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Published in: BMC Complementary Medicine and Therapies 1/2019

Open Access 01-12-2019 | Insulins | Research article

Hypoglycemic effects of esculeoside A are mediated via activation of AMPK and upregulation of IRS-1

Authors: Ziming Yang, Li Zhang, Jinglei Liu, Fenglai Lu, Lei Wang, Yueyuan Chen, Dianpeng Li

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

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Abstract

Background

Tomato fruit (Lycopersicon esculentum Mill.) has been suggested to be useful for the prevention of diabetes. Esculeoside A is the main saponin compounds in tomatoes. This study investigated the hypoglycemic effects and the underlying mechanism of esculeoside A in C57BLKS/Leprdb (db/db) mice.

Methods

Wild-type C57BLKS (db/dm) mice were used in the db/dm mouse group and db/db mice were randomly divided into 2 groups: untreated and treated db/db mouse groups. Esculeoside A (100 mg/kg) was administered by gavage for 56 days to the treated db/db mouse group. Distilled water was administered to the db/dm mouse group and the untreated db/db mouse group. The blood and liver biochemical parameters and the expression of liver insulin signaling-related proteins were examined.

Results

The results showed that esculeoside A reduced the fasting blood glucose (FBG) levels and improved the glucose tolerance. Further investigation revealed that hepatic protein expressions of total AMP-activated protein kinase (T-AMPK), phosphorylated AMP-activated protein kinase (p-AMPK), insulin receptor substrate-1 (IRS-1), and glucokinase (GCK) were significantly upregulated after esculeoside A treatment. In contrast, the hepatic protein expression of phosphoenolpyruvate carboxykinase (PEPCK) was significantly downregulated by esculeoside A treatment.

