The results could lead to interventions that reproduce many of the anti-aging effects associated with dietary restriction while also allowing people to eat as normal.
Several types of diet have been shown to increase healthspan – that is, the period of healthy lifespan. One of the proven methods of increasing healthspan in many organisms, including non-human mammals, is to restrict dietary intake of an amino acid called methionine.
Recent studies have suggested that the effects of methionine restriction on healthspan are likely to be conserved in humans. Although it might be feasible for some people to practice methionine restriction, for example, by adhering to a vegan diet, such a diet might not be practical or desirable for everyone.
In the current study, a research team from the Orentreich Foundation for the Advancement of Science (OFAS), Cold Spring, New York, US, aimed to develop an intervention that produces the same effects as methionine restriction, while also allowing an individual to eat a normal, unrestricted diet.
An important clue for developing such a treatment is that methionine restriction causes a decrease in the amounts of an energy-regulating hormone called IGF-1. If a treatment could be found that causes a similar decrease in IGF-1, this might also have beneficial effects on healthspan. Previous research has shown that selenium supplementation reduces the levels of circulating IGF-1 in rats, suggesting that this could be an ideal candidate.
The team first studied whether selenium supplementation offered the same protection against obesity as methionine restriction. They fed young male and older female mice one of three high-fat diets: a control diet containing typical amounts of methionine, a methionine-restricted diet, and a diet containing typical amounts of methionine as well as a source of selenium.
Next, they explored the effects of the three diets on physiological changes normally associated with methionine restriction. To do this, they measured the amounts of four metabolic markers in blood samples from the previously treated mice. As hoped, they found dramatically reduced levels of IGF-1 in both male and female mice.
They also saw reductions in the levels of the hormone leptin, which controls food intake and energy expenditure. Their results indicate that selenium supplementation produces most, if not all, of the hallmarks of methionine restriction, which suggests that this intervention may have a similar positive effect on healthspan.
To gain insight into the beneficial effects of selenium supplementation, the researchers used a different organism – yeast. The two most widely used measurements of healthspan in yeast are chronological lifespan, which tells us how long dormant yeast remain viable, and replicative lifespan, which measures the number of times a yeast cell can produce new offspring.
The team previously showed that methionine restriction increases the chronological lifespan of yeast, so they tested whether selenium supplementation might do the same.
As it turned out, yeast grown under selenium-supplemented conditions had a 62% longer chronological lifespan (from 13 days to 21 days) and a replicative lifespan extended by nine generations as compared with controls. This demonstrates that supplementing yeast with selenium produces benefits to healthspan detectable by multiple tests of cell aging.
“One of the major goals of aging research is to identify simple interventions that promote human healthspan,” notes senior author Jay Johnson, Senior Scientist at OFAS.
“Here we present evidence that short-term administration of either organic or inorganic sources of selenium provides multiple health benefits to mice, the most notable of which being the prevention of diet-induced obesity. In the long term, we expect that supplementation with these compounds will also prevent age-related disease and extend the overall survival of mice. It is our hope that many of the benefits observed for mice will also hold true for humans.”
With its name derived from the Greek word “Selene,” selenium has caught attention as a micronutrient since 1817, when it was first described as a by-product from sulphuric acid production. Although selenium is an essential element which is naturally occurring in the body, its endogenous level fluctuates across populations in different geographical areas, as well as different age groups in the same area, indicating that both environmental and internal factors may affect the selenium level [1, 2].
Both organic and inorganic forms of selenium can be absorbed by the small intestine and in turn can be widely distributed in various body tissues and render important biological functions, primarily through regulating the synthesis of selenoproteins [3].
Human selenoproteins are a series of 25 selenium-containing proteins whose synthesis requires insertion of a selenium-containing homolog of cysteine. The major role of multiple selenoproteins, such as glutathione peroxidase (GPX), thioredoxin reductase (TrxR), and iodothyronine deiodinases (IDD), is to act as important intracellular antioxidants in preventing oxidative injury [4]. Therefore, the importance of selenium supplementation in boosting up the internal antioxidative defence has been highlighted in recent years.
