Restricted accessResearch articleFirst published online 2021-05
Ethanol Extract of Orostachys japonicus A. Berger (Crassulaceae) Protects Against Type 2 Diabetes by Reducing Insulin Resistance and Hepatic Inflammation in Mice
Type 2 diabetes (T2D) is a threaten human health problem, and accompanied by hyperglycemia and disorder of insulin secretion, is a major cause of abnormalities in maintaining blood glucose homeostasis. Also, low-grade inflammation, as well as insulin resistance (IR), is a common feature in patients with T2D. Numerous causes of the outbreak of T2D have been suggested by researchers, who indicate that genetic background and epigenetic predisposition, such as overnutrition and deficient physical activity, hasten the promotion of T2D milieu. Orostachys japonicus A. Berger (O. japonicus) is a herbal and remedial plant whose various activities include hemostatic, antidotal, febrile, and anti-inflammatory. Hence, we designed to evaluate the antidiabetic efficacy of ethanol extracts of O. japonicus (OJE). Six-week-old C57BL/Ksj-db/db (db/db) mice were used. The results showed that mice given various concentrations of OJE (0, 50, 100, and 200 mg/kg per day) for 8 weeks showed significantly reduced hyperglycemia, IR, and liver injury, confirmed by measuring diabetic parameters, serum, and hepatic biochemicals. Furthermore, the treatment of OJE markedly decreased the mRNA levels of proinflammatory cytokines, lipid accumulation, and gluconeogenesis-related genes. Consistently, western blot analysis indicated that mice treated with OJE showed increased levels of phospho-c-Jun N-terminal kinase, phospho-Akt, glucose transporters 2 and 4 (GLUT2 and GLUT4) in T2D mice. Likewise, much the same results were obtained in in vitro experiments. Taken together, OJE had hopeful advantage in sustaining the glucose homeostasis and diminishing IR, and could be a safe alternative remedy for treating T2D.
Get full access to this article
View all access options for this article.
References
1.
VerspohlEJ: Novel pharmacological approaches to the treatment of type 2 diabetes. Pharmacol Rev, 2012; 64:188–237.
2.
ChenSY, HsuYM, LinYJ, et al.: Current concepts regarding developmental mechanisms in diabetic retinopathy in Taiwan. Biomedicine (Taipei), 2016; 6:7.
3.
ElluluMS, PatimahI, Khaza'aiH, RahmatA, AbedY: Obesity and inflammation: The linking mechanism and the complications. Arch Med Sci, 2017; 13:851–863.
4.
CookeAA, ConnaughtonRM, LyonsCL, McMorrowAM, RocheHM: Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome. Eur J Pharmacol, 2016; 785:207–214.
5.
KurylowiczA, KozniewskiK: Anti-inflammatory strategies targeting metaflammation in type 2 diabetes. Molecules, 2020; 25:2224.
6.
LeiteNC, SallesGF, AraujoAL, Villela-NogueiraCA, CardosoCR: Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int, 2009; 29:113–119.
7.
PackhamDK, AlvesTP, DwyerJP, et al.: Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: Results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database. Am J Kidney Dis, 2012; 59:75–83.
8.
KangP, TianC, JiaC: Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene, 2012; 500:1–9.
9.
InvestigatorsDAIS: Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet, 2001; 357:905–910.
TsalamandrisS, AntonopoulosAS, OikonomouE, et al.: The role of inflammation in diabetes: Current concepts and future perspectives. Eur Cardiol, 2019; 14:50–59.
12.
MatafomeP, NunesE, LouroT, et al.: A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia. Naunyn Schmiedebergs Arch Pharmacol, 2009; 379:241–251.
13.
AravindaramK, YangNS: Anti-inflammatory plant natural products for cancer therapy. Planta Med, 2010; 76:1103–1117.
14.
BussaNF, BelaynehA: Traditional medicinal plants used to treat cancer, tumors and inflammatory ailments in Harari Region, Eastern Ethiopia. S Afr J Bot, 2019; 122:360–368.
15.