Conclusion

These findings suggested that esculeoside A has a potential of alleviating the metabolic abnormalities in db/db mice via regulation of AMPK/IRS-1 pathway. Our findings supported a possible application of esculeoside A as a functional supplement for diabetes treatment.
Literature
1.
go back to reference Pok EH, Lee WJ. Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus. World J Gastroenterol. 2014;20:14315–28.CrossRef Pok EH, Lee WJ. Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus. World J Gastroenterol. 2014;20:14315–28.CrossRef
2.
go back to reference Reddy MA, Zhang E, Natarajan R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia. 2015;58:443–55.CrossRef Reddy MA, Zhang E, Natarajan R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia. 2015;58:443–55.CrossRef
3.
go back to reference Natarajan R, Nadler JL. Lipid inflammatory mediators in diabetic vascular disease. Arterioscler Thromb Vasc Biol. 2004;24:1542–8.CrossRef Natarajan R, Nadler JL. Lipid inflammatory mediators in diabetic vascular disease. Arterioscler Thromb Vasc Biol. 2004;24:1542–8.CrossRef
4.
go back to reference Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36:1047–55.CrossRef Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36:1047–55.CrossRef
5.
go back to reference Cho SJ, Park HJ, Jung UJ, Kim HJ, Moon BS, Choi MS. The beneficial effects of combined grape pomace and omija fruit extracts on hyperglycemia, adiposity and hepatic steatosis in db/db mice: a comparison with major index compounds. Int J Mol Sci. 2014;15:17778–89.CrossRef Cho SJ, Park HJ, Jung UJ, Kim HJ, Moon BS, Choi MS. The beneficial effects of combined grape pomace and omija fruit extracts on hyperglycemia, adiposity and hepatic steatosis in db/db mice: a comparison with major index compounds. Int J Mol Sci. 2014;15:17778–89.CrossRef
6.
go back to reference Sing LP. The potential protective action of vitamin D in hepatic insulin resistance and pancreatic islet dysfunction in type 2 diabetes mellitus. Nutrients. 2016;8:147–60.CrossRef Sing LP. The potential protective action of vitamin D in hepatic insulin resistance and pancreatic islet dysfunction in type 2 diabetes mellitus. Nutrients. 2016;8:147–60.CrossRef
7.
go back to reference Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes. 2002;51:1672–80.CrossRef Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes. 2002;51:1672–80.CrossRef
8.
go back to reference Fryer LG, Carling D. AMP-activated protein kinase and the metabolic syndrome. Biochem Soc Trans. 2005;33:362–6.CrossRef Fryer LG, Carling D. AMP-activated protein kinase and the metabolic syndrome. Biochem Soc Trans. 2005;33:362–6.CrossRef
9.
go back to reference Raiola A, Rigano MM, Calafiore R, Frusciante L, Barone A. Enhancing the health-promoting effects of tomato fruit for biofortified food. Mediat Inflamm. 2014;5:139873. Raiola A, Rigano MM, Calafiore R, Frusciante L, Barone A. Enhancing the health-promoting effects of tomato fruit for biofortified food. Mediat Inflamm. 2014;5:139873.
10.
go back to reference Li W, Wang G, Lu X, Jiang Y, Xu L, Zhao X. Lycopene ameliorates renal function in rats with streptozotocin-induced diabetes. Int J Clin Exp Pathol. 2014;7:5008–15.PubMedPubMedCentral Li W, Wang G, Lu X, Jiang Y, Xu L, Zhao X. Lycopene ameliorates renal function in rats with streptozotocin-induced diabetes. Int J Clin Exp Pathol. 2014;7:5008–15.PubMedPubMedCentral
11.
go back to reference Fujiwara Y, Kiyota N, Hori M, Matsushita S, Iijima Y, Aoki K, et al. Esculeogenin a, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT. Arterioscler Thromb Vasc Biol. 2007;27:2400–6.CrossRef Fujiwara Y, Kiyota N, Hori M, Matsushita S, Iijima Y, Aoki K, et al. Esculeogenin a, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT. Arterioscler Thromb Vasc Biol. 2007;27:2400–6.CrossRef
12.
go back to reference Lu FL, Liu JL, Chen Y, Wu J, Li D. Determination of esculeoside a in Lycopersicon esculentum MILL by high performance liquid chromatography with evaporative light scattering detection. Chin J Chromatogr. 2010;28:908–11. Lu FL, Liu JL, Chen Y, Wu J, Li D. Determination of esculeoside a in Lycopersicon esculentum MILL by high performance liquid chromatography with evaporative light scattering detection. Chin J Chromatogr. 2010;28:908–11.
13.
go back to reference Lu FL, Chen SC, Liu JL, et al. Separation and purification of total saponins in Lycopersicon esculentum MILL. By D101 macropere resin. Food Sci Technol. 2012;37:199–202. Lu FL, Chen SC, Liu JL, et al. Separation and purification of total saponins in Lycopersicon esculentum MILL. By D101 macropere resin. Food Sci Technol. 2012;37:199–202.
14.
go back to reference Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127–8.CrossRef Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127–8.CrossRef
