Free Radical Biology and Medicine 65 (2013) 1557–1564

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Free Radical Biology and Medicine

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Review Article

Epidemiology of selenium and type 2 diabetes: Can we

make sense of it?
Margaret P. Raymana,n, Saverio Stranges b
a
Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
b
Division of Health Sciences, University of Warwick Medical School, Gibbet Hill Campus, Coventry CV4 7AL, UK

ar t ic l e i nf o a b s t r a c t

Available online 16 April 2013 The potential of some selenoproteins to protect against oxidative stress led to the expectation that selenium
Keywords: would be protective against type 2 diabetes, and indeed in early in vivo and in vitro studies, selenium (as
Selenium selenate) was shown to have antidiabetic and insulin-mimetic effects. However, more recently, findings from
Diabetes observational cross-sectional studies have raised concern that high selenium exposure may be associated
Free radicals with type 2 diabetes or insulin resistance, at least in well-nourished populations, though trial results have
been inconsistent. Moreover, the largest trials that investigated the effects of selenium supplementation on
diabetes endpoints have had cancer prevention as their primary outcome, casting doubt on the interpretation
of posthoc analyses. Factors affecting serum/plasma selenium are not just location and level of disease-
associated inflammation but the fact that higher concentrations of plasma selenoprotein P yet lower
concentrations of glutathione peroxidase are found in type 2 diabetic patients than in normal subjects.
From a public health perspective, selenium is marketed as a dietary supplement and is commonly added to
multivitamin/mineral preparations that are consumed in many Western countries. Based on current
evidence, however, the indiscriminate use of selenium supplements in individuals and populations with
adequate-to-high selenium status cannot be justified and may increase risk. In conclusion, although there is a
clear link between certain selenoproteins and glucose metabolism or insulin resistance, the relationship
between selenium and type 2 diabetes is undoubtedly complex. It is possible that the relationship is
U-shaped, with possible harm occurring both below and above the physiological range for optimal activity of
some or all selenoproteins.
& 2013 Elsevier Inc. All rights reserved.

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
Selenium and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
Low selenium could increase the risk of type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
High selenium could increase the risk of type 2 diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
What can epidemiology tell us about the relationship between selenium and type 2 diabetes risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
Cross-sectional studies of selenium and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
Longitudinal studies of selenium and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
Randomized, controlled trials of selenium and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
Possible explanations for the epidemiological findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561
Cross-sectional associations between selenium and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561
The inconsistent results of randomized controlled trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561
Public health implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562
Need for further epidemiological research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562

n
Corresponding author. Fax: +44 1483 686401.
E-mail address: m.rayman@surrey.ac.uk (M.P. Rayman).

0891-5849/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.freeradbiomed.2013.04.003
1558 M.P. Rayman, S. Stranges / Free Radical Biology and Medicine 65 (2013) 1557–1564

