Selenium and Type 2 diabetes: does it increase the risk?

Have recent studies discovered a causal relationship between selenium and diabetes? Are such conclusions valid?

More than a few studies have found a link between serum selenium levels and incidence of diabetes. (1-4) Expectedly, these results cause concerns within the health community as well as in patients and in health-conscious individuals. It is clear to most that ‘too much of a good thing’ is very much a reality for health supplements, so it may seem logical to refrain from selenium supplements and maybe even restrict intake from diet. Despite the results of these studies, there are a number of serious considerations that deserve careful analysis.

Before the veracity of these conclusions is explored, it must be stated that danger from surpassing the upper tolerable limit of selenium is not being challenged by this article. It is known that selenium, like other trace elements, is essential at small doses and toxic at high doses. Not only do mega doses initiate toxicity in animal models but toxicity symptoms such as breath, hair, and nail changes and more serious symptoms such as organ damage (in extreme toxicities) are widely reported in humans, particularly after surpassing supplementary amounts of a few grams (~2-3000mcg/g) of the element. (5-7) What is in contention, rather, is if the results from animal and human studies prove that higher selenium intake within dietary ranges is pro-diabetic or at least justifies a withdrawal of supplementary selenium in normal diets.

The first problem is the discrepancy between studies. Indeed, several studies have found a positive relationship with selenium and higher fasting glucose levels, insulin resistance, and diabetes but studies have not replicated these positive associations and others have even reported a protective effect. (8-14) If high selenium intakes had even mildly aversive effects on diabetic markers, one would not expect to find divergent relationships in adequately controlled studies with appropriate measures of selenium intake.

This takes us to the first question – namely, the methods for approximation of whole-body selenium content. Serum selenium levels were the main method of choice used in the studies that discovered higher values with diabetic changes. Alternatively, toenail selenium was used to approximate total levels of selenium in Park et al’s (11) study, which was one of the studies that found an inverse correlation between selenium and diabetes risk where many possible confounders were controlled for (e.g., total energy/caloric intake, saturated fat intake, polyunsaturated fat intake, smoking status, alcohol intake, physical activity, BMI, multivitamin use, etc). The positive association found in the large sample sizes of the NHANES studies and the ORDET cohort study evaluated only serum selenium. Toenail selenium better reflects long-term selenium intake and moreover, is a superior estimate of selenium in tissues or whole-body levels of selenium compared to tests for serum. (15-16) A very recent study was conducted on the ORDET participants using toenail levels of selenium and interestingly did not locate an elevated risk amongst higher selenium levels by this marker.(14) Only in the studies using plasma selenium to predict dietary levels have positive associations been found. Independent of dietary selenium, dysregulated selenium metabolism as well as other factors can cause an increase in selenium plasma which will be discussed more in detail shortly. Selenium in plasma is no more than a rough approximation of actual amount in tissue and even accounting for a high correlation between plasma selenium and whole-body levels, that still does not point to a negative causal effect of selenium in glucose control as several other studies using selenium in serum have not replicated the positive association with diabetic markers in other study groups (9-10)(17) Furthermore, others have found higher serum selenium to be protective whereas lower concentrations were associated with greater risk. (12)(18)

