Aqueous and alcoholic extracts of Artemisia annua L. improved insulin resistance via decreasing TNF-alpha, IL-6 and free fatty acids in high-fat diet/streptozotocin-induced diabetic mice

Document Type : Original Research Article


1 Department of Toxicology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

2 Department of Physiology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran


Objective: Type 2 diabetes mellitus (T2DM) is a metabolic disease that influences many people worldwide.  Management of insulin resistance in T2DM without side effects of chemical drugs, is the ultimate goal of the medical community. Artemisia annua L. is used for the treatment of diabetes in folkloric medicine. The present study investigated the effects of aqueous and alcoholic extracts of A. annua (AA) on insulin resistance in high-fat diet/STZ-induced diabetic mice.
Material and methods:  Mice were divided into groups including control with a normal diet, un-treated high-fat diet/streptozotocin-induced diabetic mice, and diabetic mice treated by oral administration of 100, 200, and 400 mg/kg body weight of water (hot and cold) and alcoholic extracts of AA.  After four weeks of treatment with AA, blood sampling was carried out to measure factors involved in insulin resistance such as low-density lipoprotein/ High-density lipoprotein (LDL/HDL) ratio, free fatty acids, Tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and homeostasis model assessment of insulin resistance (HOMA-IR) as an index of insulin resistance.
Results: The results showed that all AA extracts (100, 200, and 400 mg/kg) and metformin (250 mg/kg) significantly reduced the serum levels of free fatty acids, TNF-alpha, IL-6, LDL/HDL ratio, and HOMA-IR in diabetic mice compared to untreated diabetic mice (p<0.0001). Notably, the 400 mg/kg dose of cold-water extract was more effective than metformin in reduction of TNF-alpha and IL-6 (p<0.01 and p<0.05, respectively).
Conclusion: These data illustrated that AA extracts attenuated insulin resistance by reducing the lipid profile and adipocytokines.