Introduction The potential of the selenoproteins to protect against oxidative

stress led to the expectation that selenium would be protective
The trace mineral selenium is essential for human health [1]. against type 2 diabetes, and indeed in the 1990s, selenium (as
As selenocysteine, it is the key component of a number of selenate) was shown to have antidiabetic and insulin mimetic effects
selenoproteins with essential enzymatic functions that include (see below) [17]. However, more recently, findings from observa-
redox homeostasis, thyroid hormone metabolism, and protection tional epidemiological studies and randomized clinical trials have
from oxidative stress and inflammation [2]. raised concern that high selenium exposure may lead to type 2
We know that selenoproteins play a role in certain health diabetes or insulin resistance, at least in well-nourished populations
conditions because single-nucleotide polymorphisms (SNPs) in a [18].
number of selenoprotein genes affect the risk of those conditions. The degree to which populations are adequately supplied with
Relevant to the current topic, polymorphisms in selenoproteins a nutrient is more variable for selenium than for many nutrients.
have been associated with inflammation and diabetes-related Because of wide differences in geology, soil, and climatic factors,
conditions [2,3]: SNPs in cytosolic glutathione peroxidase (GPx1) foods and fodder from various parts of the world vary greatly in
have been associated with the risks of metabolic syndrome and their ability to provide selenium for dietary intake [1,19]. Thus
macrovascular disease [4,5]; SNPs in selenoprotein S (SEPS1) have intake ranges from deficient to excessive in China, is generally low
been associated with waist-to-hip ratio, body-mass index, and in Europe, is adequate in North America and Japan, and is high in
inflammation [6]; and a SNP in type II iodothyronine deiodinase Venezuela [1,2]. Selenium status—often measured as serum,
has been associated with the prevalence of type 2 diabetes and plasma, or toenail selenium—varies accordingly, reflecting the
insulin resistance [7–9]. difference in intake in these locations [2]. Fig. 1 illustrates the
However, not all selenium in the body is present as selenopro- difference in selenium status in European countries compared to
teins; a proportion is present as selenomethionine in body proteins, those of North and South America (e.g., the United States and
e.g., in albumin in plasma [1]. Selenomethionine is the main form of Venezuela) (adapted from [20]). The fact that Finland has higher
selenium in foods, particularly in bread and cereals, and the body selenium status than other European countries reflects the man-
incorporates it as if it were methionine, being unable to distinguish dated use of selenized fertilizers in Finland since the mid-1980s
between the two [10]. To be able to be utilized for the synthesis of [21]. The figure also shows the levels of serum/plasma selenium
selenoproteins, proteins containing selenomethionine must first be required for maximal activity of plasma glutathione peroxidase
catabolized and the selenomethionine converted to hydrogen sele- (GPx3) [22] and maximal concentration of selenoprotein P (SeP)
nide (via selenocysteine and the trans-sulfuration pathway) [10]. [23], the latter being the carrier of selenium in the plasma that has
Thus selenomethionine, the form of selenium used in the largest shown an association with type 2 diabetes risk (see below). We
randomized trial to date, cannot be utilized directly. need to bear these very significant differences in selenium status
A proportion of body selenium is also present as low- in mind when interpreting epidemiological data.
molecular-weight species, some of which are derived from foods
and some of which are products of metabolism [10]. Such species
include methylselenocysteine and γ-glutamylmethylselenocys- Selenium and type 2 diabetes
teine (found in some foods and in selenium yeast) [10–12], both
of which can give rise to the unstable, reactive methyl selenol. Before examining what we can learn from the epidemiology, it is
Methyl selenol, the volatile dimethylselenol, and the trimethylse- worth noting that evidence from published studies can already be
lenonium ion are on the excretory pathway together with various adduced to show that both low and high selenium could increase the
selenosugars, these being the predominant metabolites of dietary risk of type 2 diabetes. Indeed studies in mice show that both high
selenium [10,13,14]. Selenosugars can be recycled to serve as and low expression of selenoproteins dysregulated glucose home-
substrates for the production of selenoproteins [15,16]. Thus, ostasis [24]. We will briefly examine the rationale of both approaches
selenoproteins may not be the only characters in the selenium– and the associated evidence, though other papers in this issue of the
diabetes story. journal deal with these matters in more detail [25,26].

180 America
GPx3 concentration Selenoprotein
in plasma is basis P: transports Se Finland
160
of Se requirements to body tissues Europe
Serum or plasma Se, mcg/L

140

120

100
Level
80 required
Level
required to
60 optimise
to
optimise seleno-
40 protein P
GPx3
20 activity

0
Venezuela
Toulouse, France

Spain
Barcelona, Spain
Greece
Austria

Jena, Germany
Sweden

Silesia, Poland
Hungary

Serbia
Strasburg, France

Lille, France
Bordeaux, France
Nantes, France
Verona, Italy
Veneto, Italy
Veneto, Italy

