Are targeted therapies for diabetic cardiomyopathy on the horizon?

Clinical Science

Volumn 131, Issue 10, 2017, Pages 897-915

  Tate, Mitchel ^a   Grieve, David J ^b   Ritchie, Rebecca H ^a,c  

^a BAKER IDI HEART AND DIABETES INSTITUTE   (Australia)

^b QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTILIPEMIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; MICRORNA; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR;

CARDIAC MUSCLE CELL; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DIABETIC PATIENT; DIASTOLIC DYSFUNCTION; DISEASE COURSE; DNA METHYLATION; EPIGENETICS; GLYCEMIC CONTROL; HEART FAILURE; HEART MUSCLE FIBROSIS; HISTONE MODIFICATION; HUMAN; LIPOTOXICITY; MYOCARDIAL DISEASE; MYOCARDIAL LIPOTOXICITY; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; REVIEW; ANIMAL; COMPLICATION; DIABETIC CARDIOMYOPATHIES; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOLOGY;

ANIMALS; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; HUMANS;

EID: 85018379155     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20160491     Document Type: Review

References (191)

1. Gaede, P., Lund-Andersen, H., Parving, H.-H. and Pedersen, O. (2008) Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580-591.
2. D'Elia, J.A., Weinrauch, L.A., Healy, R.W., Libertino, J.A., Bradley, R.F. and Leland, O.S. (1979) Myocardial dysfunction without coronary artery disease in diabetic renal failure. Am. J. Cardiol. 43, 193-199.
3. Regan, T.J., Lyons, M.M., Ahmed, S.S., Levinson, G.E., Oldewurtel, H.A., Ahmad, M.R. et al. (1977) Evidence for cardiomyopathy in familial diabetes mellitus. J. Clin. Invest. 60, 884-899.
4. Kannel, W.B., Hjortland, M. and Castelli, W.P. (1974) Role of diabetes in congestive heart failure: The Framingham Study. Am. J. Cardiol. 34, 29-34.
5. Rubler, S., Dlugash, J., Yuceoglu, Y.Z., Kumral, T., Branwood, A.W. and Grishman, A. (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am. J. Cardiol. 30, 595-602.
6. Du, X., Ninomiya, T., De Galan, B., Abadir, E., Chalmers, J., Pillai, A. et al. (2009) Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: Results of the ADVANCE study. Eur. Heart J. 30, 1128-1135.
7. MacDonald, M.R., Petrie, M.C., Varyani, F., Ostergren, J., Michelson, E.L., Young, J.B. et al. (2008) Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur. Heart J. 29, 1377-1385.
8. Mizamtsidi, M., Paschou, S.A., Grapsa, J. and Vryonidou, A. (2016) Diabetic cardiomyopathy: a clinical entity or a cluster of molecular heart changes? Eur. J. Clin. Invest. 46, 947-953.
9. Di Bonito, P., Moio, N., Cavuto, L., Covino, G., Murena, E., Scilla, C. et al. (2005) Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging. Diabet. Med. 22, 1720-1725.
10. Shimizu, M., Umeda, K., Sugihara, N., Yoshio, H., Ino, H., Takeda, R. et al. (1993) Collagen remodelling in myocardia of patients with diabetes. J. Clin. Pathol. 46, 32-36.
11. Huynh, K., Bernardo, B.C., McMullen, J.R. and Ritchie, R.H. (2014) Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol. Ther. 142, 375-415.
12. Schilling, J.D. and Mann, D.L. (2012) Diabetic cardiomyopathy: bench to bedside. Heart Fail. Clin. 8, 619-631.
13. Tate, M., Chong, A., Robinson, E., Green, B.D. and Grieve, D.J. (2015) Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes. Br. J. Pharmacol. 172, 721-736.
14. Fischer, V.W., Barner, H.B. and Larose, L.S. (1984) Pathomorphologic aspects of muscular tissue in diabetes mellitus. Hum. Pathol. 15, 1127-1136.
15. van Hoeven, K.H. and Factor, S.M. (1990) A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 82, 848-855.
16. Russo, I. and Frangogiannis, N.G. (2016) Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. J. Mol. Cell. Cardiol. 90, 84-93.
17. Mizushige, K., Yao, L., Noma, T., Kiyomoto, H., Yu, Y., Hosomi, N. et al. (2000) Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation 101, 899-907.