It was not until 1957 that the therapeutic role of selenium as a micronutrient was identified by Wrobel et al., who observed that selenium supplementation at a low dose can prevent a rat liver from necrosis [3]. Since then, mounting studies have suggested the beneficial effects of selenium supplementation in maintaining immune-endocrine function, metabolic cycling, and cellular homeostasis.
In addition to its essential physiological function, the potential of selenium supplementation in remitting human pathological conditions, especially chronic metabolic disorders, has been frequently proposed. Wei et al. found that daily selenium intake has a negative correlation with metabolic syndromes [5]; however, the role of selenium supplementation as antioxidants in major metabolic syndromes, such as hyperlipidaemia and hyperglycaemia, has not yet been critically reviewed.
Here, we retrieved studies from PubMed database and systematically reviewed the biological activity and underlying mechanism of selenium in various metabolic diseases. Toxicity and recommended dose of selenium were reviewed and discussed. In addition, as the molecular action of selenium was less identified, we predicted and discussed the potential interaction on gene networks and signalling proteins upon selenium supplementation.
The Role of Selenium in Treatment of Hyperlipidaemia
Hyperlipidaemia refers to a phenomenon of abnormal high concentrations of lipid products and lipoproteins in the blood. It could be primarily caused by the genetic and familial factors, but in most of the cases, it is triggered by other metabolic disorders. Secondary hyperlipidaemia is a kind of metabolic abnormality involved in several chronic human diseases, such as diabetes and obesity.
Healthy young subjects with higher dietary selenium intake (higher than 82.4 μg/day) showed lower level of sialic acid and triacylglycerol, and they exhibited reduced inflammatory response and prevalence of metabolic syndromes such as lipid profile impairment and insulin resistance [6].
It was found that increased hair selenium concentration in hyperlipidemic patients had adverse association with their lipid profiles [7]. Karita et al. showed that the selenium level in erythrocytes may be an indicative factor of decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) after menopause in Japanese premenopausal and postmenopausal women [8]. This indicated the beneficial effect of selenium intake in regulating lipid metabolism. In contrast, another study found that plasma selenium level was raised in preaging cases (aged 59–71) of lipemia [9].
In rats with hyperlipidaemia caused by diazinon, one of the most organophosphate insecticides used in agriculture and industry, selenium supplementation in the form of sodium selenite (200 μg/kg/d) could normalize the serum thiobarbituric acid reactive substances (TBARS), total lipids, cholesterol, urea, and creatinine, which may be due to the induced antioxidant enzymes and glutathione content [10].
Additionally, nicotine reduced the intestinal intake of selenium and caused hyperlipidaemia in rats. Selenium supplementation (1 μg/kg/d) improved the hyperlipidaemic condition, as evidenced by the reduced expression of hydroxymethylglutaryl-CoA reductase (HMGCoA) and lipogenic enzymes [11]. In Triton WR-1339-induced hyperlipidaemia, supplementation of selenium in the form of diphenyl diselenide (10 mg/kg) increased the high-density lipoprotein cholesterol (HDL-C) while reduced the non-HDL and triglyceride in the serum of mice, indicating its hypolipidemic effect [12].
But another study suggested that this effect was independent to its antioxidant property [13]. Furthermore, it was found that hyperlipidaemia had a significant adverse effect on male fertility, while supplementation of inorganic selenium or selenium-enriched probiotics (equivalent to 0.05 μg/g Se) was suggested to improve fertility in humans and animals [14].
Arteriosclerosis
Kalkan et al. found that dyslipidemic patients with glycogen storage disease type I and type III, which did not lead to premature atherosclerosis, exhibited lower plasma concentration of selenium compared with healthy control [15]. Chan et al. found that selenium deficiency may be associated with reduced arterial function in patients, with higher potential of vascular incidents [16].
Supplementation of selenium in the form of selenium yeast (0.1 mg/kg) subsidized the cardiac enzymes, lipid peroxidation, and inflammation, indicating that it can improve myocardial performance by preventing oxidative damage [17].
Treatment of a formula containing selenium (10 ppm for 30 days) might modulate the lipid profile of hyperlipidaemic rats, mainly reducing the level of TC, non-HDL-C, and atherogenic index [13]. In contrast, another study in British adults showed that higher level of selenium in serum indicated an adverse cardiometabolic risk, with increased total and non-HCL cholesterol [18].
