Supranutritional selenium induces alterations in molecular targets related to energy metabolism in skeletal muscle and visceral adipose tissue of pigs
Graphical abstract
Influence of a supranutritional selenium diet on the insulin-regulated energy metabolism in pigs. Selenium may induce metabolic and molecular alterations, resulting in an increase in lipid turnover and a shift in fuel selection from carbohydrates to lipids in skeletal muscle and visceral adipose tissue.
Highlights
►Feeding pigs a 16-week supranutritional selenium diet resulted in hyperinsulinaemia. ► Supranutritional Se intake (0.5 mg Se/kg) was not sufficient to induce diabetes. ► Selenoprotein biosynthesis was largely saturated in adequate-Se (0.17 mg Se/kg) pigs. ► Molecular alterations in adipose tissue and skeletal muscle suggest increased lipid turnover.
Introduction
Trace elements are known to influence the hormonal control of energy metabolism in mammals. Compounds of selenium, chromium, zinc, vanadium and lithium are capable of affecting the activation state of components of the insulin signalling cascade and thus may mimic, potentiate or interfere with actions of insulin on carbohydrate and lipid metabolism [1]. Key proteins involved in insulin signalling include the insulin receptor and its substrate IRS-2, protein kinase B (Akt), glycogen synthase kinase 3β, forkhead box class O (FoxO) transcription factors, peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and phosphatases such as the lipid phosphatase PTEN and the protein tyrosine phosphatase PTP-1B. Dysregulated biosynthesis, cellular localisation and/or activity of those proteins may impair the capacity of liver, skeletal muscle and adipose tissue to respond adequately to insulin. The resulting pathophysiological state, termed insulin resistance, represents a major step in the pathogenesis of Type 2 diabetes mellitus (T2DM) [2], [3], [4].
In this regard, the impact of the essential micronutrient selenium (Se) on metabolic pathways related to the onset and progression of T2DM is the subject of ongoing debate [5], [6]. Se has been credited with insulin-mimetic and anti-diabetic properties, following observations that high doses of sodium selenate stimulated glucose uptake in cultivated adipocytes and dissected skeletal muscle of rats [7], [8] and improved glucose homeostasis in diabetic rats [9]. By contrast, more recent evidence has suggested pro-diabetic effects of supranutritional Se intake in humans [5], [6], [10]. Se accomplishes its biological functions through selenoproteins, mostly representing antioxidant enzymes [11]. Abundant expression of selenoproteins such as cytosolic glutathione peroxidase (GPx1) and selenoprotein P (SeP) can dysregulate insulin secretion and impair insulin sensitivity [6], [12], [13], [14]. Sodium selenite delayed insulin-induced phosphorylation of Akt and FoxO1a/3 in myocytes [15], and conversely, Akt phosphorylation was increased in skeletal muscle of transgenic mice with deficient selenoprotein biosynthesis [16].
The recommended levels for adequate Se supply range between 30 and 85 μg/day for adults [17]; these doses are based on the Se intake required to maximise the activity of the selenoenzyme extracellular glutathione peroxidase (GPx3) in plasma [18]. Dietary Se intake in European countries averages 40 μg/day compared to 93 to 134 μg/day for males and females, respectively, in the U.S. [17], [19]. Although overt Se deficiency is rare in humans, the consumption of Se-enriched dietary supplements is common in Europe and more so in the U.S. due to their perceived health benefits. Supplements can provide an additional 10–200 μg Se/day [19]. Dietary Se supplementation has been invoked for the prevention of certain forms of cancer, oxidative stress-related chronic diseases of the cardiovascular system and brain and for the therapy of inflammatory disorders [11], [19]. Se appears to exert a beneficial influence on the course of autoimmune thyroid disease: daily administration of 200 μg selenite improved the quality of life and slowed the progression of orbitopathy in patients with Graves’ disease [20]. However, the action of Se on human health is characterised by a narrow therapeutic window and a U-shaped dose–response curve. Se intake above nutritional requirements could trigger adverse side-effects even below the “tolerable upper intake level” that is currently set at 300–450 μg/day for adults [17], [19]. This issue has become evident following a secondary analysis of data from the U.S. Nutritional Prevention of Cancer (NPC) trial: trial participants who received a dose of 200 μg Se/day for a mean of 4.5 years had a higher risk of developing T2DM over a mean follow-up period of 7.7 years than those assigned to placebo [10].