Aggarwal S, Shailendra G, Ribnicky DM,
Burk D, Karki N, Qingxia Wang MS. 2015.
An extract of Artemisia dracunculus L.
stimulates insulin secretion from beta cells,
activates AMPK and suppresses
inflammation. J Ethnopharmacol, 170: 98-
Ahmad W, Khan I, Khan MA, Ahmad M,
Subhan F, Karim N. 2014. Evaluation of
antidiabetic and antihyperlipidemic activity
of Artemisia indica linn (aeriel parts) in
Streptozotocin induced diabetic rats. J
Ethnopharmacol, 151: 618-623.
Albasher G, Alwahaibi M, Abdel-Daim MM,
Alkahtani S, Almeer R. 2020. Protective
effects of Artemisia judaica extract
compared to metformin against hepatorenal
injury in high-fat diet/streptozotocineinduced diabetic rats. Environ Sci Pollut
Res Int, 27: 40525-40536.
Choi E, Park H, Lee J, Kim G. 2013.
Anticancer, antiobesity, and antiinflammatory activity of Artemisia species
in vitro. J Tradit Chin Med, 33: 92-97.
Choi HN, Kang MJ, Lee SJ, Kim JI. 2014.
Ameliorative effect of myricetin on insulin
resistance in mice fed a high-fat, highsucrose diet. Nutr Res Pract, 8: 544-549.
Das S. 2012. Artemisia annua (Qinghao): a
pharmacological review. Int J Pharm Sci
Res, 3: 4573-4577.
De Magalhães PM, Dupont I, Hendrickx A,
Joly A, Raas T, Dessy S, Sergent T,
Schneider Y-J. 2012. Anti-inflammatory
effect and modulation of cytochrome P450
activities by Artemisia annua tea infusions
in human intestinal Caco-2 cells. Food
Chem, 134: 864-871.
Gao J, Cheng Y, Hao H, Yin Y, Xue J, Zhang
Q, Li L, Liu J, Xie Z, Yu S. 2019.
Decitabine assists umbilical cord-derived
mesenchymal stem cells in improving
glucose homeostasis by modulating
macrophage polarization in type 2 diabetic
mice. Stem Cell Res Ther, 10: 1-15.
Ghazanfar K, Ganai BA, Akbar S, Mubashir
K, Dar SA, Dar MY, Tantry MA. 2014.
Antidiabetic activity of Artemisia
amygdalina Decne in streptozotocin
induced diabetic rats. Biomed Res Int,
2014: 1-11.
Goldstein BJ. 2002. Insulin resistance as the
core defect in type 2 diabetes mellitus. Am
J Cardiol, 90: 3-10.
Guo Y, Fu W, Xin Y, Bai J, Peng H, Fu L, Liu
J, Li L, Ma Y, Jiang H. 2018. Antidiabetic
and antiobesity effects of artemether in
db/db mice. Biomed Res Int, 2018: 1-10.
Hamza N, Berke B, Cheze C, Le Garrec R,
Lassalle R, Agli A-N, Robinson P, Gin H,
Moore N. 2011. Treatment of high fat diet
induced type 2 diabetes in C57BL/6J mice
by two medicinal plants used in traditional
treatment of diabetes in the east of Algeria.
sJ EthnJournal 133: 931-933.
Artemisia annua and insulin resistance
AJP, Vol. 12, No. 1, Jan-Feb 2022 65
Helal EG, Abou-Aouf N, Khattab AM, Zoair
MA. 2014. Anti-diabetic effect of
Artemisia annua (kaysom) in alloxaninduced diabetic rats. Egypt J Hosp Med,
31: 1-16.
Honmore V, Kandhare A, Zanwar AA,
Rojatkar S, Bodhankar S, Natu A. 2015.
Artemisia pallens alleviates acetaminophen
induced toxicity via modulation of
endogenous biomarkers. Pharm Biol, 53:
Issa IA, Hussen Bule M. 2015. Hypoglycemic
effect of aqueous and methanolic extract of
Artemisia afra on alloxan induced diabetic
Swiss albino mice. Evid Based
Complement Alternat Med, 2015: 1-6.
Jung UJ, Baek NI, Chung HG, Bang MH, Yoo
JS, Jeong TS, Lee KT, Kang YJ, Lee MK,
Kim HJ, Yeo JY, Choi MS. 2007. The antidiabetic effects of ethanol extract from two
variants of Artemisia princeps Pampanini
in C57BL/KsJ-db/db mice. Food Chem
Toxicol, 45: 2022-2029.
Kadi I, Ouinten M, Gourine N, Yousfi M.
2019. Synergistic antinociceptive activity
of combined aqueous extracts of Artemisia
campestris and Artemisia herba-alba in
several acute pain models. Nat Prod Res,
33: 875-878.
Kang YJ, Jung UJ, Lee MK, Kim HJ, Jeon
SM, Park YB, Chung HG, Baek NI, Lee
KT, Jeong TS, Choi MS. 2008. Eupatilin,
isolated from Artemisia princeps
Pampanini, enhances hepatic glucose
metabolism and pancreatic beta-cell
function in type 2 diabetic mice. Diabetes
Res Clin Pract, 82: 25-32.
Kartikadewi A, Prasetyo A, Budipradigdo L,
Nugroho H, Tjahjono K, Lelono A. 2019.
Artemisia annua leaf extract increases
GLUT-4 expression in type 2 diabetes
mellitus rat. Indo Biomed J, h11: 78-84.
Kavitha K, Reddy AG, Reddy KK, Kumar CS,
Boobalan G, Jayakanth K. 2016.
Hypoglycemic, hypolipidemic and
antioxidant effects of pioglitazone, insulin