15.
go back to reference Kim MJ, Chung JY, Kim JH, Kwak HK. Effects of cranberry powder on biomarkers of oxidative stress and glucose control in db/db mice. Nutr Res Pract. 2013;7:430–8.CrossRef Kim MJ, Chung JY, Kim JH, Kwak HK. Effects of cranberry powder on biomarkers of oxidative stress and glucose control in db/db mice. Nutr Res Pract. 2013;7:430–8.CrossRef
16.
go back to reference Sotourquieta MG, Lópezbriones S, Pérezvázquez V, Saavedramolina A, Gonzalezhernandez GA, Ramirezemiliano J. Curcumin restores mitochondrial functions and decreases lipid peroxidation in liver and kidneys of diabetic db/db mice. Biol Res. 2014;47:74–82.CrossRef Sotourquieta MG, Lópezbriones S, Pérezvázquez V, Saavedramolina A, Gonzalezhernandez GA, Ramirezemiliano J. Curcumin restores mitochondrial functions and decreases lipid peroxidation in liver and kidneys of diabetic db/db mice. Biol Res. 2014;47:74–82.CrossRef
17.
go back to reference Fujiwara Y, Takaki A, Uehara Y, Ikeda T, Okawa M, Yamauchi K, et al. Tomato steroidal alkaloid glycosides, Esculeosides a and B, from ripe fruits. Tetrahedron. 2004;60:4915–20.CrossRef Fujiwara Y, Takaki A, Uehara Y, Ikeda T, Okawa M, Yamauchi K, et al. Tomato steroidal alkaloid glycosides, Esculeosides a and B, from ripe fruits. Tetrahedron. 2004;60:4915–20.CrossRef
18.
go back to reference Ju X, Cui Q, Zhang M, Wang W, Jiang J, Chang Y, et al. Human cholesteryl ester transfer protein enhances insulin-mediated glucose uptake in adipocytes. Life Sci. 2011;89:479–84.CrossRef Ju X, Cui Q, Zhang M, Wang W, Jiang J, Chang Y, et al. Human cholesteryl ester transfer protein enhances insulin-mediated glucose uptake in adipocytes. Life Sci. 2011;89:479–84.CrossRef
19.
go back to reference Zhang X, Yang J, Guo Y, Ye H, Yu C, Xu C, et al. Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: Enoyl–coenzyme a hydratase down-regulation exacerbates hepatic steatosis. Hepatology. 2010;51:1190–9.CrossRef Zhang X, Yang J, Guo Y, Ye H, Yu C, Xu C, et al. Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: Enoyl–coenzyme a hydratase down-regulation exacerbates hepatic steatosis. Hepatology. 2010;51:1190–9.CrossRef
20.
go back to reference Liu Q, Li X, Li C, Zhang Y, Wang F, Li H, et al. 1-Deoxynojirimycin alleviates liver injury and improves hepatic glucose metabolism in db/db mice. Molecules. 2016;21:279–90.CrossRef Liu Q, Li X, Li C, Zhang Y, Wang F, Li H, et al. 1-Deoxynojirimycin alleviates liver injury and improves hepatic glucose metabolism in db/db mice. Molecules. 2016;21:279–90.CrossRef
22.
go back to reference Narbonne P, Roy R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature. 2009;457:210–4.CrossRef Narbonne P, Roy R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature. 2009;457:210–4.CrossRef
23.
go back to reference Hu R, Yan H, Fei X, Liu H, Wu J. Modulation of glucose metabolism by a natural compound from Chloranthus japonicus via activation of AMP-activated protein kinase[J]. Sci Rep. 2017;7:778–87.CrossRef Hu R, Yan H, Fei X, Liu H, Wu J. Modulation of glucose metabolism by a natural compound from Chloranthus japonicus via activation of AMP-activated protein kinase[J]. Sci Rep. 2017;7:778–87.CrossRef
24.
go back to reference Zhong J, Gong W, Lu L, Chen J, Lu Z, Li HY, et al. Irbesartan ameliorates hyperlipidemia and liver steatosis in type 2 diabetic db/db mice via stimulating PPAR-γ, AMPK/Akt/mTOR signaling and autophagy. Int Immunopharmacol. 2017;42:176–84.CrossRef Zhong J, Gong W, Lu L, Chen J, Lu Z, Li HY, et al. Irbesartan ameliorates hyperlipidemia and liver steatosis in type 2 diabetic db/db mice via stimulating PPAR-γ, AMPK/Akt/mTOR signaling and autophagy. Int Immunopharmacol. 2017;42:176–84.CrossRef
25.
go back to reference Hu X, Wang S, Xu J, Wang DB, Chen Y, Yang GZ. Triterpenoid saponins from stauntonia chinensis ameliorate insulin resistance via the AMP-activated protein kinase and IR/IRS-1/PI3K/Akt pathways in insulin-resistant HepG2 cells. Int J Mol Sci. 2014;15:10446–58.CrossRef Hu X, Wang S, Xu J, Wang DB, Chen Y, Yang GZ. Triterpenoid saponins from stauntonia chinensis ameliorate insulin resistance via the AMP-activated protein kinase and IR/IRS-1/PI3K/Akt pathways in insulin-resistant HepG2 cells. Int J Mol Sci. 2014;15:10446–58.CrossRef
26.
go back to reference Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature. 2001;414:821–7.CrossRef Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature. 2001;414:821–7.CrossRef
27.
go back to reference Burgess SC, Hausler N, Merritt M, Jeffrey FMH, Storey C, Milde A, et al. Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. J Biol Chem. 2004;279:48941–9.CrossRef Burgess SC, Hausler N, Merritt M, Jeffrey FMH, Storey C, Milde A, et al. Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. J Biol Chem. 2004;279:48941–9.CrossRef