Supplementation of selenium was also suggested when antiatherogenic mode of nutrition was applied to patients, according to a study of 800 persons, in which the results indicated that sodium selenite treatment could give out a favourable outcome on the immune system [19]. Delattre and colleagues showed that treatment of LDL apheresis might be the direct cause of low plasma selenium in normocholesterolemic subjects [20].
This was further evidenced by the observation that LDL apheresis treatment, which eliminated cholesterol-containing LDL from bloodstream, could lower plasma level of selenium but not the other antioxidants including vitamin E and β-carotene [21]. However, an argument was raised on a long-term benefit of LDL apheresis treatment in reducing atherogenic cholesterol oxidation products (COP) in the plasma, and therefore acute drop of selenium by the treatment seemed not meaningful [22].
Hypercholesterolemia
The significance of serum selenium concentration was highlighted by the study from Galicka-Latala and colleagues. The lipid peroxidation marker malondialdehyde (MDA) had a negative correlation with serum selenium level in both normo- (plasma total cholesterol less than 5.2 mmol/L) and hypercholesterolemic (plasma total cholesterol greater than 5.2 mmol/L) patients, while the MDA, to be specific in low-density lipoprotein, was negatively associated with selenium level in patients diagnosed with hypercholesterolemia [23].
In an experimental model, deficiency of selenium in hypercholesterolemic animal led to lower expression of hepatic LDL receptor and HMG-CoA reductase but elevated apolipoprotein B (ApoB) level, which can be subsidized by selenium resupplementation (1 ppm) [24–26]. In high-fat diet-fed rats, treatment of selenite (0.173 mg/kg/d via gavage for 10 weeks) could suppress LDL-C in serum, triglyceride, and TC in the liver, which was probably due to the reduced expression of fatty acid synthase [27].
Kaur et al. found that supplementation of selenium (1 ppm) could diminish the high-fat diet-induced ROS levels by 29% and suppress the serum paraoxonase 1 but not platelet-activating factor acetylhydrolase, indicating its potential in limiting the complications of hypercholesterolemia [28].
Furthermore, selenium supplementation (1 ppm) could restore the reduced T3 and T4 hormones in the serum of high-fat diet-fed rabbits, with improvement of type I iodothyronine 5′-deiodinase (5′-DI) in the liver, indicating that selenium is capable of regulating thyroid behaviours in hyperlipidaemic state [29, 30]. Selenium supplementation (2.5 mg/kg, i.p.) was also found to improve dysregulated renal morphology caused by hypercholesterolemia [31].
The Role of Selenium in Treatment of Hyperglycaemia
A lot of studies have revealed that hyperglycaemic patients exhibited selenium deficiency in the blood, though a study in diabetic Germans showed that blood selenium level was higher in patients with hyperglycaemia [32]. Compared with some contradicting outcomes in the therapeutic effect of selenium supplementation on type 2 diabetes mellitus, it is quite a consensus that selenium is beneficial for patients with type 1 diabetes mellitus as well as for treatment of hyperglycaemia-related complications.
Type 1 Diabetes Mellitus
It was found that selenium was distinctly decreased in the red blood cells of type 1 diabetic patients and was negatively correlated with the elastic and viscous component of whole blood viscosity, indicating the selenium deficiency in red blood cells may be associated with impaired haemorpheology of type 1 diabetic patients [33]. Another study showed that selenium level in erythrocyte was lower in type I diabetic groups [34].
Sheng et al. treated alloxan-induced diabetic mice with sodium selenite (via gavage, 2 mg/kg/d for 4 weeks) and found that selenite reduced blood glucose and improved glutathione (GSH) levels in the liver and brain of diabetic mice; nonetheless, selenite treatment in normal mice surprisingly reduced hepatic GSH level [35]. Using STZ-induced diabetic model, Guney and colleagues found that combination of vitamin E (60 mg/kg/d) and sodium selenite (1 mg/kg/d) treatment decreased blood glucose level by inducing expression and activities of several antioxidant enzymes, such as catalase, superoxide dismutase, and GPX [36].