LeeS-J, SeoJ-K, ShinJ-H, LeeH-J, SungN-J: Antioxidant activity of Wa-song (Orostachys japonicus A. Berger) according to drying methods. J Korean Soc Food Sci Nutr, 2008; 37:605–611.
16.
LeeJH, LeeSJ, ParkS, et al.: Characterisation of flavonoids in Orostachys japonicus A. Berger using HPLC–MS/MS: Contribution to the overall antioxidant effect. Food Chem, 2011; 124:1627–1633.
17.
LeeH-S, BilehalD, LeeG-S, et al.: Anti-inflammatory effect of the hexane fraction from Orostachys japonicus in RAW 264.7 cells by suppression of NF-κB and PI3K-Akt signaling. J Funct Foods, 2013; 5:1217–1225.
18.
KoppulaS, YumM-J, KimJ-S, et al.: Anti-fibrotic effects of Orostachys japonicus A. Berger (Crassulaceae) on hepatic stellate cells and thioacetamide-induced fibrosis in rats. Nutr Res Pract, 2017; 11:470–478.
19.
ChoiSY, ChungMJ, SeoWD, ShinJH, ShonMY, SungNJ: Inhibitory effects of Orostachys japonicus extracts on the formation of N-nitrosodimethylamine. J Agric Food Chem, 2006; 54:6075–6078.
20.
LeeSJ, ZhangGF, SungNJ: Hypolipidemic and hypoglycemic effects of Orostachys japonicus A. Berger extracts in streptozotocin-induced diabetic rats. Nutr Res Pract, 2011; 5:301–307.
21.
KimS-G, PoudelA, KimD-K, et al.: Anti-obesitic effect of Orostachys japonicus in rats model fed a hyperlipidemic diet. Nat Prod Sci, 2011; 17:117–122.
22.
JeongH, KimJW, YangD, et al.: Orostachys japonicus A. Berger (Crassulaceae) exerts antidiabetic activity by improving glucose and lipid levels in type 2 diabetic mice. J Med Food, 2019; 22:797–809.
23.
DansAM, VillarruzMV, JimenoCA, et al.: The effect of Momordica charantia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. J Clin Epidemiol, 2007; 60:554–559.
ZhangJZ, CavetME, WardKW: Anti-inflammatory effects of besifloxacin, a novel fluoroquinolone, in primary human corneal epithelial cells. Curr Eye Res, 2008; 33:923–932.
26.
ZhangJZ, WardKW: Besifloxacin, a novel fluoroquinolone antimicrobial agent, exhibits potent inhibition of pro-inflammatory cytokines in human THP-1 monocytes. J Antimicrob Chemother, 2008; 61:111–116.
27.
QureshiW, SantarenID, HanleyAJ, WatkinsSM, LorenzoC, WagenknechtLE: Risk of diabetes associated with fatty acids in the de novo lipogenesis pathway is independent of insulin sensitivity and response: The Insulin Resistance Atherosclerosis Study (IRAS). BMJ Open Diabetes Res Care, 2019; 7:e000691.
28.
BenoitSC, KempCJ, EliasCF, et al.: Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest, 2009; 119:2577–2589.
29.
DingX, JianT, WuY, et al.: Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf2 pathway. Biomed Pharmacother, 2019; 110:85–94.
30.
HortonJD, GoldsteinJL, BrownMS: SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest, 2002; 109:1125–1131.
31.
AhmedMH, ByrneCD: Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). Drug Discov Today, 2007; 12:740–747.
32.
KangHS, ChoHC, LeeJH, et al.: Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. Sci Rep, 2016; 6:23665.
33.
MatsusueK, AibaraD, HayafuchiR, et al.: Hepatic PPARgamma and LXRalpha independently regulate lipid accumulation in the livers of genetically obese mice. FEBS Lett, 2014; 588:2277–2281.
34.
BryantNJ, GoversR, JamesDE: Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol, 2002; 3:267–277.
35.
Villanueva-PenacarrilloML, PuenteJ, RedondoA, ClementeF, ValverdeI: Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models. Endocrine, 2001; 15:241–248.
36.