19-64 yr, UK
Milan, Italy

Czech Republic

Yugoslavia

Ireland

Wales, UK
Elderly, UK
4-18 yr old, UK
Scotland, UK

Finland, 2010
USA 2003-4
Odense, Denmark
Odense, Denmark

Fig. 1. Levels of serum/plasma Se in Europe (adapted from [20]) and comparison with those in the Americas. The levels required to optimize GPx3 activity [22] and
selenoprotein P concentration are shown [23].
 M.P. Rayman, S. Stranges / Free Radical Biology and Medicine 65 (2013) 1557–1564
Low selenium could increase the risk of type 2 diabetes
Though in vivo and in vitro studies have shown antidiabetic
and insulin-mimetic effects of selenium (generally as selenate),
doses have been used that would be toxic to humans, calling into
question the relevance of these findings [17,27,28].
Type 2 diabetes is associated with oxidative stress attributable
to the production of excess levels of reactive oxygen species in
hyperglycemia [29]. As pancreatic β cells are poorly protected by
intrinsic enzymatic antioxidants and are very susceptible to
oxidative injury, it might be thought that the antioxidant sele-
noenzyme GPx could protect against that stress [29]. Indeed
overexpression of GPx in islets provided enhanced protection
against oxidative stress [29], whereas selenium, as selenite or
selenate at physiological levels, was able to stimulate pancreatic
β-cell gene expression and enhance islet function [30]. Whether
cause or consequence, plasma GPx3 concentration was decreased
in newly diagnosed, drug-naïve diabetic patients compared to
subjects with normal or impaired glucose tolerance and was lower
in db/db than in normal mice [31].
Another selenoprotein, SEPS1, seems to protect the β cell
against endoplasmic reticulum stress and oxidative stress and
may protect against β-cell apoptosis [32].
High selenium could increase the risk of type 2 diabetes
Binding of insulin to its receptor initiates the insulin-signaling
cascade which is accompanied by a burst of hydrogen peroxide
that acts as a second messenger [17]. High activity of GPx1 can
interfere with insulin signaling by removing hydrogen peroxide
[17,33]. Thus transgenic mice overexpressing GPx1 developed
insulin resistance, hyperglycemia, hyperinsulinemia, and obesity
[33,34], whereas knockout of GPx1 improved insulin-induced
glucose uptake and insulin resistance [35].
SeP has also been implicated in insulin resistance [36]. In vitro,
in the presence of insulin, SeP modulated insulin signaling to
upregulate mRNA expression of gluconeogenic enzymes, resulting
in a 30% increase in glucose release. Treatment of mice with
purified SeP impaired insulin signaling in liver and skeletal muscle
and induced glucose intolerance [36]. Conversely, knockdown of
the gene for SeP in liver improved glucose tolerance and reduced
insulin resistance in mice with type 2 diabetes, and mice deficient
in SeP showed improved glucose tolerance and enhanced insulin
signaling [36]. It is thought that the effect of SeP is at least partly
through the inactivation of AMP-activated protein kinase, a posi-
tive regulator of insulin synthesis and secretion in pancreatic
β cells [36].
In support of the above findings, individuals with a reduced
ability to synthesize many selenoproteins had enhanced systemic
and cellular insulin sensitivity [37].
Table 1
Cross-sectional studies of selenium and type 2 diabetes.
Country Study
France SU.VI.MAX
USA NHANES III
USA NHANES 2003-4
Italy Olivetti Heart Study
China Chinese population
France Eva Study
Singapore Asian population
USA Health Professionals
T2D, type 2 diabetes; FPG, fasting plasma glucose; NS, nonsignificant.
a
Unadjusted analysis.
1559
What can epidemiology tell us about the relationship between
selenium and type 2 diabetes risk?
Cross-sectional studies of selenium and type 2 diabetes
Five of eight studies identified significant positive associations
between serum/plasma selenium and type 2 diabetes or fasting
plasma glucose [38–42], two showed no significant association
[43,44], and one showed an inverse association [45] (see Table 1).
However, cross-sectional studies are notably subject to con-
founding and have the potential for reverse causation; indeed
two of these studies used unadjusted data [41,42], whereas the
Singapore-based study adjusted only for age [44]. Furthermore,
although the majority of studies seem to suggest a positive
relationship between higher selenium and type 2 diabetes, it has
to be noted that cross-sectional studies cannot show causality and
do not allow us to determine whether high selenium is a cause or
a consequence of the disease process. We will return to potential