Even if we are to accept that dietary selenium levels consistently reveal a positive relationship with diabetes development or at the very least that positive associations with selenium outnumber negative or inverse associations, there is still the fact that the high selenium is merely a false positive, representing not a risk in itself but a marker of food high in selenium that is harmful independently of its selenium content. Although a number of possible mechanisms have been proposed including an overexpression of selenium’s antioxidant enzymes glutathione peroxidase and other selenoproteins such as selenoprotein P/SelP, selenoprotein S/SelS,selenoprotein T/SelT, etc as disrupters of insulin-signaling at high levels. (19-20), the top contender for a causal role, GPx1/gluthathione peroxidase 1, is not at all likely to disturb metabolism in humans. Gluthathione peroxidase levels become saturated at around 100 micrograms per day and supplementary doses above those values do not seem to raise GPx levels and if so only slightly. (21) Maximization of GPx-1 specifically occurs at only half the requirement for GPx saturation in rodents. (22) The insulin resistance developed in mice genetically bred to overexpress GPx 1is not remotely comparable to GPX-1(23) in response to selenium consumption which plateaus and is under regulatory control. In extreme cases of selenium oversupply (0.5-3mg/kg) given to pigs, insulin was raised nonsignificantly at .5mg/kg and pigs became hyperinsulemic at 3mg/kg. (24-25) At 0.5mg/kg , although energy metabolism was altered in insulin target tissues, these changes were interpreted as not on their own sufficient to induce diabetes as no markers of insulin resistance were increased during the 16 weeks of supplementation. (24) Unlike rodents, pigs are a much closer representation of human metabolism, and importantly, the doses used to achieve supraphysiological concentrations are much too high to even remotely resemble any range available for human consumption.

Given the absence of a mode of action by which selenium could exacerbate diabetes development at normal dietary and supplementary concentrations, several likely confounders should be considered:

Over-nutrition

It is generally known that an increased energy intake will raise nutrient levels whereas nutritional inadequacies increase as energy intake decreases. Over-nutrition arises in most diets when caloric intake is excessive. Selenium levels tend to positively correlate with calories and BMI. (3)(26-27) In Bleys et al’s cross-sectional analysis of the NHANES participants, the positive association found between selenium and diabetes was nonlinear, but more strikingly, it did not extend to participants with a BMI under 25. (1) Similarly, adjusting for BMI in Stranges et al’s study modestly weakened the odds ratio for type II diabetes risk with dietary selenium. (3) Furthermore, very important factors such as family history of diabetes and physical activity were not controlled for in this study which relied on self-report of dietary intake. Those within the highest quintile selenium intake tended to have a higher energy intake. The women who developed diabetes in this study were more likely to be post-menopausal and overweight compared to those who did not develop the disease. These women were also more likely to consume a larger amount of animal protein which in other studies has been associated with a less healthy lifestyle, notably less physical activity and fewer fruits and vegetables. (28) While a statistically significant relationship between increasing dietary selenium intake and diabetes, the diabetics had a mean selenium intake of only ~4 micrograms more than the non-diabetics (60.9 vs. 56.8 μg/d). (3) Both intakes were roughly average and differed minutely with each other, only reaching statistical significance due to the large sample size (A similar problem with the Omega 3 and prostate cancer link discussed here). In other words, this is not strong ‘real life’ evidence that high selenium intakes in relation to low or average intakes predispose to diabetes.

Population data, on the other hand, presents a strong case for obesity as the driving factor behind the alarming increases in diabetes worldwide. For example, the United Kingdom is experiencing a sharp increase in diabetes in the face of an ongoing significant decline in selenium intake that fell by nearly half since the 1970s. (29-30) New Zealand, known for its marginally adequate selenium availability, has a rather high rate of diabetes among its Polynesian population, who also happen to be disproportionally obese to other populations in the region. (31-32) Selenium status may instead be a marker for general over-nutrition which in itself is a vehicle for obesity and resultant insulin resistance.

Red Meat

Although selenium in meat can vary based on the content of the mineral in soil and the diet of the livestock (33), it is the greatest source of selenium for North Americans (34) and remains to be the dominant source in many other countries as a popular food source and as a food naturally very high in selenium.(35) Even in low selenium regions in New Zealand and Denmark, selenium from red meat accounts for between one fifth and one forth of dietary selenium intake.(33) Red meat alone has multiple health benefits as a potent source of many vitamins and minerals other than selenium including vitamin A, vitamin D, vitamin E, B vitamins (B12, B6, folate, riboflavin, pantothenic acid, niacin, thiamine), zinc, iron, phosphorus, copper, potassium, magnesium, chromium, cobalt, and nickel and is known to contain numerous vital amino acids and anti-inflammatory omega 3 fats and high levels of antioxidant enzymes (e.g. glutathione, superoxide dismutase (SOD) , andcatalase (CAT)) if sourced from grass-fed cows.(36-39) The correlation with red meat and negative lifestyle factors does not impugn its nutritional value, but there is reason to speculate that post-processed highly cooked meat itself can contribute to a diabetic outcome.