Cross-sectional epidemiological studies show an association between high plasma Se and hyperglycaemia and dyslipidemia, though prospective analyses do not support the causality of this relationship [5], [6], [21], [22], [23]. To assess the risk potential of Se as a diabetogenic factor, it is important to understand its impact on insulin-regulated energy metabolism. We here present data from a study in healthy young pigs fed either a Se-adequate or a Se-supranutritional diet, where Se-yeast was the Se source. This treatment scheme was chosen with the intention of mimicking dietary Se supplementation in human populations with adequate Se nutrition. Energy metabolism is regulated similarly in humans and in pigs, and moreover, pigs may develop symptoms of the human metabolic syndrome (e.g. insulin resistance, hypertension, dyslipidemia and arteriosclerotic lesions) [24], [25]. Thus, pigs are thought to represent a suitable animal model for gaining insight into molecular actions of assumed diabetogenic factors in the human diet.
Section snippets
Animals, diet and sample collection
Experimental procedures were performed according to the regulations approved by the Home Office under the Animals (Scientific Procedures) Act 1986 UK. A total of 12 male finishing pigs (6–8 weeks old; Reading University farm) were selected and divided into two groups, a Se-adequate (n = 6) and a Se-supranutritional (high-Se) group (n = 6). For an intervention period of 16 weeks, pigs in the Se-adequate control group received a vegetable-based diet (predominantly wheat and soy) with 0.17 mg Se/kg dry
Metabolic characteristics of the animals
Healthy young male pigs (n = 6 per group) were fed either a Se-adequate or a Se-supranutritional diet for 16 weeks. In order to simulate the intake of Se-containing mineral supplements by humans, the basal (Se-adequate) diet with a natural content of 0.17 mg Se/kg dry matter was supplemented with Se-yeast to obtain the Se-supranutritional (high-Se) level of 0.50 mg Se/kg. At the beginning of the intervention period, body weights of the two groups of animals were similar with means ± SD of 15.8 ± 1.47 kg
Discussion
In this study, we investigated in healthy male pigs how a supranutritional selenium diet affected metabolic and molecular parameters related to the hormonal control of energy metabolism. Both the Se source (Se-yeast) and the Se doses fed to the two groups of animals (0.17 mg Se/kg for a Se-adequate versus 0.50 mg Se/kg for a Se-supranutritional diet) are of physiological relevance for humans, being selected with respect to dietary and supplemental Se intake. After 16 weeks of Se supplementation,
Concluding remarks
In conclusion, our study provides evidence that selenium oversupply may affect expression and activity of proteins involved in energy metabolism in major insulin target tissues, though supranutritional Se intake at the levels employed was not sufficient to induce overt diabetes in healthy animals. Indeed, humans supplemented with 200 μg Se/day in the NPC trial did not have a significantly increased risk of developing Type 2 diabetes mellitus unless their baseline plasma Se exceeded 121.6 μg/L
Abbreviations
- Akt
protein kinase B
- ALT
alanine aminotransferase
- AMPK
AMP-activated protein kinase
- ERK
extracellular signal-regulated kinase
- FoxO
forkhead box protein class O
- GPx
glutathione peroxidase
- HOMA-IR
homeostatic model assessment insulin resistance
- IRS
insulin receptor substrate
- LPL
lipoprotein lipase
- MAPK
mitogen-activated protein kinase
- NPC
Nutritional Prevention of Cancer Trial
- PGC-1α
peroxisomal proliferator-activated receptor-γ coactivator 1α
- ROS
reactive oxygen species
- RT-PCR
reverse transcription polymerase chain
Acknowledgements
This work was supported by a grant of Deutsche Forschungsgemeinschaft (DFG) (Bonn, Germany) to H. Steinbrenner (STE 1782/2-2). H. Sies is a Fellow of the National Foundation for Cancer Research (NFCR), Bethesda, MD. We thank Dr. S. Schinner (Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf) for the helpful discussions and A. Borchardt for the excellent technical assistance.
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These authors contributed equally to this work.