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Article | Open Access

Sea cucumber derived sulfated sterols alter glucose metabolism by promoting gluconeogenesis and reducing glycogenesis in healthy mice

Shanyun Yu^{^a}, Teng Wang^{^a}, Yingcai Zhao^{^a}, Xiaoyue Li^{^a}, Changhu Xue^{^a}, Yuming Wang^{^a^,^b}(), Tiantian Zhang^{^a}()

a

SKL of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao 266404, China

b

Sanya Institute of Oceanography, Ocean University of China, Sanya 572024, China

Peer review under responsibility of Beijing Academy of Food Sciences.

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Highlights

• Sea cucumber derived sulfated sterols (SS) alter glucose metabolism in healthy mice.

• SS did not affect the levels of hormones related to glucose metabolism.

• SS significantly decrease the synthesis of liver glycogen and muscle glycogen.

• SS changed blood glucose metabolism in healthy mice by reducing glycogenesis and promoting gluconeogenesis.

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Abstract

Sea cucumber derived sulfated sterols significantly ameliorated insulin resistance and decreased lipid accumulation compared to plant sterols. Interestingly, our recent study found that intervention with sea cucumber sulfated sterols could significantly increase blood glucose levels of healthy mice in the presence of glucose, while cholesterol sulfate, as one of sulfated sterols, did not have the same effect. However, the exact mechanism of sulfated sterols on glucose metabolism is still unknown. In the present study, we investigated the potential mechanism by which sulfated sterols influenced blood glucose homeostasis in healthy mice. Results showed that intervention with sea cucumber sulfated sterols did not affect the levels of hormones related to glucose metabolism, while led to a significant decrease in the synthesis of liver glycogen and muscle glycogen. Besides, the expression of proteins associated with the promotion of gluconeogenesis dramatically increased in the mice intervened with sea cucumber sulfated sterols. These findings suggested that sea cucumber sulfated sterols might change blood glucose metabolism in healthy mice by reducing glycogenesis and promoting gluconeogenesis.

Keywords

Sea cucumber Sulfated sterols Cholesterol sulfate Blood glucose Metabolism

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References

[1]

X. Li, B. Zeng, L. Wen, et al., Sea cucumber saponins derivatives alleviate hepatic lipid accumulation effectively in fatty acids-induced HepG2 cells and orotic acid-induced rats, Mar. Drugs 20 (2022) 703. http://doi.org/10.3390/md20110703.

Crossref Google Scholar

[2]

H. Gylling, J. Plat, S. Turley, et al., Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease, Atherosclerosis 232 (2014) 346-360. http://doi.org/10.1016/j.atherosclerosis.2013.11.043.

Crossref Google Scholar

[3]

T. Zhang, R.J. Liu, M. Chang, et al., Health benefits of 4,4-dimethyl phytosterols: an exploration beyond 4-desmethyl phytosterols, Food Funct. 11 (2020) 93-110. http://doi.org/10.1039/c9fo01205b.

Crossref Google Scholar

[4]

Q.Y. Zhu, L.Z. Lin, M.M. Zhao, Sulfated fucan/fucosylated chondroitin sulfate-dominated polysaccharide fraction from low-edible-value sea cucumber ameliorates type 2 diabetes in rats: new prospects for sea cucumber polysaccharide based-hypoglycemic functional food, Int. J. Biol. Macromol. 159 (2020) 34-45. http://doi.org/10.1016/j.ijbiomac.2020.05.043.

Crossref Google Scholar

[5]

N. Srihera, Y. Li, T.T. Zhang, et al., Preparation and characterization of astaxanthin-loaded liposomes stabilized by sea cucumber sulfated sterols instead of cholesterol, J. Oleo. Sci. 71 (2022) 401-410. http://doi.org/10.5650/jos.ess21233.

Crossref Google Scholar

[6]

Y.C. Zhao, C.H. Xue, T.T. Zhang, et al., Saponins from sea cucumber and their biological activities, J. Agric. Food Chem. 66 (2018) 7222-7237. http://doi.org/10.1021/acs.jafc.8b01770.

Crossref Google Scholar

[7]

H.J. Zhang, C. Chen, L. Ding, et al., Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice, Pharmacol. Res. 160 (2020) 105191. http://doi.org/10.1016/j.phrs.2020.105191.

