per liter [Hurst].

A systematic review and meta-analysis of five observational studies (note: not intervention studies) published in 2016 has also suggested a U-shaped relationship between selenium status and the risk of type-2 diabetes.  Populations with relatively low levels and relatively high levels of serum selenium were seen to be at increased risk [Wang].

Appropriate level of selenium supplementation
Given what we know about the beneficial effects of optimal selenium levels, I choose to get my blood serum selenium concentration tested.

• beneficial effects on the prevention of cancer
• beneficial effects on the prevention of thyroid disorders
• beneficial effects on the strengthening of the immune system
• beneficial effects on the prevention of heart disease

Then, with the test results in hand, I can decide which level of daily selenium supplementation – 50 or 100 or 200 micrograms daily – is appropriate for me.

Limitations of the available research
The randomized controlled studies that have been done on the effect of selenium supplementation on glucose metabolism have been done on samples with much heterogeneity with respect to age, gender, ethnic background, and medical condition.

Furthermore, most of the data come from studies in which the effect on glucose metabolism was not the primary outcome measured.

We need more and better studies.  However, we are not likely to see funding for large well-designed studies because selenium is not a substance that can be patented.  The best we can do is aim to keep our selenium status in the estimated protective range [Hurst].

Sources

Studies showing a beneficial effect:

Alizadeh, M., Safaeiyan, A., Ostadrahimi, A., Estakhri, R., Daneghian, S., Ghaffari, A., & Gargari, B. P. (2012). Effect of L-arginine and selenium added to a hypocaloric diet enriched with legumes on cardiovascular disease risk factors in women with central obesity: a randomized, double-blind, placebo-controlled trial. Annals Of Nutrition & Metabolism, 60(2), 157-168.

Asemi, Z., Jamilian, M., Mesdaghinia, E., & Esmaillzadeh, A. (2015). Effects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: Randomized, double-blind, placebo-controlled trial. Nutrition (Burbank, Los Angeles County, Calif.), 31(10), 1235-1242.

Bahmani, F., Kia, M., Soleimani, A., Asemi, Z., & Esmaillzadeh, A. (2016). Effect of Selenium Supplementation on Glycemic Control and Lipid Profiles in Patients with Diabetic Nephropathy. Biological Trace Element Research, 172(2), 282-289.

Farrokhian, A., Bahmani, F., Taghizadeh, M., Mirhashemi, S. M., Aarabi, M. H., Raygan, F., & Asemi, Z. (2016). Selenium Supplementation Affects Insulin Resistance and Serum hs-CRP in Patients with Type 2 Diabetes and Coronary Heart Disease. Hormone and Metabolic Research, 48(4).

Jamilian, M., Razavi, M., Fakhrie Kashan, Z., Ghandi, Y., Bagherian, T., & Asemi, Z. (2015). Metabolic response to selenium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clinical Endocrinology, 82(6), 885-891.

Karamali, M., Nourgostar, S., Zamani, A., Vahedpoor, Z., & Asemi, Z. (2015). The favourable effects of long-term selenium supplementation on regression of cervical tissues and metabolic profiles of patients with cervical intraepithelial neoplasia: a randomised, double-blind, placebo-controlled trial. The British Journal of Nutrition, 114(12), 2039-2045.

Studies showing no effect:

Algotar, A. M., Hsu, C., Singh, P., & Stratton, S. P. (2013). Selenium supplementation has no effect on serum glucose levels in men at high risk of prostate cancer. Journal of Diabetes, 5(4), 465-470.

Algotar, A. M., Stratton, M. S., Stratton, S. P., Hsu, C., & Ahmann, F. R. (2010). No effect of selenium supplementation on serum glucose levels in men with prostate cancer. The American Journal of Medicine, 123(8), 765-768.

Czernichow, S., Couthouis, A., Bertrais, S., Vergnaud, A., Dauchet, L., Galan, P., & Hercberg, S. (2006). Antioxidant supplementation does not affect fasting plasma glucose in the Supplementation with Antioxidant Vitamins and Minerals (SU.VI.MAX) study in France: association with dietary intake and plasma concentrations. The American Journal of Clinical Nutrition, 84(2), 395-399.

