Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : November 3, 2018
Accepted : November 18, 2018
Published online : December 31, 2018
doi:10.24659/gsr.5.4_171

Review article

Selenoprotein P and glucose metabolism: The involvement of redox signaling.
Yoshiro Saito
Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai, Japan

Abstract

Selenoprotein P (SeP; encoded by SELENOP) is a major selenium-containing protein in human plasma and plays apivotal role in the metabolism of selenium, an essential trace element. SeP possesses selenium as a selenocysteine (Sec) which
is an analog of cysteine containing selenium instead of sulfur. SeP has 10 Sec residues which are important for the functionof SeP; namely, the 1st Sec in the N-terminal region forms the active site of phosphatidylcholine hydroperoxide reducingactivity, while nine Sec residues in the C-terminal region functions as a selenium transporter to maintain antioxidative selenoenzymes. Thus, SeP is a multifunctional protein which plays a significant role in the antioxidative defense. However, recentevidence indicates that excess SeP worsens glucose metabolism and advances type 2 diabetes. In this review, the biochemical
character and biological function of SeP are described. Further, the recent evidence related to the undesired effects of excess
SeP on glucose metabolism is summarized. Finally, the molecular mechanisms of excess SeP-induced impairment effects on
glucose metabolism, particularly the involvement of redox signaling, are discussed.

KEY WORDS: selenoprotein P, selenium, type 2 diabetes, insulin resistance, exercise resistance, insulin secretion

Introduction

Selenium (Se) is an essential trace element, and its
deficiency has been associated with complications including
increased risk of mortality, poor immune function, andcognitive decline 1). Whereas Se has a high toxicity, and theoptimum range of Se between excess and deficiency is quite
narrow. The essential biological role of Se is mediated by Secontaining proteins called selenoproteins 2). Selenoprotein
P (SeP; encoded by SELENOP) is a major selenoprotein
in plasma and functions as a Se transporter to deliver Se
to several tissues 3). The function of SeP is important forthe maintenance of tissue selenoproteins; however, recent
evidence indicates that SeP levels are increased in type 2
diabetes (T2DM) patients and excess SeP impairs glucose
metabolism 4 - 6). In this review, the worse effects of excess SeP
on glucose metabolism are summarized, and the molecularmechanisms of excess SeP-induced impairment effects
on glucose metabolism, particularly the relation of redox
signaling, are discussed.

Selenoprotein P

SeP is a major selenoprotein in plasma, possessing almost
half of plasma Se 7). SeP is mainly synthesized in the liverand secreted into the plasma. SeP has a Se as selenocysteine(Sec; a cysteine analog contained Se instead of sulfur), whichis encoded by UGA stop codon 8). Sec-containing protein istermed selenoprotein, and now 25 types of selenoproteins
have been identified 2). The “P” in SeP means plasma. SeP
possesses 10 Sec residues which are important for SeP
function. The gross structure of SeP is shown in Fig. 1. The
1st Sec residue in the N-terminal region forms an active siteof enzyme activity to reduce phospholipid hydroperoxideusing glutathione as a reductant 9, 10). The C-terminal region ofSeP is rich in Sec and functions as a Se transporter to supply
Se to the cells effectively 7, 10). Cellular selenoproteins suchas glutathione peroxidase (GPx) and thioredoxin reductase(TrxR) play a significant role in removing reactive oxygenspecies (ROS) and in redox regulation. Thus, SeP is a pivotal
antioxidative protein not only to reduce lipid hydroperoxide
directly but also to maintain the cellular antioxidative system(Fig. 1).

Correspondence to:Laboratory of Molecular and Biochemical Toxicology,
Graduate School of Pharmaceutical Sciences, Tohoku University

Sendai, 980-8578, Japan
TEL: +81-22-795- 6870
e-mail: yoshiro.saito.a8@tohoku.ac. jp_ 171 _

Glycative Stress Research 2018; 5 (4): 171-176(c) Society for Glycative Stress ResearchSelenoprotein P and Glucose Metabolism

Fig. 1. Gross structure and function of selenoprotein P.