Crossref Google Scholar

[8]

B.B. Zeng, L.Y. Zhang, C. Chen, et al., Sea cucumber sterol alleviates the lipid accumulation in high-fat-fructose diet fed mice, J. Agric. Food Chem. 68 (2020) 9707-9717. http://doi.org/10.1021/acs.jafc.0c03794.

Crossref Google Scholar

[9]

L. Ding, Z.J. Xu, H.H. Shi, et al., Sterol sulfate alleviates atherosclerosis via mediating hepatic cholesterol metabolism in ApoE^−/− mice, Food Funct. 12 (2021) 4887-4896. http://doi.org/10.1039/d0fo03266b.

Crossref Google Scholar

[10]

Y. Li, T. Wang, H.H. Shi, et al., Absorption, pharmacokinetics, tissue distribution, and excretion profiles of sea cucumber-derived sulfated sterols in mice, J. Agric. Food Chem. 70 (2022) 480-487. http://doi.org/10.1021/acs.jafc.1c04218.

Crossref Google Scholar

[11]

G. Musso, R. Gambino, M. Cassader, Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis, Prog. Lipid Res. 52 (2013) 175-191. http://doi.org/10.1016/j.plipres.2012.11.002.

Crossref Google Scholar

[12]

K.B.M. Ambia, L.J. Goad, S. Hkycko, et al., The sterols of the sea cucumber Psolus phantapus, Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 86 (1987) 191-192. https://doi.org/10.1016/0305-0491(87)90196-9..

Crossref Google Scholar

[13]

P. Sauleau, M.L. Bourguet-Kondracki, Novel polyhydroxysterols from the Red Sea marine sponge Lamellodysidea herbacea, Steroids 70 (2005) 954-959. http://doi.org/10.1016/j.steroids.2005.07.004.

Crossref Google Scholar

[14]

T.N. Makarieva, V.A. Stonik, I.I. Kapustina, et al., Biosynthetic studies of marine lipids. 42. biosynthesis of steroid and triterpenoid metabolites in the sea cucumber Eupentacta fraudatrix, Steroids 58 (1993) 508-517. https://doi.org/10.1016/0039-128x(93)90026-j.

Crossref Google Scholar

[15]

M. Kates, P. Tremblay, R. Anderson,et al., Identification of the free and conjugated sterol in a non-photosynthetic diatom, Nitzschia alba, as 24-methylene cholesterol, Lipids 13 (1978) 34-41. https://doi.org/10.1007/BF02533364.

Crossref Google Scholar

[16]

J.Y. Ren, C.L. Hou, C.C. Shi, et al., A polysaccharide isolated and purified from Platycladus orientalis (L.) Franco leaves, characterization, bioactivity and its regulation on macrophage polarization, Carbohydr. Polym. 213 (2019) 276-285. http://doi.org/10.1016/j.carbpol.2019.03.003.

Crossref Google Scholar

[17]

V.A. Stonik, L.P. Ponomarenko, T.N. Makarieva, et al., Free sterol compositions from the sea cucumbers Pseudostichopus trachus, Holothuria (Microtele) nobilis, Holothuria scabra, Trochostoma orientale and Bathyplotes natans, Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 120 (1998) 337-347. https://doi.org/10.1016/S0305-0491(98)10023-8..

Crossref Google Scholar

[18]

G. Nuzzo, C. Gallo, G. D’ippolito, et al., UPLC-MS/MS identification of sterol sulfates in marine diatoms, Mar. Drugs 17 (2018) 10. https://doi.org/10.3390/md17010010..

Crossref Google Scholar

[19]

V.T. Samuel, G.I. Shulman, The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux, J. Clin. Invest. 126 (2016) 12-22. http://doi.org/10.1172/jci77812.

Crossref Google Scholar

[20]

J. Lee, M.S. Kim, The role of GSK3 in glucose homeostasis and the development of insulin resistance, Diabetes Res. Clin. Pract. 77(Suppl 1) (2007) S49-57. http://doi.org/10.1016/j.diabres.2007.01.033.