Karp, D. D., Lee, S. J., Keller, S. M., Wright, G. S., Aisner, S., Belinsky, S. A., & Khuri, F. R. (2013). Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597. Journal of Clinical Oncology, 31(33), 4179-4187.

Lippman, S. M., Klein, E. A., Goodman, P. J., Lucia, M. S., Thompson, I. M., Ford, L. G., & Coltman, C. J. (2009). Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 301(1), 39-51.

Mao, J., Bath, S. C., Vanderlelie, J. J., Perkins, A. V., Redman, C. G., & Rayman, M. P. (2016). No effect of modest selenium supplementation on insulin resistance in UK pregnant women, as assessed by plasma adiponectin concentration. The British Journal of Nutrition, 115(1), 32-38.

Rayman, M. P., Blundell-Pound, G., Pastor-Barriuso, R., Guallar, E., Steinbrenner, H., & Stranges, S. (2012). A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin. Plos One, 7(9), e45269. doi:10.1371/journal.pone.0045269

Richie, J. J., Das, A., Calcagnotto, A. M., Sinha, R., Neidig, W., Liao, J., & El-Bayoumy, K. (2014). Comparative effects of two different forms of selenium on oxidative stress biomarkers in healthy men: a randomized clinical trial. Cancer Prevention Research (Philadelphia, Pa.), 7(8), 796-804.

Thompson, P. A., Ashbeck, E. L., Roe, D. J., Fales, L., Buckmeier, J., Wang, F., & Lance, P. (2016). Selenium Supplementation for Prevention of Colorectal Adenomas and Risk of Associated Type 2 Diabetes. Journal of The National Cancer Institute, 108(12), doi:10.1093/jnci/djw152.

Studies showing a non-beneficial effect:

Faghihi, T., Radfar, M., Barmal, M., Amini, P., Qorbani, M., Abdollahi, M., & Larijani, B. (2014). A randomized, placebo-controlled trial of selenium supplementation in patients with type 2 diabetes: effects on glucose homeostasis, oxidative stress, and lipid profile. American Journal of Therapeutics, 21(6), 491-495.

Mohammad Hosseinzadeh, F., Hosseinzadeh-Attar, M. J., Yekaninejad, M. S., & Rashidi, B. (2016). Effects of selenium supplementation on glucose homeostasis and free androgen index in women with polycystic ovary syndrome: A randomized, double blinded, placebo controlled clinical trial. Journal Of Trace Elements In Medicine And Biology, 3456-61.

Stranges, S., Marshall, J. R., Natarajan, R., Donahue, R. P., Trevisan, M., Combs, G. F., & Reid, M. E. (2007). Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Annals of Internal Medicine, 147(4), 217-223.

Other relevant studies:

Clark, L. C., Combs, G. J., Turnbull, B. W., Slate, E. H., Chalker, D. K., Chow, J., & … Taylor, J. R. (1996). Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA, 276(24), 1957-1963.

Hurst, R., Armah, C. N., Dainty, J. R., Hart, D. J., Teucher, B., Goldson, A. J., & Fairweather-Tait, S. J. (2010). Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial. The American Journal of Clinical Nutrition, 91(4), 923-931.

Rayman, M. P., & Stranges, S. (2013). Epidemiology of selenium and type 2 diabetes: can we make sense of it? Free Radical Biology & Medicine, 65,1557-1564.

Song, Y., Manson, J. E., Tinker, L., Howard, B. V., Kuller, L. H., Nathan, L., & Liu, S. (2007). Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women’s Health Initiative Observational Study. Diabetes Care, 30(7), 1747-1752.

Wang, X., Yang, T., Wei, J., Lei, G., & Zeng, C. (2016). Association between serum selenium level and type 2 diabetes mellitus: a non-linear dose-response meta-analysis of observational studies. Nutrition Journal, 15(1), 48

Disclaimer: The information reported in this article is not intended as medical advice and should not be used as such.