18. González-Vílchez, F., Ayuela, J., Ares, M., Pi, J., Castillo, L. and Martín-Durá n, R. (2005) Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients. Int. J. Cardiol. 101, 53-58.
19. Brooks, B.A., Franjic, B., Ban, C.R., Swaraj, K., Yue, D.K., Celermajer, D.S. et al. (2008) Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes. Diabetes Obes. Metab. 10, 739-746.
20. Shivalkar, B., Dhondt, D., Goovaerts, I., Van Gaal, L., Bartunek, J., Van Crombrugge, P. et al. (2006) Flow mediated dilatation and cardiac function in type 1 diabetes mellitus. Am. J. Cardiol. 97, 77-82.
21. Poirier, P., Bogaty, P., Garneau, C., Marois, L. and Dumesnil, J.G. (2001) Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 24, 5-10.
22. Galderisi, M. (2006) Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J. Am. Coll. Cardiol. 48, 1548-1551.
23. Schannwell, C.M., Schneppenheim, M., Perings, S., Plehn, G. and Strauer, B.E. (2002) Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology 98, 33-39.
24. Liu, J.E., Palmieri, V., Roman, M.J., Bella, J.N., Fabsitz, R., Howard, B.V. et al. (2001) The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study. J. Am. Coll. Cardiol. 37, 1943-1949.
25. Chung, J., Abraszewski, P., Yu, X., Liu, W., Krainik, A.J., Ashford, M. et al. (2006) Paradoxical increase in ventricular torsion and systolic torsion rate in type I diabetic patients under tight glycemic control. J. Am. Coll. Cardiol. 47, 384-390.
26. Voulgari, C., Papadogiannis, D. and Tentolouris, N. (2010) Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies. Vasc. Health Risk Manag. 6, 883-903.
27. Westermann, D., Rutschow, S., Jä ger, S., Linderer, A., Anker, S., Riad, A. et al. (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56, 641-646.
28. van Linthout, S., Seeland, U., Riad, A., Eckhardt, O., Hohl, M., Dhayat, N. et al. (2008) Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res. Cardiol. 103, 319-327.
29. Kilhovd, B.K., Berg, T.J., Birkeland, K.I., Thorsby, P. and Hanssen, K.F. (1999) Serum levels of advanced glycation end products are increased in patients with type 2 diabetes and coronary heart disease. Diabetes Care 22, 1543-1548.
30. Candido, R., Forbes, J.M., Thomas, M.C., Thallas, V., Dean, R.G., Burns, W.C. et al. (2003) A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ. Res. 92, 785-792.
31. Yuen, A., Laschinger, C., Talior, I., Lee, W., Chan, M., Birek, J. et al. (2010) Methylglyoxal-modified collagen promotes myofibroblast differentiation. Matrix Biol 29, 537-548.
32. Maessen, D.E.M., Stehouwer, C.D.A. and Schalkwijk, C.G. (2015) The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases. Clin. Sci. (Lond.) 128, 839-861.
33. van Eupen, M.G.A., Schram, M.T., Colhoun, H.M., Hanssen, N.M.J., Niessen, H.W.M., Tarnow, L. et al. (2013) The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1. Diabetologia 56, 1845-1855.
34. Beisswenger, P.J., Howell, S.K., Touchette, A.D., Lal, S. and Szwergold, B.S. (1999) Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 48, 198-202.
35. Hadi, H.A.R. and Suwaidi Al, J. (2007) Endothelial dysfunction in diabetes mellitus. Vasc. Health Risk. Manag. 3, 853-876
36. Vulesevic, B., McNeill, B., Giacco, F., Maeda, K., Blackburn, N.J.R., Brownlee, M. et al. (2016) Methylglyoxal-induced endothelial cell loss and inflammation contribute to the development of diabetic cardiomyopathy. Diabetes 65, 1699-1713.
37. Brouwers, O., Niessen, P.M., Haenen, G., Miyata, T., Brownlee, M., Stehouwer, C.D. et al. (2010) Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress. Diabetologia 53, 989-1000.
38. Turkseven, S., Ertuna, E., Yetik-Anacak, G. and Yasa, M. (2014) Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase a. J. Basic Clin. Physiol. Pharmacol. 25, 109-115.