Red meat consumption – especially processed meat – has been associated with type II diabetes in men and women (40-42) An obvious possible causal factor other than selenium in red meat is the extent to what it is usually cooked to in most diets, which ineluctably raises the dietary AGE content. (46) Moreover, other components in red meat (unprocessed and processed) are linked to diabetes that should not be overlooked or underestimated such as heme iron (43-45), nitrates and nitrites in processed meats that form N-nitroso compounds to become toxic to beta cells and cause insulin resistance(47-48), heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons in highly cooked meats that can convert to N-nitrosamines to damage beta cells (49-50), high saturated fat content in meat as inducer of insulin resistance – mainly in overweight individuals (51-53), and even added sodium from processed meats – a benign factor by comparison – although it is yet another factor associated with insulin metabolic syndrome and insulin dysfunction that is probably mediated by its positive effect on cortisol secretion. (54) Selenium on the other hand could very well by an innocent bystander.

Fish and Mercury Exposure

Highest selenium contents are present in seafood. In East Asian countries, fish intake is responsible for over half of dietary selenium exposure. (55) If meat does not provide the highest source of daily selenium, fish is usually the next prominent source in most populations.

Therefore, serum selenium levels may also be a marker for frequent fish consumption and like meat, fish intake is positively related to incidence of diabetes (56-58) As is the case with meat, the heating of marine foods produces volatile reactions mainly due to their high PUFA content. Lipid oxidation is a known inducer of glycation, but cholesterol oxidation, also a notable feature of cooked fish, is likely underestimated as a contributor to diabetes. Cholesterol is quite vulnerable to oxidation, being especially susceptible to the length of cooking time that includes gentler heating methods such as steaming irradiation, and solar drying. (59-61) Eventually, even long-term storage at room temperature will unavoidably increase cholesterol oxidation as well. (62) Processing of seafood through canning also increases the content of oxidized cholesterol since high-heat methods are incorporated in this procedure. (63) As a form of oxidative stress, oxidized cholesterol reduces insulin secretion and is damaging to beta cells in vitro. (64) Correspondingly, oxLDL is consistently associated with diabetes and fasting glucose. (65) Oxidation is greatly accelerated by the presence of fat (66), and delicate fats like EPA and DHA (PUFAs) even further exacerbate the oxidation of cholesterol. (67)In East Asian populations where fish is normally eaten raw or lightly steamed, high fish intake (and dependently high selenium intake) is associated with a lower diabetes risk. (68) This diametrical difference was found in a meta-study to partially explain the inconsistent relationship between selenium and diabetes. (69) In non-Eastern sample groups, consumption of lean fish also correlates negatively to diabetes risk (70), which of course remains to be the highest sources of selenium irrespective of fatty acid content. Despite a much lower trend for East Asian fish preparation (raw or lightly cooked), the favorable relationship in Western groups with high consumption of lean fish remains as a low fat (PUFA) content obviates the lipid peroxidation that would otherwise occur in any form of cooking with fatty fish. Leaner fish also have a lower contaminant load than fish with higher levels of fat. Fatty fish are a source of persistent organic pollutants, or POPs, in the diet and given that they induced insulin resistance syndrome in rats (71), a higher burden of POPs could be at least partially to blame if higher dietary selenium becomes consistently associated with diabetic symptoms.