ZhangC, SunC, WangB, et al.: Orexin-A stimulates the expression of GLUT4 in a glucose dependent manner in the liver of orange-spotted grouper (Epinephelus coioides). Comp Biochem Physiol A Mol Integr Physiol, 2016; 199:95–104.
37.
HotamisligilGS, ShargillNS, SpiegelmanBM: Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science, 1993; 259:87–91.
38.
QiaoZ, DuX, ZhuangW, et al.: Schisandra chinensis acidic polysaccharide improves the insulin resistance in type 2 diabetic rats by inhibiting inflammation. J Med Food, 2020; 23:358–366.
39.
BursalE, KöksalE: Evaluation of reducing power and radical scavenging activities of water and ethanol extracts from sumac (Rhus coriaria L.). Food Res Int, 2011; 44:2217–2221.
40.
AdedotunA, OdukoyaK: Antifungal activities of ethanol and aqueous crude extracts of four Nigerian chewing sticks. Ethnobot Leaf, 2006; 10:24–40.
41.
JungJH, KangJI, KimHS: Effect of quercetin on impaired immune function in mice exposed to irradiation. Nutr Res Pract, 2012; 6:301–307.
42.
LeeS-J, ShinJ-H, KangJ-R, HwangC-R, SungN-J: In vitro evaluation of biological activities of Wa-song (Orostachys japonicus A. Berger) and Korean traditional plants mixture. J Korean Soc Food Sci Nutr, 2012; 41:295–301.
43.
ParkH-J, YoungH-S, KimJ-O, RheeS-H, ChoiJ-S: A study on the chemical constituents of Orostachys japonicus A. Berger. Korean J Pharmacogn, 1991; 22:78–84.
44.
ParkH-J, LimS-C, LeeM-S, YoungH-S: Triterpene and steroids from Orostachys japonicus. Korean J Pharmacogn, 1994; 25:20–23.
45.
ParkJ, ParkJ, HurJ, et al.: Phenolic compounds from Orostachys japonicus having anti-HIV-1 protease activity. Nat Prod Sci, 2000; 6:117–121.
46.
LeeG-S, LeeH-S, KimS-H, SukD-H, RyuD-S, LeeD-S: Anti-cancer activity of the ethylacetate fraction from Orostachys japonicus for modulation of the signaling pathway in HepG2 human hepatoma cells. Food Sci Biotechnol, 2014; 23:269–275.
47.
UsmanUZ, BakarAA, MohamedM: Phytochemical screening and comparison of antioxidant activity of water and ethanol extract propolis from Malaysia. Int J Pharm Pharm Sci, 2016; 8:413–415.
48.
ZhangL, HuJ-J, LinJ-W, FangW-S, DuG-H: Anti-inflammatory and analgesic effects of ethanol and aqueous extracts of Pterocephalus hookeri (CB Clarke) Höeck. J Ethnopharmacol, 2009; 123:510–514.
49.
JohnsonAM, OlefskyJM: The origins and drivers of insulin resistance. Cell, 2013; 152:673–684.
50.
KammounHL, AllenTL, HenstridgeDC, et al.: Evidence against a role for NLRP3-driven islet inflammation in db/db mice. Mol Metab, 2018; 10:66–73.
51.
HuiQ, AsadiA, ParkYJ, et al.: Amyloid formation disrupts the balance between interleukin-1beta and interleukin-1 receptor antagonist in human islets. Mol Metab, 2017; 6:833–844.
PetersenMC, ShulmanGI: Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol Sci, 2017; 38:649–665.
58.
OzcanU, CaoQ, YilmazE, et al.: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 2004; 306:457–461.
59.
MuJ, XinG, ZhangB, WangY, NingC, MengX: Beneficial effects of Aronia melanocarpa berry extract on hepatic insulin resistance in type 2 diabetes mellitus rats. J Food Sci, 2020; 85:1307–1318.
60.
RodriguezA, CatalanV, Gomez-AmbrosiJ, et al.: Insulin- and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade. J Clin Endocrinol Metab, 2011; 96:E586–E597.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