39. Tirziu, D., Giordano, F.J. and Simons, M. (2010) Cell communications in the heart. Circulation 122, 928-937.
40. Iltis, I., Kober, F., Dalmasso, C., Cozzone, P.J. and Bernard, M. (2005) Noninvasive characterization of myocardial blood flow in diabetic, hypertensive, and diabetic-hypertensive rats using spin-labeling MRI. Microcirculation 12, 607-614.
41. Boudina, S. and Abel, E.D. (2007) Diabetic cardiomyopathy revisited. Circulation 115, 3213-3223.
42. Rerkpattanapipat, P., D'Agostino, R.B., Link, K.M., Shahar, E., Lima, J., Bluemke, D. et al. (2009) Location of arterial stiffening differs in those with impaired fasting glucose versus diabetes: implications for left ventricular hypertrophy from the Multi-Ethnic Study of Atherosclerosis. Diabetes 58, 946-953.
43. Frustaci, A., Kajstura, J., Chimenti, C., Jakoniuk, I., Leri, A., Maseri, A. et al. (2000) Myocardial cell death in human diabetes. Circ. Res. 87, 1123-1132.
44. Katare, R.G., Caporali, A., Oikawa, A., Meloni, M., Emanuel, C. and Madeddu, P. (2010) Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway. Circ. Heart Fail. 3, 294-305.
45. Fang, Z.Y., Leano, R. and Marwick, T.H. (2004) Relationship between longitudinal and radial contractility in subclinical diabetic heart disease. Clin. Sci. (Lond.) 106, 53-60.
46. Ernande, L., Rietzschel, E.R., Bergerot, C., De Buyzere, M.L., Schnell, F., Groisne, L. et al. (2010) Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. J. Am. Soc. Echocardiogr. 23, 1266-1272.
47. Mogelvang, R., Sogaard, P., Pedersen, S.A., Olsen, N.T., Schnohr, P. and Jensen, J.S. (2009) Tissue Doppler echocardiography in persons with hypertension, diabetes, or ischaemic heart disease: The Copenhagen City Heart Study. Eur. Heart J. 30, 731-739.
48. Karason, K., Sjö ström, L., Wallentin, I. and Peltonen, M. (2003) Impact of blood pressure and insulin on the relationship between body fat and left ventricular structure. Eur. Heart J. 24, 1500-1505.
49. Cook, S.A., Varela-Carver, A., Mongillo, M., Kleinert, C., Khan, M.T., Leccisotti, L. et al. (2010) Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. Eur. Heart J. 31, 100-111.
50. Belke, D.D., Betuing, S., Tuttle, M.J., Graveleau, C., Young, M.E., Pham, M. et al. (2002) Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J. Clin. Invest. 109, 629-639.
51. Bahrami, H., Bluemke, D.A., Kronmal, R., Bertoni, A.G., Lloyd-Jones, D.M., Shahar, E. et al. (2008) Novel metabolic risk factors for incident heart failure and their relationship with obesity. The MESA (Multi-Ethnic Study of Atherosclerosis) Study. J. Am. Coll. Cardiol. 51, 1775-1783.
52. Kim, M., Ohkyun, J., Sakata, S., Liang, I., Park, W., Hajjar, R.J. et al. (2008) Role of resistin in cardiac contractility and hypertrophy. J. Mol. Cell. Cardiol. 45, 270-280.
53. Xu, F.P., Chen, M.S., Wang, Y.Z., Yi, Q., Lin, S.B., Chen, A.F. et al. (2004) Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 110, 1269-1275.
54. Barouch, L.A., Berkowitz, D.E., Harrison, R.W., O'Donnell, C.P. and Hare, J.M. (2003) Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 108, 754-759.
55. Widyantoro, B., Emoto, N., Nakayama, K., Anggrahini, D.W., Adiarto, S., Iwasa, N. et al. (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121, 2407-2418.
56. Huynh, K., Kiriazis, H., Du, X.-J., Love, J.E., Gray, S.P., Jandeleit-Dahm, K.A. et al. (2013) Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. Free Radical Biol. Med. 60, 307-317.
57. Chowdhry, M.F., Vohra, H.A. and Galinñanes, M. (2007) Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: role of caspases and poly-adenosine diphosphate-ribose polymerase. J. Thorac. Cardiovasc. Surg. 134, 5-7.
58. Ares-Carrasco, S., Picatoste, B., Benito-Martín, A., Zubiri, I., Sanz, A.B., Sanchez-Ninñ o, M.D. et al. (2009) Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes. Am. J. Physiol. Heart Circ. Physiol. 297, H2109-H2119.