Mercury is another inevitable concern of fish-based selenium acquisition. This contaminant is fat soluble and therefore concentrated in fatty fish and will accumulate to a higher degree in those with more body fat. (72-73) Similar to POPs, methylmercury promotes diabetogenic effects by causing beta cell dysfunction and apoptosis. (74.) Longitudinal human data based on toenail mercury levels (i.e. a reliable, long-term indicator of mercury status) indicates a positive correlation with diabetes incidence after adjusting for multiple variables (e.g., family risk, alcohol intake, physical activity, smoking status, magnesium and omega 3 intake, etc.) (75) Additionally, a statistically significant relationship between mercury status and decreased beta function was reported (76), strongly supporting the earlier findings of animal studies. Other evidence is implied, such as the disappearance of the usual protective effect seen with fish consumption in East Asians with a heavier consumption of larger predatory fish. (77) At equal concentrations (1:1 ratio), selenium forms complexes with mercury to mitigate its toxicity (78) but larger fish have higher loads of mercury that meagerly lag behind, equal, or even surpass the selenium content as is the case with mako shark. (79) There is also appreciable variation in the selenium-mercury ratio within species and although a higher level of mercury over selenium is very rare, it is worthwhile to consider that lower ratios, not necessarily lower than one, can create a ‘functional selenium deficiency’ with more selenium being required to bind to mercury. Other authors have speculated on this issue, arguing that these complexes could irrevocably inhibit selenium-dependant enzymes that would otherwise be active as ‘free selenium’. (80-81) The diminished availability of selenium in tissues of mercury mine workers lends credence to this recent school of thought. (82) To much misunderstanding, the concurrently elevated plasma selenium level with the largely increased serum levels of mercury that have been shown to exist in those whose selenium intake derives primarily from seafood (83) might instead be representing decreased selenium activity. If that is indeed the case, the positive correlation with high serum selenium amounts and poor glucose control may actually be attributed a deficiency in bioavailable selenium due to binding demand. After all, a selenium deficiency features a similar diabetes-resembling outcome with insulin resistance and higher fasting glucose levels. (84-86)

Polyunsaturated Fats (PUFAs)

High selenium foods such as fish, beef, poultry, pork, lamb, eggs, and nuts are also recognized for their high PUFA content. Omega 3 PUFAs are for the most part beneficial; omega 6 PUFAs, on the other hand, can be potentially harmful. Considering the main sources of dietary selenium, it should not come as a surprise that serum selenium directly (positively) correlates with omega 6 PUFA levels. (87) The primary dietary omega 6 fatty acid, linoleic acid, is abundant in the high selenium foods mentioned above and also comprises the majority of vegetable oil, which are often used together with other high 6-PUFA (also high selenium) foods for cooking. Linoleic acid is a required omega 6 fatty acid converted to arachidonic acid to regulate (essential) inflammatory responses, although excess arachidonic acid contributing to a high omega 6 to omega 3 fatty acid ratio will promote chronic low-grade inflammation by negating the anti-inflammatory effects of omega 3 through competition for molecular signaling pathways if not in balanced proportions. (88-89) Alternatively expressed, this will create a relative omega 3 deficiency. A diet high in omega 6 fatty acids (or an omega 3 deficiency) causes gut dysbiosis (an imbalance in intestinal microbiota favoring ‘bad bacteria’), bacterial overgrowth, and bacterial translocation from increased ‘leakiness’ in the small intestine, which altogether produces subclinical inflammation. (90-93) Generalized inflammation is a unifying underlying cause of the development of diabetes in individuals (94), and furthermore is exacerbated after its inception. (95-96) Although 6-PUFA-induced inflammation is universally harmful, the overweight and obese are more susceptible than their leaner counterparts to the inflammatory side effects of a high arachidonic acid intake. Independent of diet, tissue arachidonic acid is already significantly higher with increased weight, particularly in the abdominal area. (97) Adipose tissue generates inflammation and oxidative stress which oxidizes arachidonic acid – both the amount stored in tissue and incoming dietary arachidonic acid – forming arachidonic acid-derived inflammatory markers that further induce insulin resistance. (98-100) In South Asia where a high n-6 to n-3 ratio is predominant, higher ratios have shown to be significantly related to subclinical inflammation as well as to fasting hyperinsulinemia. (101) HOMA-IR is also positively correlated to n-6 intake and inversely so with n-3 fatty acids in patients with metabolic syndrome. (102) Likewise, a positive association with tissue arachidonic acid and insulin resistance was found in healthy children. (103) Irrespective of body fat, increasing glucose levels foment oxidative stress known as F2 isoprostanes that are produced from the oxidation of arachidonic acid (104), meaning an elevated omega 6 intake and not the selenium content from certain foods can fuel and hasten the development of diabetes beginning from unrelated causes.