explanations of the cross-sectional study results below.
Longitudinal studies of selenium and type 2 diabetes
Longitudinal studies have generally not supported a causal role
for selenium in type 2 diabetes [46–48]. In an 8-year follow-up
analysis of 445 adult males in the Olivetti Heart Study, baseline
selenium status was not prospectively associated with type 2
diabetes; however, the cumulative incidence was only 1.4%, con-
straining the statistical power of the analysis [46]. Prospective
findings from the Epidemiology of Vascular Aging study in France
over a 9-year follow-up period showed that high plasma selenium
(94–156 μg/L) was associated with a marginally significantly
reduced risk of hyperglycemia (impaired fasting glucose or dia-
betes) in men [47]. Recently, a pooled longitudinal analysis from
two U.S. cohorts (i.e., Health Professionals Follow-up Study and
Nurses’ Health Study) showed inverse associations between toe-
nail selenium and incident type 2 diabetes; diabetes risk reduced
as quintile of toenail selenium increased [48]. Conversely, in a
prospective study on a large sample of women from northern Italy,
an increased risk of type 2 diabetes was associated with higher
dietary selenium intake; however, it has to be admitted that
dietary assessments of selenium intake are unreliable so not much
weight can be attached to this result [49].
Randomized, controlled trials of selenium and type 2 diabetes
A number of randomized, controlled trials have examined the
effects of selenium on the risk of type 2 diabetes [50–55]. These
were generally cancer trials in which type 2 diabetes was only a
secondary outcome.
The Nutritional Prevention of Cancer (NPC) trial randomized
1312 U.S. subjects with a history of nonmelanoma skin cancer to
Matrix Association Ref.
Plasma Higher Se, higher FPG [38]
Serum Higher Se, higher T2D [39]
Serum Higher Se, higher T2D [40]
Serum Higher Se, higher T2Da [41]
Fingernails Higher Se, higher T2Da [42]
Plasma Higher Se, higher T2D but NS [43]
Serum No significant association [44]
Toenails Higher Se, lower T2D [45]
1560 M.P. Rayman, S. Stranges / Free Radical Biology and Medicine 65 (2013) 1557–1564
0.15
Selenium
0.10
Incidence
Placebo
0.05
Log-rank test p value = 0.050
0.00
0 5 10
Years of follow-up
Fig. 2. Cumulative incidence of type 2 diabetes. The P value was derived from the
log-rank test (reproduced with permission from [50]).
200 μg/day selenium as high-selenium yeast or placebo yeast [50].
The mean lengths of treatment and follow-up were 4.5 and 7.7 years,
respectively. In a posthoc analysis, the risk of developing type 2
diabetes was significantly higher in the selenium-supplemented
group than in the placebo group (hazard ratio (HR) 1.55; 95% CI,
1.03 to 2.33) (see Fig. 2). Mean baseline plasma selenium in the
cohort was 114 μg/L, low for the United States, but much higher than
in Europe. When subjects were divided into tertiles by baseline
plasma selenium, a significantly increased risk of type 2 diabetes was
found only in the highest tertile, i.e., those with plasma selenium
>121.6 μg/L (HR 2.70; 95% CI, 1.30 to 5.61) [50].
Based on the reduction in risk of prostate cancer seen in the
NPC [56] and ATBC [57] trials, SELECT (Selenium and Vitamin E
Cancer Prevention Trial) was initiated to investigate the effects of
supplementation with selenium and vitamin E on prostate cancer
[51,52]. Men (n ¼35,533) from 427 participating sites in the United
States, Canada, and Puerto Rico were randomized to selenium
(200 μg/day as selenomethionine), or vitamin E (400 IU/day of all
rac-α-tocopheryl acetate), or selenium plus vitamin E, or matched
placebos. The trial was stopped early, after 5.5 years of follow-up,
when it became apparent that there was no benefit to prostate-
cancer risk. As a secondary outcome, the effect of selenium
treatment on type 2 diabetes risk was reported as follows:
“A statistically nonsignificant increase in type 2 diabetes mellitus
(diagnosed after randomization) occurred in the selenium alone
group vs placebo group” [51]. However, it would have been more
correct to report that selenium had no effect on type 2 diabetes
risk: RR 1.07; 99% CI 0.94 to 1.22; P ¼0.16 [51]. After a further 33
months of follow-up, the risk was correctly reported as “not
statistically significant”: HR 1.04; 99% CI 0.93 to 1.17; P ¼0.34
[52]. Given the difference in effect seen on type 2 diabetes risk in
this trial and the NPC trial, it should be noted that SELECT men had
quite high selenium status at baseline (serum selenium 136 μg/L)