Similar antioxidant treatment could also reverse the skin lipid peroxidation and subsequent damage [37]. Furthermore, Satyanarayana et al. found that half or single therapeutic dose of selenium (0.9 and 1.8 μg/200 g, resp.) had hypoglycaemic effect in alloxan-induced diabetic animal, while double dose of selenium (3.6 μg/200 g rat) increased blood glucose. Combination treatment of selenium improved the hypoglycaemic effect of gliclazide in both normal and diabetic animals [38].
Atalay et al. compared the effect of oral administration of sodium selenate (0.3 mg/kg/d) and doxycycline on STZ-induced hyperglycaemic rats and concluded that selenate can reduce blood glucose level without triggering significant loss of body weight. Selenate preserved thioredoxin-1 (TRX-1) level in skeletal muscle but not in the liver, while the protein carbonyl capacity and oxygen radical absorbance capacity in the liver were suppressed.
In addition, free and total protein thiol levels were restored by selenate treatment (0.3 mg/kg, p.o.) in both the skeletal muscle and liver of diabetic rats [39]. Bajpai et al. had similar conclusion about the hypoglycaemic effect of sodium selenite, another inorganic form of selenium in STZ-induced diabetic rats. Treatment of selenite (10–30 μg/ml for 14 days) can reduce serum glucose and improve the wound closure of diabetic mice by normalizing the low levels of vascular endothelial growth factor (VEGF) and extracellular superoxide dismutase.
It also improved angiogenesis in the wound site of diabetic rats [40]. Mechanistically, Chen et al. suggested that selenium (1 ppm) might play an insulin-like role to normalize the glucose metabolism and improve glucose uptake and metabolism in the liver of alloxan-induced diabetic animals [41]. Selenium supplementation (5 ppm/d for 4 weeks) could restore glucagon-like peptide 1 receptor (GLP-1R) expression and suppress insulin receptor substrate-1 (IRS-1) and Raf-1 in the liver, which may render hypoglycaemic effect on STZ-induced diabetic rats [42].
In addition, Kahya et al. showed that 1.5 mg/kg/d of sodium selenite treatment can improve brain and erythrocyte lipid peroxidation and plasma IL-1β and IL-4 levels due to the restoration of antioxidant status in STZ-induced diabetic rats [43]. Erbayraktar et al. compared the hypoglycaemic effect of different forms of selenium in STZ-induced diabetic rats and found that both sodium selenate and selenomethionine (2 μmol/kg/day via orogastric route for 12 weeks) can suppress elevation of blood glucose in diabetic mice.
However, sodium selenate seemed to have a stronger effect in inducing GPX activity than selenomethionine [44]. Xu et al. examined the combination effect of low-dose insulin and selenium (180 μg/kg/d) in treatment of STZ-induced hyperglycaemia and found that this combination could facilitate reduction of blood glucose and lipid levels, with remarkable restoration of PI3K and GLUT4 in cardiac muscle, which eventually improved myocardial function [45].
Selenium supplementation (0.3 mg/kg Se) in the form of selenium-enriched Catathelasma ventricosum mycelia can normalize serum glucose, insulin, and antioxidant enzyme activity in STZ-induced diabetic mice and suppress α-amylase and α-glucosidase activities in in vitro gastric and intestinal models [46]. Supplementation of sodium selenite (intraperitoneal injection of 0.3 mg/d for 25 days) can increase vitamin E level in the liver and plasma of STZ-induced diabetic animals. Treatment of selenium can increase GPX activity and GSH concentration in the red blood cells and liver, which reduces TBARS concentration [47].
Type II Diabetes Mellitus
Anderson et al. found that in patients with type 2 diabetes the selenium level and antioxidant status in plasma remained normal, though 30% of the subjects may have Zn deficiency [48]. A clinical study conducted by Stranges et al. showed that selenium uptake (200 ug/d) had no significant beneficial effect to the incidence of type 2 diabetes.