To correct this metabolic imbalance, the functional omega 3 deficiency arising from abundant n-6 fatty acids needs to be adjusted in a more favorable ratio to down-regulate inflammation and thereby increase insulin sensitivity. (105-108) Disruption in tight junctions resulting in gut permeability and runaway inflammation is commonly referred to being caused by a ‘high fat’ diet, but this only pertains to certain fats like omega 6 PUFAs. Conversely, omega 3 PUFAS do not increase intestinal permeability and instead reverse the generation of inflammation. (91) In rodents, lowering the omega 6 to omega 3 ratio resulted in attenuation of obesity-mediated inflammation and insulin resistance. (109) Vegetarian diets high in omega 6 positively correlated with inflammatory markers (e.g, Il-6, TNF-α) in volunteers (110) and in a separate study, elevated omega 6 levels predicted the development of inflammatory diseases (111) Since inflammation precedes the upset in insulin function, it is also observed that higher ratios of omega 3 to omega 6 fatty acids were able to predict improvement in glucose disturbances during dietary intervention in a study population of Japanese Brazilians at high risk for diabetes with glucose intolerance. (112) If fish is not a large part of one’s diet, it is safe to assume that a high selenium diet from alternative sources would indicate a high n-6 to n-3 ratio in which poor glucose control would be expected.

Pesticides and Other Contaminants (PCBs, PCDFs)

Fruits and vegetables are regarded as the main culprits of pesticide content whereas meat and dairy as sources of pesticides are overlooked. In non-vegetarians, meat and eggs – two excellent selenium sources – are most responsible for dietary pesticide exposure (113.), and this likely issue was touched upon with fish, the greatest (by far) source of dietary selenium. Various types of meat (all high in selenium) such as beef, pork, mutton, and lamb as well as eggs and dairy carry possibly problematic amounts of pesticides and positively correlate with higher pesticide concentrations. (114-115) One kind of organochlorine pesticide’s (DDT/ 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) metabolite, p,p’-DDE, has increased in recent years in some countries and is still detectable in fatty foods and continues to be measured in human tissues in other countries where it has been banned due to bioaccumulation throughout the food chain and its extremely long half-life in the body. (116) It has been shown to cause hyperglycemia in mice (117) and was strongly associated with greatly increased fasting glucose levels and insulin in those living in a highly polluted zone. (118) Less subtle exposures at first did not uncover a connection until subjects were diagnosed with diabetes more than 6 years after baseline values were recorded. (119)After long-term exposure, a positive association (fivefold increased risk) with those in the highest quartile of p,p′-DDE became strikingly evident. (120) These findings have been noted in a number of separate studies mostly recognized as a dose-response relationship and the same has held true for other groups of contaminants as well, mostly where long follow-ups take place. (121-124) Children exposed to PCBs and p,p’-DDE also seem to show pre-diabetic changes such as declining insulin values with normal fasting glucose, possibly indicating early beta cell damage. (125) Most interestingly, a statistically significant association was found between urinary bisphenol A (BPA) and type II diabetes in the 03-04 NHANES group (126) … the very group used by Laclaustra et al (2) to reveal a positive relationship with selenium and type II diabetes. Foods detected for high concentrations of BPA that are also important sources for selenium include cheese, canned luncheon meats, fast food meats (hotdogs, hamburgers, chicken burgers, prepared sandwiches, canned soups containing meat, mushrooms, and canned fish, the highest source of selenium, has been detected to contain astronomically high levels of BPA compared to other sources. (127) Given selenium’s safety and antioxidant effect at dietary levels, it seems more likely the intake of BPA modified what seemingly appeared to be a positive relationship between selenium and diabetes risk in this study group in particular and possibly in others where it was not accounted for.

