Objective: Diabetic cardiomyopathy (DCM) is a serious complication of type 2 diabetes mellitus (T2DM), resulting in unfavorable prognosis. Icariin (ICA) is a major flavonoid isolated from the traditional oriental herbal medicine Epimedium that has been recently proved to show potential therapeutic efficacy on T2DM. The aim of this study was to investigate the underlying mechanism of how ICA improved DCM in rat models. Methods: To corroborate myocardial improvement by ICA, we managed to establish the T2DM rat model by streptozotocin (STZ) administration and high-glucose-high-fat diet. Results: The rats with T2DM showed severe insulin resistance, left ventricular dysfunction, aberrant lipids deposition, cardiac inflammation, and fibrosis compared with the control group. All these pathological symptoms were ameliorated by the treatment of ICA. The levels of extracellular matrix proteins of heart tissue significantly declined in ICA-treated rats. Conclusion: ICA may exert as a protector in T2DM-induced DCM by reducing extracellular matrix proteins in the heart tissue, implicating its potential role for the treatment of human DCM.

1.
Balk EM, Earley A, Raman G, Avendano EA, Pittas AG, Remington PL. Combined Diet and Physical Activity Promotion Programs to Prevent Type 2 Diabetes Among Persons at Increased Risk: A Systematic Review for the Community Preventive Services Task Force.
Ann Intern Med
. 2015 Sep;163(6):437–51.
2.
Hu C, Jia W. Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication.
Diabetes
. 2018 Jan;67(1):3–11.
3.
Ma RC, Lin X, Jia W. Causes of type 2 diabetes in China.
Lancet Diabetes Endocrinol
. 2014 Dec;2(12):980–91.
4.
Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis.
Circ Res
. 2006 Mar;98(5):596–605.
5.
Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options.
J Am Coll Cardiol
. 2008 Jan;51(2):93–102.
6.
Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart.
Diabetes
. 2002 Aug;51(8):2587–95.
7.
Chen YJ, Zheng HY, Huang XX, Han SX, Zhang DS, Ni JZ, et al. Neuroprotective -Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer’s Disease Mice.
CNS Neurosci Ther
. 2016 Jan;22(1):63–73.
8.
Li F, Gong QH, Wu Q, Lu YF, Shi JS. Icariin isolated from Epimedium brevicornum Maxim attenuates learning and memory deficits induced by d-galactose in rats.
Pharmacol Biochem Behav
. 2010 Sep;96(3):301–5.
9.
Urano T, Tohda C. Icariin improves memory impairment in Alzheimer’s disease model mice (5xFAD) and attenuates amyloid β-induced neurite atrophy.
Phytother Res
. 2010 Nov;24(11):1658–63.
10.
Zeng KW, Ko H, Yang HO, Wang XM. Icariin attenuates β-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells.
Neuropharmacology
. 2010 Nov;59(6):542–50.
11.
Song YH, Cai H, Gu N, Qian CF, Cao SP,  Zhao ZM. Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure.
J Pharm Pharmacol
. 2011 Apr;63(4):541–9.
12.
Xu CQ, Liu BJ, Wu JF, Xu YC, Duan XH, Cao YX, et al. Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-kappaB signaling pathway.
Eur J Pharmacol
. 2010 Sep;642(1-3):146–53.
13.
Zhou H, Yuan Y, Liu Y, Deng W, Zong J, Bian ZY, et al. Icariin attenuates angiotensin II-induced hypertrophy and apoptosis in H9c2 cardiomyocytes by inhibiting reactive oxygen species-dependent JNK and p38 pathways.
Exp Ther Med
. 2014 May;7(5):1116–22.
14.
Adamski J. Key elements of metabolomics in the study of biomarkers of diabetes.
Diabetologia
. 2016 Dec;59(12):2497–502.
15.
Griffin JL, Atherton H, Shockcor J, Atzori L. Metabolomics as a tool for cardiac research.
Nat Rev Cardiol
. 2011 Sep;8(11):630–43.
16.
Li H, Zhu W, Zhang L, Lei H, Wu X, Guo L, et al. The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment.
Sci Rep
. 2015 Feb;5(1):8421.