Nonetheless, in the highest tertile of baseline plasma selenium level, selenium statistically increased the risk for type 2 diabetes occurrence (hazard ratio, 2.70 (CI, 1.30 to 5.61)) [49]. Another study revealed that inactivation of selenium-dependent enzymes by glycation might eventually lead to oxidative stress in patients with type II diabetes [50].
Study on growing rats with developing obesity and diabetes, from Mueller and colleagues, revealed that a recommended dietary level or superanutritional level of selenium uptake (1-2 mg/kg in diet), in the forms of either selenite or selenate in diets, increased the body weight of rats. The expression of GPX1 in the liver was upregulated by selenium supplementation, which then triggered overexpression of PTP1B and reduction of glutathionylation [51].
Wang et al. reported that overexpression of GPX1 may deliver a beneficial effect by changing pancreatic expressions of PDX1 and UCP2 via elimination of ROS and hyperacetylation of H3 and H4 histone in islet. However, in long term, it may lead to chronic hyperinsulinaemia by dysregulating beta cell mass and pancreatic content [52]. Surprisingly, Zhou et al. found that, instead of being an antioxidant, selenium might foster lipid peroxidation and decrease GSH/GSSG in the liver and promote ASK1/MKK4/JNK oxidative stress pathway [53].
These observations revealed a plausible mechanism underlying the action of selenium supplementation on the development of obesity and diabetes [51]. Furthermore, Faghihi et al. observed, in a clinical study of type 2 diabetes patients, that selenium intake (200 μg/d for 3 months) accelerated disease progression by increasing fasting plasma glucose, glycosylated haemoglobin A1c, and serum HDL-C level, indicating an unflavoured outcome of selenium uptake in type 2 diabetes despite the restoration of serum selenium level towards optimal concentration of antioxidant activity [54].
In contrast, an experimental observation in high-fat diet/STZ-induced type 2 diabetic rats showed that supplementation of selenium (180–500 μg/kg/d) can reduce blood glucose, cholesterol, and triglyceride level and improve antioxidant status and nitric oxide (NO) release [55]. Additionally, treatment of selenium-containing tea polysaccharides (Se-GTP, 200–800 mg/kg/d for 8 weeks) in high fructose-induced resistant animals could significantly improve hyperglycaemia and hyperinsulinemia and restore antioxidant and hepatic lipid levels.
However, this does not prove the direct effect of selenium supplementation in improving type 2 diabetic condition as no comparative study has been made to understand the independent efficacy of tea polysaccharides without selenium [56]. Similar concern was raised by the research from Tanko et al., which showed selenium-enriched yeast (0.1–0.2 mg/kg/d via oral administration for 6 weeks) can improve cholesterol diet-induced type 2 diabetes mellitus in rats by reducing blood glucose and increasing antioxidant activities, yet it could not rule out the possibility of independent therapeutic effect of nonselenium components in the yeast [57].
Gestational Diabetes
Al-Saleh et al. measured the serum concentration of selenium in gestational diabetic patients, and the results showed that plasma selenium was significantly lower (102.3 versus 75.2 μg/L) [58]. Hawkes observed that pregnant women at between 12 and 34 weeks of gestation had a lower level of serum selenium, which was inversely correlated with increased fasting glucose, but not the insulin level, suggesting that selenium may affect glucose metabolism independent to insulin [59]. Bo and colleagues found that dietary intakes of selenium but not vitamins were significantly lower in hyperglycaemic subjects; in particular, the intake of selenium was negatively correlated with gestational hyperglycaemia.
Selenium level was particularly lower in patients with impaired glucose tolerance [60]. However, maternal intake of selenium (6.3/95 μg/d, mean/maximum) had neither positive nor negative correlation with the incidence of advance beta cell autoimmunity in early childhood [61].
Guney et al. applied a combination treatment of vitamin E (60 mg/kg/d) and sodium selenite (1 mg/kg/d) onto diabetic pregnant rats and found that after 21 days of treatment, the abnormal lipid peroxidation (LPO) level in rats was significantly normalized, which may be related to the potent increase of antioxidant enzymes [62]. Asemi et al. conducted a RCT clinical study of selenium supplementation in patients with gestational diabetes.