[51], considerably higher than NPC trial participants(114 μg/L)
[56].
The PRECISE trial (Prevention of Cancer by Intervention with
Selenium) was planned in Denmark, Sweden, and the United
Kingdom but only 500-person pilot studies were ever carried out
as funding was never secured for the main trial [58–60]. However,
stored plasma samples from the U.K. PRECISE pilot trial were used
to investigate the effect of selenium supplementation on type 2
diabetes risk in 501 elderly volunteers treated for 6 months with
100, 200, or 300 mg selenium/day as high-selenium yeast or
placebo yeast [53]. Plasma adiponectin, a recognized independent
predictor of type 2 diabetes risk and a valid biomarker in
nonfasted samples [61–65], was measured at baseline and at the
6-month follow-up to assess the effect on type 2 diabetes risk.
Echoing the findings of a number of cross-sectional studies
[38–42], and remembering that higher adiponectin is associated
with lower type 2 diabetes risk [61–63], we found an inverse
association between selenium and adiponectin concentrations at
baseline, which became significant after adjustment for high-
density lipoprotein cholesterol. However, we found no effect of
selenium supplementation on plasma adiponectin (Poverall ¼0.86).
Limitations of this trial were the short duration (6 months) and the
limited age range (60–74 years) of the participants.
As a secondary endpoint, the effect of selenium supplementa-
tion on serum glucose levels was investigated in a small trial on
140 men with prostate cancer enrolled in a clinical trial to test the
effects of selenium on prostate cancer progression (Watchful
15 Waiting Trial) [54]. Participants were randomly assigned to sele-
nium yeast or placebo yeast for up to 5 years as follows: 46 men to
200 μg/day selenium, 47 men to 800 μg/day selenium, 47 men to a
yeast placebo. Serum glucose levels were obtained every 6 months
for up to 5 years. Despite the considerable length of the study and
the amount of selenium given (and a high baseline plasma
selenium of 135 μg/L), no significant difference was found in serum
glucose levels between any of the groups.
Finally, there was a small trial of selenium supplementation
(200 μg selenium/day as selenium yeast) in 84 premenopausal
Iranian women with central obesity, though all participants were
also on a hypocaloric diet enriched in legumes [55]. Selenium
status was not measured either at baseline or at follow-up. After
6 weeks, selenium supplementation had significantly lowered
fasting concentrations of serum insulin (P ¼0.05) and the home-
ostasis model assessment of insulin resistance index (P ¼0.04),
suggesting that even such a short intervention with selenium had
a beneficial effect on type 2 diabetes risk. It should be noted,
however, that only the 81% of subjects who finished the trial were
included in the data analysis.
Obviously, there are concerns about the robustness of results
from secondary endpoints or subgroup analyses of clinical trials, and
the potential usefulness of these results to inform public health
guidelines or clinical recommendations has been questioned [66,67].
Caution is therefore needed in the interpretation of findings from
posthoc analyses of clinical trials and secondary endpoints, such as
type 2 diabetes in the SELECT and the NPC trial, given the intrinsic
limitations and potential biases of such an approach.
Specifically, in both the NPC trial and the SELECT, diagnosis of
type 2 diabetes was based on self-report or use of diabetes medica-
tion rather than on biomarker data. This may have led to some
misclassification of diabetes at baseline or during the trials, particu-
larly as type 2 diabetes is believed to be substantially underdiag-
nosed. However, given the randomized design and blinding,
differential misclassification according to treatment assignment is
unlikely. Furthermore, the effect of nondifferential misclassification
would probably be to underestimate the true relative risk and
decrease the statistical power of these studies [68].
A further limitation of the evidence to date concerns the
generalizability of results from the above-mentioned trials to the
general public because of the selective nature of the participants
randomized. Specifically, SELECT recruited only male participants
from a selenium-replete population, therefore, the applicability of
SELECT findings to the female gender or to populations with lower
dietary selenium intakes and suboptimal or deficient selenopro-
tein status is uncertain. The NPC trial sample consisted of indivi-
duals (mean age, 63.2 years) from the eastern United States who