28.
go back to reference Hakimi P, Johnson MT, Yang J, Lepage DF, Conlon RA, Kalhan SC, et al. Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism. Nutr Metab. 2005;2:33–44.CrossRef Hakimi P, Johnson MT, Yang J, Lepage DF, Conlon RA, Kalhan SC, et al. Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism. Nutr Metab. 2005;2:33–44.CrossRef
29.
go back to reference Hardie DG. The AMP-activated protein kinase pathway-new players upstream and downstream. J Cell Sci. 2004;117:5479–87.CrossRef Hardie DG. The AMP-activated protein kinase pathway-new players upstream and downstream. J Cell Sci. 2004;117:5479–87.CrossRef
30.
go back to reference Taniguchi CM, Ueki K, Kahn CR. Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005;115:718–27.CrossRef Taniguchi CM, Ueki K, Kahn CR. Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005;115:718–27.CrossRef
31.
go back to reference Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414:1–18.CrossRef Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414:1–18.CrossRef
32.
go back to reference Irwin DM, Tan H. Evolution of glucose utilization: Glucokinase and glucokinase regulator protein. Mol Phylogenet Evol. 2014;70:195–203.CrossRef Irwin DM, Tan H. Evolution of glucose utilization: Glucokinase and glucokinase regulator protein. Mol Phylogenet Evol. 2014;70:195–203.CrossRef
34.
go back to reference Poovitha S, Parani M. Protein extract from the fruit pulp of Momordica charantia potentiate glucose uptake by up-regulating GLUT4 and AMPK. J Funct Foods. 2017;37:507–12.CrossRef Poovitha S, Parani M. Protein extract from the fruit pulp of Momordica charantia potentiate glucose uptake by up-regulating GLUT4 and AMPK. J Funct Foods. 2017;37:507–12.CrossRef
35.
go back to reference Shidfar F, Froghifar N, Vafa M, Rajab A, Hosseini S, Shidfar S, et al. The effects of tomato consumption on serum glucose, apolipoprotein B, apolipoprotein A-I, homocysteine and blood pressure in type 2 diabetic patients. Int J Food Sci Nutr. 2011;62:289–94.CrossRef Shidfar F, Froghifar N, Vafa M, Rajab A, Hosseini S, Shidfar S, et al. The effects of tomato consumption on serum glucose, apolipoprotein B, apolipoprotein A-I, homocysteine and blood pressure in type 2 diabetic patients. Int J Food Sci Nutr. 2011;62:289–94.CrossRef
36.
go back to reference Montonen J, Knekt P, Järvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004;27:362–6.CrossRef Montonen J, Knekt P, Järvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004;27:362–6.CrossRef
37.
go back to reference Zidani S, Benakmoum A, Ammouche A, Benali Y, Bouhadef A, Abbeddou S. Effect of dry tomato peel supplementation on glucose tolerance, insulin resistance, and hepatic markers in mice fed high-saturated-fat/high-cholesterol diets. J Nutr Biochem. 2016;40:164–71.CrossRef Zidani S, Benakmoum A, Ammouche A, Benali Y, Bouhadef A, Abbeddou S. Effect of dry tomato peel supplementation on glucose tolerance, insulin resistance, and hepatic markers in mice fed high-saturated-fat/high-cholesterol diets. J Nutr Biochem. 2016;40:164–71.CrossRef
38.
go back to reference Ali MM, Agha FG. Amelioration of streptozotocin-induced diabetes mellitus, oxidative stress and dyslipidemia in rats by tomato extract lycopene. Scand J Clin Lab Invest. 2009;69:371–9.CrossRef Ali MM, Agha FG. Amelioration of streptozotocin-induced diabetes mellitus, oxidative stress and dyslipidemia in rats by tomato extract lycopene. Scand J Clin Lab Invest. 2009;69:371–9.CrossRef
39.
go back to reference Wang L, Liu S, Manson JE, Gaziano LM, Buring JE, Sesso HD. The consumption of lycopene and tomato-based food products is not associated with the risk of type 2 diabetes in women. J Nutr. 2006;136:620–5.CrossRef Wang L, Liu S, Manson JE, Gaziano LM, Buring JE, Sesso HD. The consumption of lycopene and tomato-based food products is not associated with the risk of type 2 diabetes in women. J Nutr. 2006;136:620–5.CrossRef
40.
go back to reference Upritchard JE, Sutherland WHF, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes. Diabetes Care. 2000;23:733–8.CrossRef Upritchard JE, Sutherland WHF, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes. Diabetes Care. 2000;23:733–8.CrossRef
41.
go back to reference Reaganshaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.CrossRef Reaganshaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.CrossRef
Metadata
Title
Hypoglycemic effects of esculeoside A are mediated via activation of AMPK and upregulation of IRS-1
Authors
Ziming Yang
Li Zhang
Jinglei Liu
Fenglai Lu
Lei Wang
Yueyuan Chen
Dianpeng Li
Publication date
01-12-2019
Publisher
BioMed Central
Keywords
Insulins
Insulins
Published in
BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-019-2543-3

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