The results indicated that selenium (200 μg/d for 6 wk from weeks 24 to 28 of gestation) could significantly reduce fasting plasma glucose, serum insulin level, and insulin resistance. In addition, selenium could reduce serum high-sensitivity C-reactive protein and increase GSH, resulting in reduction of plasma MDA. However, there was no significant changes on β-cell function, lipid profiles, plasma NO, or total antioxidant capacity concentrations observed [63].
Hyperglycaemic Complications
The direct evidence of antioxidant effects of selenium in STZ-induced diabetes was obtained by Naziroglu and colleagues. Treatment of sodium selenite (0.3 mg/d for 21 days) improved vitamin E concentration, reduced MDA level in the plasma, and suppressed testicular lipid peroxidation, indicating that selenium supplementation may reduce reactive oxygen substances and improve testicular complications in diabetes [64].
Aliciguzel et al. found that in diabetic rats fed with 10% sucrose following alloxan injection, GPX activity was lower in the liver, brain, kidney, and heart in both early and late stages of diabetes [65]. Furthermore, Liu and colleagues found that supplementation of selenium in the form of Se-polysaccharide from Catathelasma ventricosum (100 mg/kg/d) could also reduce MDA and LDL-C in diabetic mice, which was associated with the increased antioxidant enzymes in the liver and kidney.
These together with restoration of LDL-C rendered protective effect on the pancreas, liver, and kidney against peroxidative damage [66]. In addition, nanoparticles of selenium exhibited a beneficial effect (0.1 mg/kg via oral administration for 28 days) in improving the testicular tissue condition in STZ-induced diabetic rats.
This was related to reduce lipid peroxidation and NO with increased glutathione content and antioxidant enzyme activities. Molecular studies showed that mRNA level of Bcl-2 was upregulated in testicular tissue of selenium nanoparticle-treated rats while Bax was suppressed. Treatment of selenium nanoparticles (0.1 mg of SeNPs/kg) increased PCNA expression as well as testicular function [67].
Faure et al. found that selenoprotein GPX activity in diabetic patients was lower than that in healthy subjects, which was associated with thrombosis and cardiovascular complications [68]. In STZ-induced diabetic animals, Ayaz et al. observed that sodium selenite treatment (i.p. 5 μmol/kg/d for 4 weeks) could prevent myofibril loss and reduce myocyte size. Selenium supplementation (5 μmol/kg/d) rendered remission on discus intercalaris and nucleus in the heart and preserved myofilament and Z-lines [69].
Treatment of sodium selenite (10 μmol/kg/d for 3 weeks) corrected adenosine-induced negative chronotropic effect in STZ-induced diabetic animals, but selenium supplementation had a minimal effect on carbachol-induced inotropic and chronotropic responses in the left and right atria [70]. In the aorta of STZ-induced diabetic rats, sodium selenate treatment (0.3 mg/kg/d for 4 weeks) can improve isoproterenol-induced relaxation and contraction responses and preserve the morphology of smooth muscle cells.
This may be related to the regulation on MMP-2 activity and protein loss in aorta, as well as the inhibition of tissue nitrite and protein thiol oxidation. Pathway study revealed that selenium supplementation might improve endothelin-1, PKC, and cAMP production in the aorta [71].
Aydemir-Koksoy et al. found that treatment of sodium selenite (0.3 mg/kg/d) could prevent depression in the left ventricular development pressure and the rates of changes in developed pressure in STZ-induced diabetic rats, and this effect was much greater than antioxidant treatment using vitamin E combined with omega-3 fish oil. The increase of myocardial oxidized protein sulfhydryl and nitrite concentration in the heart of diabetic rats was normalized by selenium supplementation [72].
Mechanism study revealed that myocardial MMP-2 and TIMP-4 were normalized, and selenite treatment increased expression of Tnl and α-actin in the heart of diabetic mice [73]. Liu et al. also revealed that high glucose-induced cardiomyocyte apoptosis could be attenuated by selenium supplementation through regulating TLR-4/MyD-99 signalling pathway and ROS formation [74].