had a history of nonmelanoma skin cancer, thus limiting the
generalizability of the NPC findings to other population subgroups.
Finally, the PRECISE trial sample was based on a group of relatively
healthy, elderly white volunteers [mean (SD) age, 67.5 (4.1) years],
recruited from four general practices in various parts of the
United Kingdom. Again, the generalizability of PRECISE findings
 M.P. Rayman, S. Stranges / Free Radical Biology and Medicine 65 (2013) 1557–1564
Table 2
Summary of randomized controlled trials with selenium as a single agent.
Trial and Ref. Participants (n) Baseline
plasma/serum Se (μg/L)
PRECISE [53] 473 92
NPC [50] 1,202 o 105
105–122
>122
SELECT [51,52] 34,888 136
136
Watchful Waiting [54] 140 135
HDEL and selenium [55] 68 Not measured
T2D, type 2 diabetes; HDEL, hypocaloric diet enriched in legumes; HOMA-IR, homeostasis model assessment of insulin resistance index.
to younger adults or to other population subgroups is uncertain.
Altogether, the relatively selective nature of participants in these
trials makes the generalizability of their evidence questionable.
The trials that used selenium as a single agent are summ-
arized in Table 2. We attempt to explain the various trial
outcomes below.
Possible explanations for the epidemiological findings
Cross-sectional associations between selenium and type 2 diabetes
The cross-sectional associations between serum/plasma selenium
and type 2 diabetes, which were mainly positive, have a number of
possible explanations: selenium could cause an increased risk of type 2
diabetes, the associations could be the result of reverse causation
through behavioral changes after diagnosis [18], the association
between selenium and type 2 diabetes could be a result of pathophy-
siological changes associated with diabetes, or both selenium and type
2 diabetes may be affected by a third factor or factors.
Dealing with the last two possibilities first, we know that the
expression of SeP and gluconeogenic enzymes is linked. Increased
expression of SeP will raise plasma selenium and increased expres-
sion of gluconeogenic enzymes will raise plasma glucose. There are
two plausible mechanisms: (i) interaction of HNF-4α and FoxO1a
with their coactivator PGC-1α on the SeP promoter stimulates the
expression of SeP. PGC1-α interacts with FoxO1a to stimulate the
expression of gluconeogenic enzymes. Insulin inactivates FoxO1a,
inhibiting the transcription of gluconeogenic enzymes and SeP,
whereas high glucose has the opposite effect [69,70]; (ii) hepatoce-
lular S-adenosyl methionine-dependent protein methylation is
required for both SeP and gluconeogenic enzyme expression. Tran-
scriptional regulation of SeP is directed by the same transcription
factors that control the expression of glucose-6-phosphatase and
phosphoenolpyruvate carboxykinase 1, and these factors are acti-
vated by methylation of arginine residues [71].
This linked expression could explain a number of findings:
(i) the significant upregulation of SeP expression found in subjects
with type 2 diabetes [72]; (ii) the significant correlations found
between SeP, a major component of selenium in plasma, and
fasting plasma glucose and between SeP and glycosylated hemo-
globin (HbA1c), a marker of type 2 diabetes [36]; and (iii) the
significantly higher serum SeP concentrations in people with type
2 diabetes or prediabetes than in those with normal glucose
tolerance [73].
Of course the cross-sectional associations could result from
selenium, as SeP, causing type 2 diabetes. However, longitudinal
and prospective studies have not supported such a causal role nor
have trial results been as consistent as would be expected if this
were the case.
1561
Effect of Se supplementation Length of
on T2D/plasma glucose treatment/follow-up
No effect 6 months/6 months
No effect 4.5 years/7.7 years
No effect
Significant adverse effect
No effect 5.5 years/5.5 years
No effect 5.5 years/8.2 years
No effect ≤5 years
Significantly lowered fasting 6 weeks
serum insulin and HOMA-IR
The inconsistent results of randomized controlled trials
From Table 2, there appears to be no adverse effect of selenium
supplementation when selenium status is low. However, the effect
of supplementation with selenium in those of higher selenium
status is not consistent, i.e., an increased risk of type 2 diabetes in
those in the top tertile of selenium status at baseline in the NPC
trial [50] but no effect in SELECT [51,52]. A number of possible
explanations for this inconsistency can be explored.
