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Electronic letters published:
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Impaired redox signaling may link selenium therapy with type 2 diabetes
Comments on Study Designs and Study Variables
Selenium and diseases: Cancer or Diabetes? A few micrograms make a difference!
Bias Against Nutrition Supplements
This may be due to excessive testosterone...
BMI and selenium confounding?
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Lucas Liaudet, Assistant Professor Department of Intensive Care Medicine, University Hospital Center, Lausanne 1011, Switzerland
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lucas.liaudet{at}chuv.ch Lucas Liaudet
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We read with interest the article by Stranges and colleagues reporting an increased risk for diabetes among participants receiving 200 μg of selenium daily for 7.7 years compared with placebo (1). These negative results add to those of multiple studies on long-term antioxidant supplementation, showing either no benefit, or harmful effects. If one considers oxidants solely as cytotoxic chemical species, these results are disappointing, but they are not totally surprising if one also considers the roles of oxidants in the physiological control of cell function. Two types of oxidants and free radicals, namely reactive oxygen (ROS) and nitrogen (RNS) species, are continuously produced at low levels under normal conditions (2). Oxidant clearance and redox homeostasis are ensured by various antioxidants, including enzymes and small compounds like vitamin C, vitamin E or selenium, which exerts its biological activity through its incorporation as selenocysteine into selenoproteins (2). An imbalance between oxidant production and clearance results in oxidative stress, which has been implicated in numerous pathological and degenerative processes, providing the conceptual basis for the development of antioxidant-based therapies (2). Whereas such therapies may prove beneficial in the treatment of many pathological states, they may be hazardous if applied over the long-term in the general population. Indeed, a chronic rise of antioxidant status may interfere with fundamental redox- based mechanisms controlling a myriad of cellular functions, such as cell growth and differentiation, apoptosis, and the regulation of inflammation (2). These mechanisms involve oxidation, nitrosylation and nitration of critical protein-bound aminoacids (especially cysteine and tyrosine). These post-translational modifications modulate the function of hundreds of proteins, including ion channels, receptors, metabolic enzymes and signaling proteins (2). A major signaling protein subject to particular redox-based regulation is IKKβ, a protein kinase that coordinates inflammatory responses through activation of the transcription factor NF-κB (3-5). Recent findings indicated that IKKβ activity is also critically involved in the molecular etiology of insulin resistance (5). Importantly, we (3) and others (4) found that ROS and RNS repress IKKβ activity through oxidation/nitrosylation of a critical cysteine residue, a regulatory mechanism likely disrupted by excessive antioxidant status. Putting these pieces together may provide a molecular basis for the increased incidence of type 2 diabetes associated with selenium supplements, as reported by Stranges (1). Beyond their well-described cytotoxic potential, oxidants and free radicals also behave as important controllers of key cellular functions. Chronic antioxidant-based therapies may have unpredictable effects on these functions, and should therefore only be used with caution. References 1. Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, et al. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 2007;147:217-23 2. Pacher P, Beckman J, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007;87:317-424 3. Levrand S, Pesse B, Feihl F, Waeber B, Pacher P, Rolli J, et al. Peroxynitrite is a potent inhibitor of NF-κB activation triggered by inflammatory stimuli in cardiac and endothelial cell lines. J Biol Chem 2005;280:34878-87 4. Reynaert NL, Ckless K, Korn SH, Vos N, Guala AS, Wouters EF, et al. Nitric oxide represses inhibitory kappaB kinase through S- nitrosylation. Proc Natl Acad Sci U S A. 2004;101:8945-50 5. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005;11:191-8. Conflict of Interest:Lucas Liaudet is supported by a grant from the Swiss National Fund for Scientific Research (Nr PP00B/68882-1) |
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Kumud Dahal, MBBS Institute of Medicine, Nepal, Arya Karki
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drkumuddahal{at}gmail.com Kumud Dahal, et al.