17.
Cooke JP, Wilson AM; JP. Biomarkers of peripheral arterial disease.
J Am Coll Cardiol
. 2010 May;55(19):2017–23.
18.
Yang F, Qin Y, Wang Y, Meng S, Xian H, Che H, et al. Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy.
Int J Biol Sci
. 2019 Mar;15(5):1010–9.
19.
Qiao C, Ye W, Li S, Wang H, Ding X. Icariin modulates mitochondrial function and apoptosis in high glucose-induced glomerular podocytes through G protein-coupled estrogen receptors.
Mol Cell Endocrinol
. 2018 Sep;473:146–55.
20.
Li YC, Ding XS, Li HM, Zhang C. Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1.
Clin Exp Pharmacol Physiol
. 2013 Sep;40(9):635–43.
21.
Jardine MA, Trapp C, Levin S. Comment on Evert et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes care 2013;36:3821-3842.
Diabetes Care
. 2014 May;37(5):e101.
22.
Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010.
N Engl J Med
. 2014 Apr;370(16):1514–23.
23.
Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer.
Nat Rev Endocrinol
. 2014 Mar;10(3):143–56.
24.
Sze SC, Tong Y, Ng TB, Cheng CL, Cheung HP. Herba Epimedii: anti-oxidative properties and its medical implications.
Molecules
. 2010 Nov;15(11):7861–70.
25.
Yan S, Wu B, Lin Z, Jin H, Huang J, Yang Y, et al. Metabonomic characterization of aging and investigation on the anti-aging effects of total flavones of Epimedium.
Mol Biosyst
. 2009 Oct;5(10):1204–13.
26.
Wu B, Yan S, Lin Z, Wang Q, Yang Y, Yang G, et al. Metabonomic study on ageing: NMR-based investigation into rat urinary metabolites and the effect of the total flavone of Epimedium.
Mol Biosyst
. 2008 Aug;4(8):855–61.
27.
Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor.
Circulation
. 2005 Apr;111(16):2073–85.
28.
Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat.
Metabolism
. 2000 Nov;49(11):1390–4.
29.
Dhalla NS, Rangi S, Zieroth S, Xu YJ. Alterations in sarcoplasmic reticulum and mitochondrial functions in diabetic cardiomyopathy.
Exp Clin Cardiol
. 2012 Sep;17(3):115–20.
30.
Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V. Mechanisms of subcellular remodeling in heart failure due to diabetes.
Heart Fail Rev
. 2014 Jan;19(1):87–99.
31.
Labbé SM, Grenier-Larouche T, Noll C, Phoenix S, Guérin B, Turcotte EE, et al. Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans.
Diabetes
. 2012 Nov;61(11):2701–10.
32.
McGill JB, Peterson LR, Herrero P, Saeed IM, Recklein C, Coggan AR, et al. Potentiation of abnormalities in myocardial metabolism with the development of diabetes in women with obesity and insulin resistance.
J Nucl Cardiol
. 2011 May;18(3):421–9.
33.
Fancher IS, Dick GM, Hollander JM. Diabetes mellitus reduces the function and expression of ATP-dependent K+ channels in cardiac mitochondria.
Life Sci
. 2013 Mar;92(11):664–8.
34.
Galloway CA, Yoon Y. Mitochondrial Morphology in Metabolic Diseases. Antioxid Redox Signal. 2013 Aug 1;19(4):415–30.
35.
Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA; DP. RAGE biology, atherosclerosis and diabetes.
Clin Sci (Lond)
. 2011 Jul;121(2):43–55.
36.
Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside.
Heart Fail Clin
. 2012 Oct;8(4):619–31.
37.
Howarth FC, Qureshi MA, Hassan Z, Al Kury LT, Isaev D, Parekh K, et al. Changing pattern of gene expression is associated with ventricular myocyte dysfunction and altered mechanisms of Ca2+ signalling in young type 2 Zucker diabetic fatty rat heart.
Exp Physiol
. 2011 Mar;96(3):325–37.
38.
Ng AC, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Hooi Ewe S, et al. Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus.
Circulation
. 2010 Dec;122(24):2538–44.
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