59. Fiordaliso, F., Li, B., Latini, R., Sonnenblick, E.H., Anversa, P., Leri, A. et al. (2000) Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. Lab. Invest. 80, 513-527.
60. Cai, L., Li, W., Wang, G., Guo, L., Jiang, Y. and Kang, Y.J. (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51, 1938-1948.
61. Bojunga, J., Nowak, D., Mitrou, P.S., Hoelzer, D., Zeuzem, S. and Chow, K.U. (2004) Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats. Diabetologia 47, 2072-2080.
62. Sari, F.R., Watanabe, K., Thandavarayan, R.A., Harima, M., Zhang, S., Muslin, A.J. et al. (2010) 14-3-3 protein protects against cardiac endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis in experimental diabetes. J. Pharmacol. Sci. 113, 325-334.
63. Kajstura, J., Fiordaliso, F., Andreoli, A.M., Li, B., Chimenti, S., Medow, M.S. et al. (2001) IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50, 1414-1424.
64. Rijzewijk, L.J., van der Meer, R.W., Smit, J.W.A., Diamant, M., Bax, J.J., Hammer, S. et al. (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793-1799.
65. Listenberger, L.L., Ory, D.S. and Schaffer, J.E. (2001) Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J. Biol. Chem. 276, 14890-14895.
66. Brookheart, R.T., Michel, C.I., Listenberger, L.L., Ory, D.S. and Schaffer, J.E. (2009) The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and endoplasmic reticulum stress. J. Biol. Chem. 284, 7446-7454.
67. Michel, C.I., Holley, C.L., Scruggs, B.S., Sidhu, R., Brookheart, R.T., Listenberger, L.L. et al. (2011) Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab 14, 33-44.
68. Son, N., Yu, S., Tuinei, J., Arai, K., Hamai, H., Homma, S. et al. (2010) PPAR? -induced cardiolipotoxicity in mice is ameliorated by PPARa deficiency despite increases in fatty acid oxidation. J. Clin. Invest. 120, 3443-3454.
69. Lee, Y., Naseem, R.H., Park, B.-H., Garry, D.J., Richardson, J.A., Schaffer, J.E. et al. (2006) Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem. Biophys. Res. Commun. 344, 446-452.
70. Lee, Y., Naseem, R.H., Duplomb, L., Park, B.-H., Garry, D.J., Richardson, J.A. et al. (2004) Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 101, 13624-13629.
71. Singh, G.B., Sharma, R. and Khullar, M. (2011) Epigenetics and diabetic cardiomyopathy. Diabetes Res. Clin. Pract. 94, 14-21.
72. Bird, A. (2007) Perceptions of epigenetics. Nature 447, 396-398.
73. Kuroda, A., Rauch, T.A., Todorov, I., Ku, H.T., Al-Abdullah, I.H., Kandeel, F. et al. (2009) Insulin gene expression is regulated by DNA methylation. PLoS ONE 4, e6953.
74. Ling, C., Del Guerra, S., Lupi, R., Rö nn, T., Granhall, C., Luthman, H. et al. (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51, 615-622.
75. Fujimoto, K. and Polonsky, K.S. (2009) Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes. Metab. 11 (Suppl 4), 30-37.
76. Macfarlane, W.M., Frayling, T.M., Ellard, S., Evans, J.C., Allen, L.I., Bulman, M.P. et al. (1999) Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J. Clin. Invest. 104, R33-R39.
77. Cheng, Y., Liu, G., Pan, Q., Guo, S. and Yang, X. (2011) Elevated expression of liver X receptor alpha (LXRa) in myocardium of streptozotocin-induced diabetic rats. Inflammation 34, 698-706.
78. Kao, Y.-H., Chen, Y.-C., Cheng, C.-C., Lee, T.-I., Chen, Y.-J. and Chen, S.-A. (2010) Tumor necrosis factor-alpha decreases sarcoplasmic reticulum Ca2+ -ATPase expressions via the promoter methylation in cardiomyocytes. Crit. Care Med. 38, 217-222.
79. Mönkemann, H., De Vriese, A.S., Blom, H.J., Kluijtmans, L.A.J., Heil, S.G., Schild, H.H. et al. (2002) Early molecular events in the development of the diabetic cardiomyopathy. Amino Acids 23, 331-336.