Inhibition of NF-κB-mediated proinflammatory cytokine transcription and suppression of leukotriene pathway by sodium selenite treatment also contributed to the protective effect of selenium against diabetic cardiac hypertrophy [75]. Ng et al. observed that a water-soluble selenium-containing sugar rendered antioxidant activity in the aortae and prevented hyperglycaemia-induced endothelial dysfunction through reducing superoxide levels, as well as improving basal NO availability and vasoconstrictor prostanoids [76]. Combination of selenium with low-dose insulin can restore PI3K-mediated GLUT4 in cardiac muscle, which reduced damage and dysfunction of myocardial cells in STZ-induced diabetic rats [45].
Kornhauser et al. observed that, in type 2 diabetic patients, plasma selenium level was reduced. Serum concentration of GPX was significantly lower in diabetic patients with microalbuminuria than in those without nephropathy. Notably, microalbuminuria was negatively correlated with plasma level of selenium and GPX in patients with type 2 diabetes [77].
The role of selenium in diabetic nephropathy was evident by the observation that animal fed with selenium-deficient diet developed albuminuria and glomerular sclerosis as well as increased expression of TGF-β1 mRNA. Supplementation of selenium (0.27 mg/kg Se in diet) in the form of sodium selenite in diabetic rats improved glomerular sclerosis and tubulointerstitium [78].
Roy et al. observed that sodium selenate treatment (16 μmol/kg) could improve serum creatinine, urea, and albumin levels, as well as the renal antioxidant enzyme activities, such as superoxide dismutase (SOD), catalase, and GSH in STZ-induced diabetic rats. Selenate treatment could reduce lipid peroxidation and TGF-β1 in the diabetic rat kidney and improve cellular architecture of the kidney.
This may lead to reduce apoptotic renal cells in diabetic mice [79]. In contrast, study from Bas et al. found that sodium selenite treatment (1 mg/kg for 28 days) had a minimal effect on diabetes-mediated toxicity in kidneys through improving lead nitrate-induced nephrotoxicity in nondiabetic animals [80].
Intraperitoneal injection of sodium selenite (5 μmol/kg/day) for 4 weeks did not significantly improve high blood glucose and body weight loss in diabetic animals, but seemed to improve diabetes-induced structural alterations in the mandible [81]. Ozdemir et al. observed in STZ-induced diabetes that intraperitoneal injection of 5 μmol/kg/d for 4 weeks could prevent deterioration of structural and ultrastructural changes in the long bones of diabetic rats [82].
In type 1 diabetic rats induced by STZ injection, treatment of sodium selenite (5 μg/kg/d, intraperitoneal injection for 4 weeks) could significantly improve liver antioxidant enzymes in diabetic rats. The ultrastructure of the liver tissue, including variation in staining quality of hepatocyte nuclei, density, and eosinophilia of the cytoplasm, focal sinusoidal dilatation and congestion, and number of abnormal mitochondria, was normalized by sodium selenite treatment [83].
Intraperitoneal injection of sodium selenite (1.5 mg/kg/d for 4 weeks) could improve the liver function of STZ-induced diabetic animals and increase the hepatic expression of superoxide dismutase, reduce glutathione, lactate dehydrogenase, pyruvate kinase, and hexokinase, which rendered inhibition to NO, MDA, and phosphoenolpyruvate carboxykinase (PEPCK) in the liver [84].
Supplementation of selenium in the form of sodium selenite (1 ppm in drinking water) reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in diabetic rats, with a significant improvement in serum antioxidant enzymes and reduction of GSH level. Improvement of hepatic lipid accumulation and centrilobular hepatocyte degeneration was also observed [85].
In addition, treatment of sodium selenite (0.5 mg/kg/d for 4 weeks) could significantly reduce aldehyde oxidase and xanthine oxidase activities in the liver, but not in the kidney or heart, which might be associated with improvement of total antioxidant status after selenium supplementation [86].
The Role of Selenium in Treatment of Hyperphenylalaninemia
Phenylketonuria (PKU) is a born error in amino acid metabolism which leads to mildly or strongly elevated concentrations of the amino acid phenylalanine in the blood. PKU is the major cause of hyperphenylalaninemia. Studies have supported that in patients with PKU, the antioxidant defence in plasma and erythrocytes was decreased, which can be due to the secondary deprivation of micronutrients [87]. An observation from 156 patients with hyperphenylalaninemia showed that selenium was diminished in 25% of the subjects, 95% of which exhibited phenylketonuric phenotype [88].