Crossref Google Scholar

[21]

Q.Q. Li, Q.Y. Zhao, J.Y. Zhang, et al., The protein phosphatase 1 complex is a direct target of AKT that links insulin signaling to hepatic glycogen deposition, Cell Rep. 28 (2019) 3406-3422. http://doi.org/10.1016/j.celrep.2019.08.066.

Crossref Google Scholar

[22]

K. Li, C. Qiu, P. Sun, et al., Ets1-mediated acetylation of FoxO1 is critical for gluconeogenesis regulation during feed-fast cycles, Cell Rep. 26 (2019) 2998-3010. http://doi.org/10.1016/j.celrep.2019.02.035.

Crossref Google Scholar

[23]

E.A. Richter, M. Hargreaves, Exercise, GLUT4, and skeletal muscle glucose uptake, Physiol. Rev. 93 (2013) 993-1017. http://doi.org/10.1152/physrev.00038.2012.

Crossref Google Scholar

[24]

J.J. Holst, W. Holland, J. Gromada, et al., Insulin and glucagon: partners for life, Endocrinology 158 (2017) 696-701. http://doi.org/10.1210/en.2016-1748.

Crossref Google Scholar

[25]

S. Hædersdal, A. Lund, F.K. Knop, et al., The role of glucagon in the pathophysiology and treatment of type 2 diabetes, Mayo Clin. Proc. 93 (2018) 217-239. http://doi.org/10.1016/j.mayocp.2017.12.003.

Crossref Google Scholar

[26]

G. Jiang, B.B. Zhang, Glucagon and regulation of glucose metabolism, Am. J. Physiol. Endocrinol. Metab. 284 (2003) 671-678. http://doi.org/10.1152/ajpendo.00492.2002.

Crossref Google Scholar

[27]

C. Bataglini, I. Ramos Mariano, S.C.F. Azevedo, et al., Insulin degludec and glutamine dipeptide modify glucose homeostasis and liver metabolism in diabetic mice undergoing insulin-induced hypoglycemia, J. Appl. Biomed. 19 (2021) 210-219. http://doi.org/10.32725/jab.2021.025.

Crossref Google Scholar

[28]

L. Agius, Glucokinase and molecular aspects of liver glycogen metabolism, Biochem. J. 414 (2008) 1-18. http://doi.org/10.1042/bj20080595.

Crossref Google Scholar

[29]

R.M. Esquejo, B. Albuquerque, A. Sher, et al., AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism, Heliyon. 8 (2022) e11091. http://doi.org/10.1016/j.heliyon.2022.e11091.

Crossref Google Scholar

[30]

A. Gautier-Stein, G. Mithieux, Intestinal gluconeogenesis: metabolic benefits make sense in the light of evolution, Nat. Rev. Gastroenterol. Hepatol. 20 (2023) 183-194. http://doi.org/10.1038/s41575-022-00707-6.

Crossref Google Scholar

[31]

S. Payankaulam, A.M. Raicu, D.N. Arnosti, Transcriptional regulation of INSR, the insulin receptor gene, Genes (Basel) 10 (2019) 984. http://doi.org/10.3390/genes10120984.

Crossref Google Scholar

[32]

W.K. Wang, B. Shi, R.T. Cong, et al., RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism, Cell Death Discov. 8 (2022) 372. http://doi.org/10.1038/s41420-022-01162-7.

Crossref Google Scholar

[33]

M.A. Hermida, J.K. Dinesh, N.R. Leslie, GSK3 and its interactions with the PI3K/AKT/mTOR signalling network, Adv. Biol. Regul. 65 (2017) 5-15. http://doi.org/10.1016/j.jbior.2017.06.003.

Crossref Google Scholar

[34]

Z.Y. Cheng, M.F. White, Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models, Antioxid. Redox. Signal 14 (2011) 649-661. http://doi.org/10.1089/ars.2010.3370.

Crossref Google Scholar

[35]

M.C. Petersen, G.I. Shulman, Mechanisms of insulin action and insulin resistance, Physiol. Rev. 98 (2018) 2133-2223. http://doi.org/10.1152/physrev.00063.2017.