80. Gaikwad, A.B., Sayyed, S.G., Lichtnekert, J., Tikoo, K. and Anders, H.-J. (2010) Renal failure increases cardiac histone h3 acetylation, dimethylation, and phosphorylation and the induction of cardiomyopathy-related genes in type 2 diabetes. Am. J. Pathol. 176, 1079-1083.
81. Glenisson, W., Castronovo, V. and Waltregny, D. (2007) Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochim. Biophys. Acta 1773, 1572-1582.
82. Suzuki, M., Shigematsu, H., Shames, D.S., Sunaga, N., Takahashi, T., Shivapurkar, N. et al. (2005) DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br. J. Cancer 93, 1029-1037.
83. Wang, Y., Fan, P.S. and Kahaleh, B. (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54, 2271-2279.
84. Ikeda, K., Iyama, K.-I., Ishikawa, N., Egami, H., Nakao, M., Sado, Y. et al. (2006) Loss of expression of type IV collagen alpha5 and alpha6 chains in colorectal cancer associated with the hypermethylation of their promoter region. Am. J. Pathol. 168, 856-865.
85. Qin, L. and Han, Y.-P. (2010) Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: implication in tissue fibrosis. Am. J. Pathol. 177, 1915-1928.
86. Sun, H., Yang, X., Zhu, J., Lv, T., Chen, Y., Chen, G. et al. (2010) Inhibition of p300-HAT results in a reduced histone acetylation and down-regulation of gene expression in cardiac myocytes. Life Sci 87, 707-714.
87. McGee, S.L., Van Denderen, B.J.W., Howlett, K.F., Mollica, J., Schertzer, J.D., Kemp, B.E. et al. (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57, 860-867.
88. Jordan, S.D., Krüger, M., Willmes, D.M., Redemann, N., Wunderlich, F.T., Brönneke, H.S. et al. (2011) Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat. Cell Biol. 13, 434-446.
89. Zhou, B., Li, C., Qi, W., Zhang, Y., Zhang, F., Wu, J.X. et al. (2012) Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 55, 2032-2043.
90. Trajkovski, M., Hausser, J., Soutschek, J., Bhat, B., Akin, A., Zavolan, M. et al. (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649-653.
91. Diao, X., Shen, E., Wang, X. and Hu, B. (2011) Differentially expressed microRNAs and their target genes in the hearts of streptozotocin-induced diabetic mice. Mol. Med. Rep. 4, 633-640
92. Thum, T., Galuppo, P., Wolf, C., Fiedler, J., Kneitz, S., Van Laake, L.W. et al. (2007) MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258-267.
93. Thum, T., Gross, C., Fiedler, J., Fischer, T., Kissler, S., Bussen, M. et al. (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980-984.
94. Zhang, C. (2008) MicroRNAs: role in cardiovascular biology and disease. Clin. Sci. (Lond.) 114, 699-706.
95. Costantino, S., Paneni, F., Lüscher, T.F. and Cosentino, F. (2016) MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur. Heart J. 37, 572-576.
96. Yu, X.-Y., Song, Y.-H., Geng, Y.-J., Lin, Q.-X., Shan, Z.-X., Lin, S.-G. et al. (2008) Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1. Biochem. Biophys. Res. Commun. 376, 548-552.
97. Katare, R., Caporali, A., Zentilin, L., Avolio, E., Sala-Newby, G., Oikawa, A. et al. (2011) Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ. Res. 108, 1238-1251.
98. Chen, S., Puthanveetil, P., Feng, B., Matkovich, S.J., Dorn, G.W. and Chakrabarti, S. (2014) Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J. Cell. Mol. Med. 18, 415-421.
99. Raut, S., Kumar, A. and Khullar, M. (2016) Epigenetic role of micrornas in diabetic cardiomyopathy. J. Pract. Cardiovasc. Sci. 2, 79-85.
100. Li, J., Dai, Y., Su, Z. and Wei, G. (2016) MicroRNA-9 inhibits high glucose-induced proliferation, differentiation and collagen accumulation of cardiac fibroblasts by down-regulation of TGFBR2. Biosci. Rep. 36, e00417.
101. Duisters, R.F., Tijsen, A.J., Schroen, B., Leenders, J.J., Lentink, V., Van Der Made, I. et al. (2009) MiR-133 and miR-30 regulate connective tissue growth factor: implications for a role of micrornas in myocardial matrix remodeling. Circ. Res. 104, 170-178.