The reason of low plasma selenium could be diet related, as PKU patients are often required to take natural protein and phenylalanine-restricted diet, which brings risk of low selenium intake [89]. Plasma level of selenium was significantly lower in patients with phenylketonuria or milder hyperphenylalaninemia, consistent with low total antioxidant status. The plasma selenium was correlated with erythrocyte GPX activity, which was lower in phenylketonuria, but inversely associated with free triiodothyronine and thyroxine [90, 91].
In contrast, Artuch and colleagues showed that plasma selenium concentration in patients with phenylketonuria had no different change compared with the healthy population [92]. In maternal Czech women with hyperphenylalaninemia, reduction of serum and urinary selenium level was observed [93]. Selenium deficiency led to defective GPX activities and consequently an increased level of MDA and organic hydroperoxides in the serum [94].
Further study showed that selenium deficiency in phenylketonuria might be the aetiology of dysrhythmia and cardiac dysfunction [95, 96]. Selenium deficiency in phenylketonuria might cause reduced response to OKT3 mitogenesis via T-cell antigen receptor complex (TCR/CD3) [97].
Gassio et al. reported a consistent observation of low-serum selenium level in patients with phenylketonuria and found that selenium concentration was associated with worsen Conners’ Continuous Performance Test measures (more omission errors, fluctuating attention and inconsistency of response times, and slowing reaction time as the test progressed) [98].
However, another study showed that the neuropsychological disturbance in phenylketonuria patients might be independent to selenium level, as plasma selenium seems to be normal in patients, while patients with lower selenium GPX had more severe neuropsychological disturbances [99].
The decreased level of serum selenium in phenylketonuric patients did not improve by dietotherapy [100, 101]. A study in Czech patients with phenylketonuria and hyperphenylalaninemia showed that controlled diet with low protein may cause serum selenium deficiency in adults, while prealbumin, zinc, and iron remained unchanged [102].
Consistent observation was found in another 12-year study on selenium status in 78 phenylketonuric children (aged 1–16) [103]. In patients with phenylalanine-restricted diet, intake of sodium selenite (115 μg/d) for 3 months could increase selenium level in plasma and blood cells and improve plasma GPX activity and left ventricular cardiac index, which led to decrease of thyroxin, free thyroxin, reverse triiodthyronin, TC, mean erythrocyte and thrombocyte volume, and lymphocytic CD2 expressions [104].
In patients with phenylalanine-restricted diet, selenium supplementation (1 μg/kg/d for 3 weeks) could reduce both concentrations of prohormone thyroxine (T4) and metabolic inactive reverse triiodothyronine (rT3), which could be probably due to the increase in activity of type I 5′-deiodinase [105, 106].
A pilot observation on 5 patients was conducted by Lombeck and colleagues, who showed that supplementation of selenium (45 μg/d) could render a normal selenium level in blood of phenylketonuric patients after a 4-week treatment, though GPX activity was only partially normalized [107].
However, Zachara et al. found that GPX activity in red blood cells of patients with phenylketonuria well indicated the functional restoration of selenium supplementation [108]. A possible mechanism underlying this discrepancy may be understood from the observation that selenium supplementation (0.13 mmol/kg/day) could only result in a short-term (within 10 days) but not long-term increase of plasma selenium level [109].
Using a special formula containing 31.5 μg/d selenium and 98 mg/d L-carnitine reduced lipid peroxidation and protein oxidative damage and improved GPX activity in phenylketonuric patients, indicating that selenium supplementation was important for the amelioration of neurological symptoms of phenylketonuria via regulating oxidative stress pathways [110]. Alves observed in a clinical study of phenylketonuric children that selenium supplementation could significantly increase serum selenium and GPX in erythrocytes, which in turn reduced serum concentration of free thyroxin and improved patient conditions [111].
REFERENCE LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758946/
Original Research: Open access.
“Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice” by Jason D Plummer, Spike DL Postnikoff, Jessica K Tyler, Jay E Johnson. eLife