Crossref Google Scholar

[36]

D. Das, N.U. Afzal, S.B. Wann, et al., A ~24 kDa protein isolated from protein isolates of Hawaijar, popular fermented soy food of North-East India exhibited promising antidiabetic potential via stimulating PI3K/AKT/GLUT4 signaling pathway of muscle glucose metabolism, Int. J. Biol. Macromol. 224 (2023) 1025-1039. http://doi.org/10.1016/j.ijbiomac.2022.10.187.

Crossref Google Scholar

Food Science and Human Wellness

Volume 14 Issue 2,
February 2025

Article number: 9250046

DOI: 10.26599/FSHW.2024.9250046

Cite this article:

Yu S, Wang T, Zhao Y, et al. Sea cucumber derived sulfated sterols alter glucose metabolism by promoting gluconeogenesis and reducing glycogenesis in healthy mice. Food Science and Human Wellness, 2025, 14(2): 9250046. https://doi.org/10.26599/FSHW.2024.9250046

Fig. 1 Effects of intervention of sea cucumber sulfated sterolss and cholesterol sulfate on blood glucose level in mice (n = 6). (A) Oral administration curve of sea cucumber sterolss and cholesterol sulfate. (B) The area under the curve of oral administration. (C) Intraperitoneal administration curve of sea cucumber sulfated sterols. (D) The area under the curve of intraperitoneal administration. Data are given as the mean ± SEM. Different letters indicate significant difference at P < 0.05 among all groups determined by ANOVA (Tukey’s test).
Fig. 2 Effect of sea cucumber sulfated sterols on glucose tolerance, serum insulin and glucagon in mice (n = 6). (A) Glucose levels of healthy BALB/c mice after different treatments. (B) Insulin levels of healthy BALB/c mice after different treatments. (C) glucagon levels of healthy BALB/c mice after different treatments. Different letters indicate significant difference at P < 0.05 among the other three groups except for group N determined by ANOVA (Tukey’s test), and * indicate significant difference at P < 0.05 compared to the N group determined by Student’s t-test.
Fig. 3 Effect of sea cucumber sulfated sterols on glycogen content and related protein expression in mice (n = 6). (A) Content of hepatic glycogen of healthy BALB/c mice after different treatments. (B) Content of muscle glycogen of healthy BALB/c mice after different treatments. (C) The protein expression of GSK3β and p-GSK3β were measured by Western blotting. (D) GSK3β/β-actin. (E) p-GSK3β/GSK3β. Different letters indicate significant difference at P < 0.05 among the other three groups except for group N determined by ANOVA (Tukey’s test) and * indicate significant difference at P < 0.05 compared to the N group determined by Student’s t-test.
Fig. 4 Effects of sea cucumber sulfated sterols on protein expression level of hepatic insulin signals in mice (n = 6). (A) The protein expression of InsR, p-InsR, AKT and p-AKT were measured by Western blotting. (B) InsR/β-actin. (C) p-InsR/InsR. (D) AKT/β-actin. (E) p-AKT/AKT. Different letters indicate significant difference at P < 0.05 among the other three groups except for group N determined by ANOVA (Tukey’s test) and * indicate significant difference at P < 0.05 compared to the N group determined by Student’s t-test.
Fig. 5 Effects of sea cucumber sulfated sterols on gluconeogenesis of liver (n = 6). (A) The PEPCK activity was measured by the kit instruction. The mRNA and protein expressions of G6Pase (B), PEPCK (C), p-FOXO1 and FOXO1 (D) were measured by qPCR and Western blotting. Different letters indicate significant difference at P < 0.05 among the other three groups except for group N determined by ANOVA (Tukey’s test) and * indicate significant difference at P < 0.05 compared to the N group determined by Student’s t-test.
Fig. 6 Effects of sea cucumber sulfated sterols on intramuscular GLUT4 proteins expressions in mice (n = 6). The protein expression of GLUT4 and Na,K-ATPase (A), membrane GLUT4 and cytoplasmic GLUT4 (B) were measured by Western blotting. Different letters indicate significant difference at P < 0.05 among the other three groups except for group N determined by ANOVA (Tukey’s test) and * indicate significant difference at P < 0.05 compared to the N group determined by Student’s t-test.
Fig. 7 Possible underlying mechanism involved in the effects of sea cucumber sulfated sterols on glucose metabolism in healthy mice.

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