1. Could the NPC trial results be a chance finding? Results derive
from a posthoc analysis of a small trial—only 58 subjects on
selenium and 39 on placebo developed type 2 diabetes [50].
SELECT was a much larger study and its findings are therefore
more robust [51,52].
2. Was the selenium status of SELECT men at baseline already
above a threshold of risk? SELECT men on placebo had a greater
risk of type 2 diabetes than NPC subjects on placebo (cases per
1000 person-years, 14.1 vs 8.4) [50,51], perhaps because of their
higher selenium status, and an additional supplement of
selenium may have conferred little extra risk.
3. Selenium supplementation would have increased SeP, impair-
ing insulin signaling in NPC subjects [36], but not in SELECT
subjects, whose baseline selenium status was already high
enough at baseline for SeP to be maximized [23].
4. The form of selenium used in SELECT was different from
that used in the other trials summarized in Table 2 and notably
from that used in the NPC trial. SELECT men were supplemen-
ted with selenomethionine, which as explained in the intro-
duction, cannot be utilized directly. Furthermore, depending
on the manufacturer, between 26 and 46% of the selenium
in selenium yeast is present as other selenium species [10],
including low-molecular-weight species that may have a dif-
ferent biological effect.
5. Was there an additional risk factor in NPC participants that was
not there in SELECT? NPC trial subjects had all had nonmela-
noma skin cancer [74]. Many worked on farms with great
potential for arsenic pesticide exposure [74]. Sixty percent of
the NPC participants had at least one punctate keratosis of the
palm, believed to result from arsenic exposure [72]. Arsenic
exposure increases the risk of type 2 diabetes as shown by data
from 788 adults in NHANES 2003–2004 who had urine arsenic
determinations; the OR for type 2 diabetes in participants at
the 80th vs the 20th percentile of total arsenic was 3.58 (95% CI,
1.18 to 10.83) [75]. A copious literature documents interactions
between selenium and arsenic (e.g., [76,77]). Could arsenic
exposure have contributed to the significant effect of selenium
supplementation on type 2 diabetes risk seen in this trial?
Arguing against this is the fact that SELECT men on placebo
appeared to have a greater risk of type 2 diabetes than NPC
1562 M.P. Rayman, S. Stranges / Free Radical Biology and Medicine 65 (2013) 1557–1564
subjects on placebo [50,51], assuming that the comparison of
cases per 1000 person-years between trials is valid.
Public health implications
Selenium is marketed as a dietary supplement and a component
of enriched foods based on its essentiality for optimal health. It is
commonly added to multivitamin/mineral preparations that are
consumed by the general public in many Western countries. How-
ever, results from the available evidence, based on observational
studies and a small number of clinical trials, do not support a
beneficial role for selenium supplementation in the primary preven-
tion of type 2 diabetes. Indeed, given the limited trial evidence to
date, an increased risk of diabetes with selenium supplementation
cannot be ruled out, particularly in those individuals and populations
with adequate-to-high selenium status, i.e., plasma/serum selenium
≥122 mg/L [50]. Current trial evidence mostly comes from U.S.-based
studies, in which average selenium intake is above the levels required
for maximal selenoprotein activity/concentration [1,2]. Health bene-
fits of additional selenium from supplementation in such populations
are therefore unlikely. In line with this view, recent findings from
SELECT showed no benefit of selenium supplementation for cancer
prevention among healthy male individuals from the selenium-
replete populations of the United States and Canada, with a median
baseline serum selenium concentration of 136 μg/L [51,52], probably
approximating to a baseline intake of around 130 mg/day, by inter-
polation from other data [23,58]. Not only that, SELECT men taking
selenium (200 mg/day as selenomethionine) had a significantly
greater risk of alopecia and dermatitis than those on placebo,
suggesting marginal selenium toxicity [1] and illustrating the inad-
visability of selenium supplementation in people of adequate or high
selenium status.
Though we warn against the indiscriminate and widespread
use of selenium supplements in individuals and populations with
adequate-to-high selenium status, there are specific population
groups that might benefit from additional selenium intake, nota-
bly those living in areas with low selenium in the food supply, as