High Serum Selenium as a Consequence, Not a Cause of Diabetes

Finally, it is of great likelihood that elevated serum selenium and enhanced activity of selenoproteins are a result of metabolic changes rather than the cause of adverse metabolic activity. About 60% of plasma selenium is comprised of selenoprotein P (128), which is produced in the liver. (129) Curiously, hyperglycemic conditions increase its expression as seen in rat hepatocytes and in live animal models. (130-131) Conversely, the expression of liver-derived selenoprotein P is downregulated by insulin, further supporting increased SelP as a response rather than a cause of insulin resistance. (129) This is not to say SelP activity does not directly increase insulin resistance as this was seen in animals, but a dysregulation of SelP activity arises not from high selenium supplementation or high intake but instead from emerging defects in energy metabolism triggered by the progression of a diabetic state. Since SelP (selenoprotein P) is within plasma, levels of selenoprotein P correlate with serum selenium concentrations. (132.) Ultimately, higher plasma selenium concentrations found to correlate to diabetes seem to be a reflection of upregulated SelP in response to rising glucose levels. In that case, we would expect the type II diabetics in Bleys et al’s (1) study and the participants with high fasting glucose levels and higher glycated hemoglobin in Laclaustra et al’s (2) cross-sectional analysis to have greater amounts of selenium in plasma … only in this interpretation as a marker of the disease process as opposed to an initiating factor.

Additionally, it is worthy to remark the elevation of antioxidant activity in early diabetes. Oxidative stress in general and oxidative stress seen in pre-diabetes and diabetes (e.g., hyperglycemia, lipid oxidation) recruits antioxidants for neutralization. (133) High plasma antioxidants can either reflect a high dietary intake and overall high antioxidant reserve, or it can reflect a greater toll on the antioxidant system. Those with uncomplicated diabetes have higher antioxidant capacity in plasma despite increased oxidative stress.(134) Selenium specifically was significantly higher in children with diabetes (135). Due to the heightened antioxidant requirement of the diabetic milieu, whole-body levels of antioxidants like selenium become depleted in spite of misleadingly normal to high serum levels. (136) With the progression of poorly controlled diabetes, this original defense mechanism is sooner or later wholly diminished which eventually leads to lower serum selenium and less selenium-based antioxidant activity where diabetic complications are soon to follow. (137-139)

Finally, hyperglycemia in new onset or poorly-controlled diabetes can induce dehydration and therefore enhance apparent concentration of selenium in the blood. (140)