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I would like to critically comment on the selection and exclusion criteria of the study groups. Self reporting of diabetes was how the authors used to exclude study population without diabetes. And they have made a statement that self reporting of type 2 DM may have led to some under diagnosis at the baseline or during the trial.(1) .However, current literature clearly mentions that a large number of individuals who meet the current criteria for DM-type 2 are asymptomatic and unaware that they have the disorder. Epidemiological studies suggest that type 2 DM may be present for up to a decade before diagnosis. It is estimated that in up to 50% of affected people, DM is undiagnosed. And as many as 50% of individuals with type 2 DM have diabetes specific complications at the time of their diagnoses.(2) So, how could we make a concluding remark like that? I seriously doubt if this method of selection of study variables would rather not underestimate the true relative risk. Lets see what variables the authors have tried to study and adjust for (age, sex, smoking status, alcohol consumption status, BMI) and variables like family history of DM, body fat distribution and physical inactivity are not included. (1) On what basis? The missed risk factors are amongst the most important risk factors for type 2 DM compared to the included ones(except BMI). Could smoking status(and pack-years of smoking) and alcohol consumption be contributory or confounding to this study? They are far less important than those omitted variables for this study. This is further supported by the results which have clearly shown that there is no statistically significant difference in evaluated baseline characteristics between treatment groups. There is no mention of data and discussion of study regarding alcohol consumption in this study though this was one of the collected baseline data. It is very interesting to note that the risk for type 2 DM did not differ significantly between treatment groups( rather it is the same) within the top fertile of BMI (1) and the authors have not tried to give explanation for that. Finally , excluding all nonwhite persons in the study citing that the primary aim of the trial was to determine the effects of Se on non melanoma skin cancer itself is confusing because race/ethnicity is also one of the risk factor for DM. In 2000, prevalence of DM in USA was 13% in African Americans, 10.2% in Hispanic Americans, 15.5% in Native Americans and 7.8% in non-Hispanic whites. 1.Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME. Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial. Ann Intern Med 2007;147:217-223 2.AMERICAN DIABETES ASSOCIATION: Clinical practice recommendations 2002 Diabetes care 27:51, 2004 Conflict of Interest:None declared |
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Andreas S. Mueller, PhD, nutrition physiology Justus Liebig University Giessen, Department of Nutritional Physiology, Astrid C. Bosse and Josef Pallauf
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andreas.s.mueller{at}agrar.uni-giessen.de Andreas S. Mueller, et al.
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Selenium and diseases: Cancer or Diabetes? A few micrograms make a difference!
Presently a controversial and partially somewhat emotional discussion regarding benefits and disadvantages of selenium (Se) supplements for human health is in progress.
Most recent data obtained from the NPC trial (1) as well as data from the NHANES III trial (2) however indicate a distinct correlation between a long-term high selenium status (measured by serum Se) and the incidence of diabetes in humans. We share the author’s concluding remarks “that in populations with an adequate selenium supply an increased selenium intake should not be recommended for the prevention of diabetes. Quite the contrary long-term selenium supplementation above the current recommendations (50 – 70 µg Se daily) should be avoided because it may accelerate the development of obesity, insulin resistance and type II diabetes.
This point of view can be substantiated on the basis of the facts from biochemical basic research on selenium:
1. Only in a very narrow therapeutic range selenium acts as an antioxidant. Antioxidant properties of selenium are only achieved by its biochemical functions in glutathione peroxidases and thioredoxin reductases whose maximum expression and activity is obtained already with relatively low selenium supply (3). The current recommendations (4) are absolutely sufficient for an optimum selenoprotein synthesis. A permanent surplus of selenium reverses its antioxidant effects, since selenium is a highly thiol reactive element. 2. Selenate (selenium oxidation state +VI) is the only selenium compound with proved antidiabetic effects (5, 6). An increased insulin signalling (phosphorylation) and can be obtained only with very high supranutritional doses through the intermediary formation of the selenium oxidation state +IV and the inhibition of insulin antagonistic protein tyrosine phosphatases. Selenate doses for the realization of antidiabetic effects are however by far too high for humans, and they were tested only in animal models and in tissue cultures so far (5, 6). 3. Both a permanent moderate surplus of selenium (7) as well as high activities of glutathione peroxidase (8) (shown by ~ 1.5-fold GPx1 overexpression in mice) can lead to a higher activity of the insulin antagonistic protein tyrosine phosphatase 1B (PTP1B) and therefore contribute to the development of obesity, insulin resistance and type II diabetes. In the mice study GPx1 overexpression reduced the phosphorylation of the subunit of the insulin receptor as well as of the downstream signalling protein Akt (at Thr308 and Ser473) indicating the insulin resistance (8). 4. Tragically one crucial mechanism by which a surplus of selenium may inhibit the progression of prostate cancer also involves Akt phosphorylation at Thr308 and Ser473 (9) With regard to the prevention of prostate cancer (10) a reduction of Akt phosphorylation therefore is desirable (9). By its powerful influence on cellular signalling processes selenium is at the interface of two diseases (cancer and diabetes) which seem to be regulated in a contrary manner (Schema).
