Chen Y et al. (2019), Glycosaminoglycan from Apostichopus japonicus I...

ECB-ART-48693

Mar Drugs 2019 Dec 18;181:. doi: 10.3390/md18010001.

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Glycosaminoglycan from Apostichopus japonicus Improves Glucose Metabolism in the Liver of Insulin Resistant Mice.

Chen Y , Wang Y , Yang S , Yu M , Jiang T , Lv Z .

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Holothurian glycosaminoglycan isolated from Apostichopus japonicus (named AHG) can suppress hepatic glucose production in insulin resistant hepatocytes, but its effects on glucose metabolism in vivo are unknown. The present study was conducted to investigate the effects of AHG on hyperglycemia in the liver of insulin resistant mice induced by a high-fat diet (HFD) for 12 weeks. The results demonstrated that AHG supplementation apparently reduced body weight, blood glucose level, and serum insulin content in a dose-dependent manner in HFD-fed mice. The protein levels and gene expression of gluconeogenesis rate-limiting enzymes G6Pase and PEPCK were remarkedly suppressed in the insulin resistant liver. In addition, although the total expression of IRS1, Akt, and AMPK in the insulin resistant liver was not affected by AHG supplementation, the phosphorylation of IRS1, Akt, and AMPK were clearly elevated by AHG treatment. These results suggest that AHG could be a promising natural marine product for the development of an antihyperglycemic agent.

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Genes referenced: fat4 LOC100888004 LOC100890677 LOC578064 LOC582192 LOC752532

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	Figure 1. Chemical Structure of AHG from Sea Cucumber Apostichopus japonicus.
	Figure 2. Effects of AHG supplementation on body weight in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50, and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Body weight gain; (B) food intake per week. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 3. Effects of AHG supplementation on glucose metabolism in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Fasting blood glucose; (B) serum insulin content; (C) Oral glucose tolerance test (OGTT); (D) The values of AUC for OGTT; (E) Insulin tolerance test (ITT); (F) The values of AUC for ITT. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 4. Effects of AHG supplementation on liver injury and inflammation induced by HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Liver/body weight ratio; (B) The values of ALT; (C) The values of AST; (D) The mRNA expression analysis of TNF-α, IL-6 and IL-1β were measured by RT-PCR and normalized by Cyclophilin. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group
	Figure 5. Effects of AHG supplementation on gluconeogenesis in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eightweeks. (A) The protein levels of G6Pase and PEPCK in livers were measured by Western blot. (B) Quantification of protein levels of G6Pase and PEPCK was performed by Image J. GAPDH as a control to normalize the expression of the protein. Data are showed as mean ± SD, n = 3; (C) Gene expression of G6Pase and PEPCK in livers were quantified by RT-PCR. Data are shown as mean ± SD, n = 4; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 6. Effects of AHG supplementation on insulin signaling pathway in the livers of insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. At the end of treatment, mice were fasted for 12 h and intraperitoneally injected with either saline or insulin (20 units/kg). (A) The protein expression of p-IRS (S302), IRS1, p-Akt (T308) and Akt were measured by Western blot. (B) Quantification of p-IRS (S302)/IRS1 and p-Akt (T308)/Akt was performed by Image J. Data are showed as mean ± SD, n=3; p < 0.5, p < 0.1, **p < 0.01 vs. insulin untreated HFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. insulin treated HFD group.
	Figure 7. Effects of AHG supplementation on AMPK signaling pathway in the livers of insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) The protein expression of p-ACC (S79), ACC, p-AMPKα (T172) and AMPKα were measured by Western blot. (B) Quantification of p-ACC (S79)/ACC and p-AMPKα (T172)/ AMPKαwas performed by Image J. Data are showed as mean ± SD, n = 3; * p < 0.5, p < 0.1, *p < 0.01 vs. LFD group, # p < 0.5, ## p < 0.1, ### p < 0.01 vs. HFD group.

References [+] :

Adeva-Andany, Liver glucose metabolism in humans. 2016, Pubmed

	Figure 1. Chemical Structure of AHG from Sea Cucumber Apostichopus japonicus.
	Figure 2. Effects of AHG supplementation on body weight in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50, and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Body weight gain; (B) food intake per week. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 3. Effects of AHG supplementation on glucose metabolism in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Fasting blood glucose; (B) serum insulin content; (C) Oral glucose tolerance test (OGTT); (D) The values of AUC for OGTT; (E) Insulin tolerance test (ITT); (F) The values of AUC for ITT. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 4. Effects of AHG supplementation on liver injury and inflammation induced by HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) Liver/body weight ratio; (B) The values of ALT; (C) The values of AST; (D) The mRNA expression analysis of TNF-α, IL-6 and IL-1β were measured by RT-PCR and normalized by Cyclophilin. Data are showed as mean ± SD, n = 8; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group
	Figure 5. Effects of AHG supplementation on gluconeogenesis in insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eightweeks. (A) The protein levels of G6Pase and PEPCK in livers were measured by Western blot. (B) Quantification of protein levels of G6Pase and PEPCK was performed by Image J. GAPDH as a control to normalize the expression of the protein. Data are showed as mean ± SD, n = 3; (C) Gene expression of G6Pase and PEPCK in livers were quantified by RT-PCR. Data are shown as mean ± SD, n = 4; p < 0.5, p < 0.1, **p < 0.01 vs. LFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. HFD group.
	Figure 6. Effects of AHG supplementation on insulin signaling pathway in the livers of insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. At the end of treatment, mice were fasted for 12 h and intraperitoneally injected with either saline or insulin (20 units/kg). (A) The protein expression of p-IRS (S302), IRS1, p-Akt (T308) and Akt were measured by Western blot. (B) Quantification of p-IRS (S302)/IRS1 and p-Akt (T308)/Akt was performed by Image J. Data are showed as mean ± SD, n=3; p < 0.5, p < 0.1, **p < 0.01 vs. insulin untreated HFD group, #p < 0.5, ##p < 0.1, ###p < 0.01 vs. insulin treated HFD group.
	Figure 7. Effects of AHG supplementation on AMPK signaling pathway in the livers of insulin resistant mice induced with HFD. C57BL/6J mice were fed with HFD for 12 weeks and treated with low, medium and high doses (20, 50 and 100 mg/kg/day, respectively) of AHG for eight weeks. (A) The protein expression of p-ACC (S79), ACC, p-AMPKα (T172) and AMPKα were measured by Western blot. (B) Quantification of p-ACC (S79)/ACC and p-AMPKα (T172)/ AMPKαwas performed by Image J. Data are showed as mean ± SD, n = 3; * p < 0.5, p < 0.1, *p < 0.01 vs. LFD group, # p < 0.5, ## p < 0.1, ### p < 0.01 vs. HFD group.