Evaluating Selenium Directly

If high selenium intake through diet has a role in diabetes development, then surely concentrated doses of supplementary selenium would confer adverse metabolic effects within a reasonable measure of time. Rather, supplementation with selenium in amounts around 2 to 15 times the RDA does not upset glucose control. Dietary capsules containing 120mg vitamin C, 30mg vitamin E, 6mg beta-carotene, 20mg, and 100mcg of selenium (as yeast) did not lead to a worsening in fasting glucose levels in adults with a balanced diet after 7.5 years of examination. (8) Selenium as selenium yeast in doses 100, 200, or 300mcg did not induce a diabetic effect when give to over 500 elderly volunteers in a six month trial as measured by plasma adiponectin levels. (10) Furthermore, there was an inverse association with baseline selenium levels and plasma adiponectin concentration in this study. Selenium yeast was also given to NSCLC (non-small cell lung cancer) patients in 200mcg doses in a chemopreventive trial with no elevation in diabetes risk after 4 years. (141) Subjects with prostate cancer with already high baseline selenium values given an additional 200mcg to 800mcg of selenium daily did not experience negative changes in blood glucose over the course of 5 years of frequent re-testing. (142) This study design was repeated by the same researchers only this time in men with high risk of prostate cancer and selenium in doses of 200mcg or 400mcg. Results once again did not detect any detrimental effect in serum glucose throughout the study’s duration (5 years). (143)

Two studies, however, are worth mentioning where direct use of selenium supported the hypothesis that moderately high amounts of selenium increase the risk of and/or worsen existing diabetes. One of such studies was conducted by Stranges et al as a secondary analysis of the Nutritional Prevention of Cancer (NPC) trial involving the administration of 200mcg of selenized yeast daily. From statistical value alone (e.g., diabetes developed in 58 selenium recipients versus in 39 placebo recipients, equating to 12.6 cases per 1000 person/years vs. 8.4 cases per 1000 person/years – hazard ratio 1.55, 2.70 hazard ratio for the highest tertile of baseline selenium)(4), this provides strong evidence for selenium as a diabetogenic nutrient. At closer inspection, this study is not without problems and limitations. A 55% increased risk is highly significant, but it is undermined by the study’s modest sample size (~1200) and the fact the development of diabetes was self-diagnosed and could not be confirmed in all participants.

As a comparison, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) consisted of a larger much sample size (~35,500) and on the other hand, did not find an increase in diabetes in men taking 200mcg of selenium daily as L-selenomethionine with vitamin E (400IU) over a 5 year follow-up (144) There was another group in this study that was taking selenium alone in the form same and dosage which did present a nonsignificant increase in risk (diabetes development according to self-report or new glitazone use), although this appeared to dissipate after an extended follow-up. (145) Moreover, the baseline selenium values in the SELECT study were even higher than those of the NPC study (135µg/L vs. 114µg/L). (146) If higher concentrations of selenium predispose a higher risk of developing diabetes, then relative risk should have been more dramatic in the SELECT study as opposed to achieving no noticeable risk elevation compared to controls. Rather, the selenium plus vitamin E group had the lowest relative risk of all groups (selenium alone and vitamin E alone) by the additional follow-up. (145) Stranges et al’s (4) results may be attributed to chance.

In the event that these results did not occur due to chance and rather as a result of 200mcg of additional supplementary selenium, there are still alterative explanations for an increased diabetes risk other than that of selenium-induced insulin resistance. If we consider the fact that dietary minerals compete with each other for absorption, then it must be considered that supplementing 200mcg of selenium in a group beyond repletion will result in a selenium surplus at the expense of other mineral deficiencies. Chromium is one of the most important minerals for preserving proper insulin control and becomes depleted in preceding stages of diabetes from increased levels of stress (i.e., simple sugar intake, chronic stress, corticosteroid use). (147-148) A chromium deficiency of any cause will lead to defects in insulin-signaling (as much as an 8-fold reduction in efficacy) and subsequent hyperglycemia. (149-150) Selenium and chromium are in direct competition for absorption and high levels of selenium can exacerbate an already low chromium status that is nowadays common due to highly refined diets, chromium-depleted soil, high-sugar intake, and high-stress lifestyles and drive it to a deficiency state. (151-153.) Similarly, selenium supplementation increases fecal excretion of copper (154), whose RDA is already only marginally met under a Western-influenced diet. (155) Low copper status leads to insulin resistance by inhibiting glucose-stimulated insulin secretion. (156-157) Judging from rodent studies, it is also suspected that high selenium may adversely affect magnesium distribution such as reducing its concentrations in the kidney (158) which could contribute to reduced glucose utilization and insulin action. (159) In a modern diet with borderline-adequate nutritional value, supplementing any mineral in supraphysiological amounts could theoretically cause reduced availability of other minerals by competing for the absorption and tissue sites. Another explanation could be that these men were already developing insulin resistance judging by their high selenium values at baseline. As was discussed, declines in insulin can cause selenium levels to rise.