PL-OOH, Phospholipid hydroperoxide; Sec, Selenocysteine; SeP, selenoprotein P.

The increase of selenoprotein P in type 2
diabetes patients and model animals

Transcriptome analysis of liver biopsy samples fromT2DM patients revealed an increase of SeP mRNA in
these patients 4). This analysis was conducted to identify“Hepatokine,” a liver secretion protein influencing thepathophysiology of diabetes. The mRNA levels of SeP in theliver significantly correlated with blood glucose levels at 120
min after glucose ingestion 4). SeP protein levels in serum
are also positively correlated with fasting plasma glucose,indicating the increase of SeP in T2DM 4). To explore therole of increased SeP in the pathophysiology of diabetes, theeffects of excess SeP was investigated. Several in vivo andin vitro experiments indicate that increased SeP worsens
glucose metabolism and precedes diabetes 4). The treatmentof hepatocytes with high glucose resulted in the increase ofSeP mRNA and protein levels. Similar to this observation,
SeP levels in plasma increased in animal models of T2DM.

Although the biological significance of the increase of SeP
in high glucose conditions is not understood, the increaseof SeP in diabetes is common between human and modelanimals.
It has been reported that the risk of diabetes increases
from Se supplements 11, 12); however, this observation islimited to the population with high Se content in plasma 13, 14).
In addition, it is considered to be unlikely that high Se intake
alone could induce diabetes condition. Actually, CE2, usual
fed to mice, contains 0.4 mg Se/kg, which is enough quantity
to maintain maximum levels of selenoproteins, while it could
not induce diabetes 15). On the other hand, a high fat and highsucrose diet containing 0.2 mg Se/kg can induce diabetes.
It appears that the high glucose and high lipid stimulus isimportant to induce SeP expression under diabetic conditions.
Of course, Se is essential to synthesis SeP protein. It is,therefore, considered that high Se is not a sufficient condition
but the necessary condition to achieve high SeP levels indiabetes patients. To induce SeP expression, the inhibition of_ 172 _Glycative Stress Research

AMP-activated kinase (AMPK) activity and sterol regulatory
element- binding protein-1c (SREBP -1c) transcriptional
activityin hepatocytes are important, and these are known asa target of therapeutics of diabetes and metabolic syndrome16, 17). Metformin, an AMPK activator, suppressed theexpression of SeP, via the decreased binding of FoxO3a, a
direct target of AMPK, to the SELENOP promoter 16). Whileeicosapentaenoic acid (EPA) suppressed SeP expression by
the decrease of SREBP-1c binding of SELENOP promoter
in AMPK-independent manner 17). These results indicate
the regulation of SeP expression by several transcriptional
factors related to metabolism, suggesting the importance ofdeveloping the therapeutic reagents targeting SeP expression.

The effects of excess selenoprotein P oninsulin and exercise resistanceAn increasing volume of evidence has demonstrated
that increased SeP impairs insulin resistance and secretion,
indicating the involvement of the onset as well as theprocession of T2DM (Fig. 2) 4-6). It has been reported that
low levels of reactive oxygen species (ROS) positively workfor the insulin signal 18) . Several factors related to the signaltransduction of insulin are regulated by ROS. AMPK, one of
the important regulators of energy metabolism, is regulated
not only by AMP but also by several factors including ROS19, 20). It has also been known that ROS regulates the activityof protein tyrosine phosphatase 1b (PTP1B) via the oxidationof the reactive cysteine, and its phosphatase activity is related
to insulin signaling 21). The increase of insulin resistancehas been reported in transgenic ( TG) mice of selenoenzyme
GPx1, suggesting the physiological role of ROS in the insulin
signal 22). In the case of diabetes model mice with excess SeP,
insulin signal transduction was disturbed, and the negative
effect of SeP was diminished by the inhibitor of glutathione
synthesis, buthionine sulphoximine (BSO), suggesting therelation of antioxidant effects on the increase of insulin
resistance was induced by excess SeP 4). On the other hand,
exercise is commonly used as a leading cure to improve
insulin resistance. In this beneficial effect of exercise, thesignificant role of ROS has been discussed 23). It has beenreported that positive intake of antioxidants counteracts theFig. 2. Effects of excess selenoprotein P on glucose metabolism.
AMPK, AMP-activated kinase; SeP, selenoprotein P.