and synbiotic in diabetic rats. Vet World, 9:
Kheterpal I, Scherp P, Kelley L, Wang Z,
Johnson W, Ribnicky D, Cefalu WT. 2014.
Bioactives from Artemisia dracunculus L.
enhance insulin sensitivity via modulation
of skeletal muscle protein phosphorylation.
Nutrition, 30: 43-51.
Kim KE, Ko KH, Heo RW, Yi CO, Shin HJ,
Kim JY, Park JH, Nam S, Kim H, Roh GS.
2016. Artemisia annua leaf extract
attenuates hepatic steatosis and
inflammation in high-fat diet-fed mice. J
Med Food, 19: 290-299.
Li YJ, Guo Y, Yang Q, Weng XG, Yang L,
Wang YJ, Chen Y, Zhang D, Li Q, Liu XC,
Kan XX, Chen X, Zhu XX, Kmoniekova E,
Zidek Z. 2015. Flavonoids casticin and
chrysosplenol D from Artemisia annua L.
inhibit inflammation in vitro and in vivo.
Toxicol Appl Pharmacol, 286: 151-158.
Liu C, Feng X, Li Q, Wang Y, Li Q, Hua M.
2016. Adiponectin, TNF-alpha and
inflammatory cytokines and risk of type 2
diabetes: A systematic review and metaanalysis. Cytokine, 86: 100-109.
Liu IM, Tzeng TF, Liou SS, Lan TW. 2007.
Improvement of insulin sensitivity in obese
Zucker rats by myricetin extracted from
Abelmoschus moschatus. Planta Med, 73:
Nathan D, Turgeon H, Regan S. 2007.
Relationship between glycated
haemoglobin levels and mean glucose
levels over time. Diabetologia, 50: 2239-
Nofal SM, Mahmoud SS, Ramadan A,
Soliman G, Fawzy R. 2009. Anti-diabetic
effect of Artemisia judaica extracts. Res J
Med Sci, 4: 42-48.
Ogbonna C, Ogbonna A, Itelima J, Umar A,
Onyezili N, Istifanus M. 2017. Combined
anti-diabetic effects of extracts of
Artemisia annua var. chiknensis
(CBGE/CHNA/09/LTNGS/G) and each of
three other plants (Momordica charantia
Linn. Vernonia amygdalina Del. and Aegle
marmelos Correa) traditionally used in
Nigeria for the treatment of diabetes. J Sci
Res Rep, 16: 1-12.
Ribnicky D, Poulev A, Watford M, Cefalu W,
Raskin I. 2006. Antihyperglycemic activity
of Tarralin™, an ethanolic extract of
Artemisia dracunculus L. Phytomedicine,
13: 550-557.
Richard AJ, Burris TP, Sanchez-Infantes D,
Wang Y, Ribnicky DM, Stephens JM.
2014. Artemisia extracts activate PPARγ,
promote adipogenesis, and enhance insulin
sensitivity in adipose tissue of obese mice.
Nutrition, 30: 31-36.
Sah SP, Singh B, Choudhary S, Kumar A.
2016. Animal models of insulin resistance:
A review. Pharmacol Rep, 68: 1165-1177.
Ghanbari et al.
AJP, Vol. 12, No. 1, Jan-Feb 2022 66
Sefi M, Fetoui H, Makni M, Zeghal N. 2010.
Mitigating effects of antioxidant properties
of Artemisia campestris leaf extract on
hyperlipidemia, advanced glycation end
products and oxidative stress in alloxaninduced diabetic rats. Food Chem Toxicol,
48: 1986-1993.
Sun X, Sun H, Zhang J, Ji X. 2016. Artemisia
extract improves insulin sensitivity in
women with gestational diabetes mellitus
by up-regulating adiponectin. J Clin
Pharmacol, 56: 1550-1554.
Tonk S, Bartarya R, Kumari KM, Bhatnagar
V, Srivastava S. 2006. Effective method for
extraction of larvicidal component from
leaves of Azadirachta indica and Artemisia
annua Linn. J Environ Biol, 27: 103-105.
Turner R, Holman R, Matthews D, Hockaday
T, Peto J. 1979. Insulin deficiency and
insulin resistance interaction in diabetes:
estimation of their relative contribution by
feedback analysis from basal plasma
insulin and glucose concentrations.
Metabolism, 28: 1086-1096.
Vandanmagsar B, Haynie KR, Wicks SE,
Bermudez EM, Mendoza TM, Ribnicky D,
Cefalu WT, Mynatt RL. 2014. Artemisia
dracunculus L. extract ameliorates insulin
sensitivity by attenuating inflammatory
signalling in human skeletal muscle culture.
Diabetes Obes Metab, 16: 728-738.
Yaribeygi H, Farrokhi FR, Butler AE,
Sahebkar A. 2019. Insulin resistance:
review of the underlying molecular
mechanisms. J Cell Physiol, 234: 8152-
Zhang X, Wang Z, Huang Y, Wang J. 2011.
Effects of chronic administration of
alogliptin on the development of diabetes
and β‐cell function in high fat
diet/streptozotocin diabetic mice. Diabetes
Obes Metab, 13: 337-347.
Zhao RR, O'sullivan AJ, Fiatarone Singh MA.
2018. Exercise or physical activity and
cognitive function in adults with type 2
diabetes, insulin resistance or impaired
glucose tolerance: a systematic review. Eur
Rev Aging Phys Act, 15: 1-16.