High selenium supplementation in those who are already diabetic is even more controversial. One other study that raises concern and attempts to make a case for selenium as a pro-diabetic mineral involved type II diabetic patients with low baseline selenium status given 500mcg a day to raise levels to high mid-range that observed a disturbance in glucose homostatis when compared to a control group of other diabetic patients. (160) First and foremost, reactions to supplementary selenium in type II diabetics do not extrapolate to healthy individuals. Second of all, this study only involved 60 participants, so the results, despite achieving statistical significance, cannot easily rule out coincidence. It is not foolhardy to postulate that the group of diabetics randomized to receive selenium progressed in their disease state naturally throughout the 3 months of testing. It may also be that, given the change of selenium metabolism in diabetes (130), selenoprotein P was over-expressed and adding dietary selenium accentuated that loss of regulation. These patients did have rather modest selenium levels compared to other trials, but this was not a measure of selenoprotein P activity. After all, high expression of selenoprotein P in the liver has been shown to coexist with low plasma selenium and depletion from other tissues. (161.) Regardless, the possibly of selenium worsening an established metabolic disease does not extend to those without diabetes, as stated.

Furthermore, other studies utilizing selenium supplementation have yielded opposite results. In diabetic rats, selenium prevented a significant rise in glucose concentrations that was observed in the control group. (162) Unlike with selenate, rats given selenomethionine experienced the best long-term glucose control. (163) Another rat study demonstrated decreased glucose values and glycated hemoglobin content, increased antioxidant activity, a reduction in lipid peroxidation, lower inflammation, and downregulated glycation expression.(164) Positive results of selenium supplementation are not species-specific. In humans, a selenium-enriched diet given to newly-diagnosed Russian diabetic patients improved measures of lipid peroxidation and decreased glucose levels in capillary and venous blood. (165) Complications in patients with long-term diabetes were improved by 100mcg of sodium selenite as measured by reduced markers of lipid peroxidation and progressive kidney damage without a report of adverse effects on glucose control. (166) Additionally, symptoms of diabetic neuropathy were ameliorated by the antioxidant intervention. (167) A different trial with type II diabetics noticed a dramatic decline in inflammation (based on nFκB activity in blood) that equaled nondiabetics after 3 months of daily supplementation with 940mcg of selenium daily (168) … an amount well passed the parsimoniously set upper tolerable limit of 300-400mcg (169-170)

Concluding Remarks

Based on current research, there is no justifiable reason to limit supplementary (100-200mcg) intake of selenium and high selenium diets in healthy people as well as those with disease. At a range of doses, selenium is clearly an antioxidant (171-175), anti-inflammatory (176-179), opposes heavy metal toxicity (180-182.), and even is a chemopreventative nutrient for those with certain genetic polymorphisms. (183-185) Selenium levels are inversely related to metabolic syndrome and its features such as sialic acid and C3 both in children and in young adults. (13)(186-187) Considering the absence and/or near absence of any glucose-related issues and general toxicity in doses up to 1600 and 3600mcg for extended time periods (5), speculations of an even narrower U shaped relationship between benefit and overall harm is unsupported. Health-conscious individuals need not cease supplementing with reasonable amounts of selenium.

Regarding those currently afflicted with diabetes, data is so far inconclusive as to whether or not extra selenium negatively impacts glucose homeostasis. So far evidence is leaning towards an overall benefit from selenium supplementation, but as with any nutritional changes, guidance from a health professional is strongly encouraged.

References

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