implied by Fig. 1 for countries of Europe (other than Finland).
However, even in Europe, except under exceptional circumstances,
there can be little or no justification for supplementation with
selenium above 100 mg/day; e.g., UK PRECISE trial volunteers with
a baseline dietary intake of approximately 40 mg/day, supplemen-
ted with 100 mg selenium/day as selenium-enriched yeast experi-
enced a rise in plasma selenium from 92 to 148 mg/L [58], which is
well above the level required to maximize the concentration of SeP
[23] and possibly all other selenoproteins. The potential benefit of
selenium supplementation in certain genetic subgroups, those
with poor antioxidative capacity, or in patients with chronic
conditions (e.g., HIV, chronic kidney disease) may warrant further
investigation [78].
Need for further epidemiological research
There is a lack of trials specifically designed to address the role
of selenium (as a single nutrient) in diabetes prevention that
encompass a wide range of selenium concentrations. Such rando-
mized trials, particularly in populations with suboptimal selenium
status, would help to determine the optimal level of selenium
intake in the general population that would maximize health
benefits while avoiding potential toxic effects. As optimal intake
for any individual is likely to depend on polymorphisms in
selenoprotein genes that affect disease risk [2–9], future studies
should genotype participants and investigate the potential inter-
action between genotype and selenium intake or status. Further
trial evidence with a larger representation of women is also
desirable, given the well-known differences in cardiometabolic
risk factor profiles between women and men [79] and the
suggested gender differences in the response of selenoprotein
biomarkers to selenium supplementation [80].
Conclusions
As the foregoing sections show, the relationship between
selenium and type 2 diabetes is undoubtedly complex. There is
no doubt that there is a relationship between plasma SeP and type
2 diabetes in that higher concentrations of SeP have been found in
type 2 diabetic than in nondiabetic subjects [36,73]. By contrast,
significantly lower plasma GPx3 protein concentrations were
found in type 2 diabetes patients than in subjects with normal
glucose tolerance resulting from lower GPx3 expression [31]. As
major contributors to plasma selenium, these two factors will have
opposing effects on apparent selenium status. A further complica-
tion is that plasma selenium is lowered by the systemic inflam-
matory response [81,82] that is a feature of type 2 diabetes [83].
Indeed the expression of SeP is normally reduced in the inflam-
matory state [84,85], despite the finding of higher concentrations
in diabetics. These contradictions may possibly be explained by
taking into account stage of disease—whether impaired glucose
tolerance or well-established type 2 diabetes—and associated
level of oxidative stress, which may influence the levels of these
selenoproteins in the plasma.
It should of course be remembered that SeP and GPx3 are not
the only components of measured plasma selenium. In selenium-
replete U.S. populations, selenium from nonspecific components,
which may have some functionality, amounted to 36% of a total
plasma selenium of 125 mg/L [86] and 46% of a total plasma
selenium of 142 mg/L [87]. In populations of lower selenium status,
the ratio of selenoproteins to nonspecific components will be
higher [2] and indeed, if the selenium supply is sufficiently low,
the ratio of selenoproteins to one another will alter according to
selenoprotein hierarchy [88]. Thus some of the inconsistencies
between studies may be explained by the variability in selenium
status and plasma components between various countries and
population groups [1,2].
Inconsistencies could also stem from the use of different
biomarkers. According to Ray Burk (personal communication,
2012), it is possible that selenium incorporation into toenails is
mostly nonspecific (selenomethionine, selenotrisulfides, other
forms) and therefore that toenail selenium concentration is a
mere bystander. He is therefore skeptical of relating toenail
selenium measurements to disease.
Finally, it may be that the association between selenium and
cardiometabolic outcomes is U-shaped, with potential harm
occurring both below and above the physiological range for
optimal activity of some or all selenoproteins [2,18,89]. Such
relationships are common with nutrients [90].
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