Schema: Interactions between selenium and cellular signalling processes influencing metabolic disorders (obesity, insulin resistance, diabetes) and cancer In conclusion a permanent use of selenium supplements should be reconsidered well. The evidence that a few micrograms of selenium may determine the accelerated or slowed development of diabetes and/or cancer demonstrates the necessity for intensified research in this field. Until then selenium supplements should not be recommended in populations with a sufficient intake by common nutrition. 1. Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME. Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial. Ann Intern Med 2007;147:217-223 2. Bleys J, Navas-Acien A, Guallar E. Serum selenium and diabetes in U.S. adults. Diabetes Care 2007; 30: 829-834 3. Gromer S, Eubel JK, Lee BL, Jacob J: Human selenoproteins at a glance. Cell Mol Life Sci 62: 2414 – 2437, 2005 4. NIH (National Institute of Health): ods.od.nih.gov/factsheets/selenium.asp. (Updated: 08/01/2004) 5. Stapleton SR, Garlock GL, Foellmi-Adams L, Kletzien RF. Selenium: potent stimulator of tyrosyl phosphorylation and activator of MAP kinase. Biochim Biophys Acta 1997; 1355(3): 259-269 6. Mueller AS, Pallauf J. Compendium of the antidiabetic effects of supranutritional selenate doses. In vivo and in vitro investigations with type II diabetic db/db mice. J Nutr Biochem 2006; 17: 548-560 7. Mueller AS, Pallauf J. Regulatory mechanisms of selenium and its compounds on protein tyrosine phosphatase 1B. In: Anke M et al. (eds): 23rd Workshop Macro and Trace Elements, Friedrich Schiller University Jena, Schubert-Verlag Leipzig, 2006, ISBN 3-929526-85-9, p. 196 – 203 8. McClung JP, Roneker CA, Mu W, Lisk DJ, Langlais P, Liu F, Lei XG. Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci U S A 2004; 101: 8852-8857 9. Wu Y, Zu K, Warren MA, Wallace PK, Ip C. Delineating the mechanism by which selenium deactivates Akt in prostate cancer cells. Mol Cancer Ther 2006;5: 246-252 10. Vogt TM, Ziegler RG, Patterson BH, Graubard BI. Racial Differences in Serum Selenium Concentration: Analysis of US Population Data from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 2007; 166: 280-88 Conflict of Interest:None declared |
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Kenneth N. Woliner, M.D. Holistic Family Medicine, LLC - Boca Raton, FL
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knw6{at}cornell.edu Kenneth N. Woliner
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Does anyone else notice the disturbing trend in the medical literature (and the lay press that reads the headlines of these articles) of having a bias against anything that is "non-patentable" such as nutrition supplements. I see drugs such as Avandia have terrible side effects being talked up as "the cure for diabetes", with hardly a mention of the side effects they cause, no matter how devastating (heart attacks, etc). But when one study, which was designed to study a different outcome (in this case - incidence of prostate cancer), shows a mildly increased risk of diabetes (absolute increased risk of only 4.2 cases per 1000 patient years) - there is tremendous houpla with very strong conclusions of "Selenium supplementation ... may increase risk for the disease." Perhaps the editors of this journal should re-examine all their articles for bias for medications whose companies advertise in their journal and bias against "non-patentable" therapies which do not. Conflict of Interest:None declared |
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James M. Howard, Biologist independent
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jmhoward{at}anthropogeny.com James M. Howard
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A case may be made that testosterone increases type 2 diabetes. For example, blacks produce more testosterone than whites and exhibit more type 2 diabetes. Selenium has been connected with testosterone production. As you know, type 2 diabetes is increasing. It is my hypothesis that the "secular trend," the increase in size and earlier puberty in children, is caused by an increase in the percentage of individuals of higher testosterone over time within the population. I suggest all of this points to increasing testosterone increasing obesity, type 2 diabetes, etc. as a single cause. Conflict of Interest:None declared |
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David Sokal, MD
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dcsokal{at}gmail.com David Sokal
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Dear Sir/Madam, Your article includes a confusing mention of a difference in diabetes incidence by BMI, but you do not show a table on this issue. Could there be confounding between selenium levels and BMI? People who have higher BMI's are likely to eat more - and eating more could be associated with both higher selenium levels and with higher risk of type II diabetes. Please provide a tabulation of the incidence of diabetes by BMI tertiles and by study group. Dave Sokal Conflict of Interest:None declared |
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