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health-promoting effects of exercise, namely increasing theexercise resistance. Increased SeP induced exercise resistancethrough its muscle receptor low-density lipoprotein receptorrelated protein 1 (LRP1) 5). Interestingly, SeP-deficient mice
showed a ‘super-endurance’ phenotype after exercise training,enhanced ROS production, and AMPK phosphorylation.
Human studies also showed a significant correlation between
SeP levels and the ineffectiveness of training on endurance
capacity, suggesting the increased amounts of circulating SePas a predictor of exercise resistance 5).

The effects of excess selenoprotein P on
insulin secretion

Recent evidence indicates that excess SeP inhibits
secretion of insulin from pancreatic β cells (Fig. 2) 6). The
addition of excess SeP to MIN6 cells, a model of pancreatic
β cells, and rat primary pancreatic islets significantly
decreased cellular insulin levels and high glucose-induced

insulin secretion. Selenocystine, an equal amount to excess
SeP, showed similar inhibitory effects on insulin secretion,suggesting the relation with Se-transport activity of SeP.
The impairment effects of excess SeP were observed in vivo
experiments, and the injection of purified SeP protein resulted
in the decrease of pancreatic insulin levels, the area of islets,and glucose-induced insulin secretion ( Fig. 3) 6). Interestingly,
SeP injection resulted in a decrease of both α- and β - cells
in the pancreas, accompanied by the rearrangement of theposition of these cells in the pancreatic island ( Fig. 3 ). The
rearrangement and decrease of both α- and β - cells havebeen observed in the diabetes model of animals and humancases 24). The details of molecular mechanisms of the change
in the pancreas of SeP-injected mice are still unknown, andfurther research is necessary to elucidate these molecularmechanisms. In the diabetic model animals, such as KKAy
mice and high-fat and high-sucrose (HFHS) fed mice,neutralizing the SeP antibody effectively improved theinsulin secretion, suggesting the impairment effects of excess
SeP on pancreatic function 6).

Fig. 3. Effects of excess selenoprotein P on pancreatic islets: Immunohistochemical analysis.

After administration of purified SeP protein and its neutralizing antibody AE2 to C57BL/6J mice, a histochemical
analysis was conducted on pancreas tissues using HE stain, anti-insulin Ab (green) and Glucagon (red, indicativeof α-cells). Scale bars = 100 μm. HE, haematoxylin and eosin; Ab, antibody; SeP, selenoprotein P. Adapted from
Mita et al., (2017, ref 6) with permission.

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Conclusion

Acknowledgements

SeP is a powerful antioxidant protein to control cellular
redox status; however, the excess quantity of circulating
SeP is quite bad for our health, causing insulin and exercise
resistance and impaired insulin secretion. However, its detailmolecular mechanism is still not cleared, and the relationshipbetween selenoproteins and glycative stress is also currently
unknown. Further studies are necessary to elucidate themechanisms of the undesired action of excess SeP. The
development of SeP-targeting therapeutic agents is necessary
to realize the effective treatment of diabetic individuals withhigh SeP (Fig. 4 ).

A part of this work was supported by JSPS KAKENHI
Grant Number 967099.

Conflict of Interest StatementThe author claims no conflict of interest in thismanuscript.

Fig. 4. Possible therapeutic strategies for metabolic disorder induced by excess selenoprotein P.
EPA, eicosapentaenoic acid; SeP, selenoprotein P.

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