102. Feng, B., Cao, Y., Chen, S., Chu, X., Chu, Y. and Chakrabarti, S. (2016) miR-200b mediates endothelial-to-mesenchymal transition in diabetic cardiomyopathy. Diabetes 65, 768-779.
103. Zheng, D., Ma, J., Yu, Y., Li, M., Ni, R., Wang, G. et al. (2015) Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia 58, 1949-1958.
104. Wang, N., Yang, C., Xie, F., Sun, L., Su, X., Wang, Y. et al. (2012) Gadd45a: a novel diabetes-associated gene potentially linking diabetic cardiomyopathy and baroreflex dysfunction. PLoS ONE 7, e49077.
105. Kuwabara, Y., Horie, T., Baba, O., Watanabe, S., Nishiga, M., Usami, S. et al. (2015) MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ. Res. 116, 279-288.
106. Raut, S.K., Singh, G.B., Rastogi, B., Saikia, U.N., Mittal, A., Dogra, N. et al. (2016) miR-30c and miR-181a synergistically modulate p53-p21 pathway in diabetes induced cardiac hypertrophy. Mol. Cell. Biochem. 417, 191-203.
107. Jeyabal, P., Thandavarayan, R.A., Joladarashi, D., Suresh Babu, S., Krishnamurthy, S., Bhimaraj, A. et al. (2016) MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem. Biophys. Res. Commun. 471, 423-429.
108. Qiao, Y., Zhao, Y., Liu, Y., Ma, N., Wang, C., Zou, J. et al. (2016) miR-483-3p regulates hyperglycaemia-induced cardiomyocyte apoptosis in transgenic mice. Biochem. Biophys. Res. Commun. 477, 541-547.
109. Kannel, W.B. and McGee, D.L. (1979) Diabetes and cardiovascular risk factors: the Framingham Study. Circulation 59, 8-13.
110. Tatti, P., Pahor, M., Byington, R.P., Di Mauro, P., Guarisco, R., Strollo, G. et al. (1998) Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 21, 597-603.
111. Lorber, D. (2014) Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes. 7, 169-183.
112. Armario, P. and Waeber, B. (2013) Therapeutic strategies to improve control of hypertension. J. Hypertens 31 (Suppl 1), S9-S12.
113. DeMarco, V.G., Aroor, A.R. and Sowers, J.R. (2014) The pathophysiology of hypertension in patients with obesity. Nat. Rev. Endocrinol. 10, 364-376.
114. Iribarren, C., Karter, A.J., Go, A.S., Ferrara, A., Liu, J.Y., Sidney, S. et al. (2001) Glycemic control and heart failure among adult patients with diabetes. Circulation 103, 2668-2673.
115. Devereux, R.B., Roman, M.J., Paranicas, M., O'Grady, M.J., Lee, E.T., Welty, T.K. et al. (2000) Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 101, 2271-2276.
116. Gilbert, R.E., Connelly, K., Kelly, D.J., Pollock, C.A. and Krum, H. (2006) Heart failure and nephropathy: catastrophic and interrelated complications of diabetes. Clin. J. Am. Soc. Nephrol. 1, 193-208.
117. Nathan, D.M., Buse, J.B., Davidson, M.B., Ferrannini, E., Holman, R.R., Sherwin, R. et al. (2009) American Diabetes Association, European Association for the Study of Diabetes. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52, 17-30.
118. von Bibra, H., Hansen, A., Dounis, V., Bystedt, T., Malmberg, K. and Rydé n, L. (2004) Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart 90, 1483-1484.
119. Holman, R.R., Paul, S.K., Bethel, M.A., Matthews, D.R. and Neil, H.A.W. (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577-1589.
120. Ginsberg, H.N. (2011) The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial: what we learn from subgroup analyses. Diabetes Care (Suppl 2), S107-S108.
121. Duckworth, W., Abraira, C., Moritz, T., Reda, D., Emanuele, N., Reaven, P.D. et al. (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129-139.
122. Kooy, A., de Jager, J., Lehert, P., Bets, D., Wulffele, M.G., Donker, A.J.M. et al. (2009) Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch. Intern. Med. 169, 616-625.
123. Eurich, D.T., Majumdar, S.R., McAlister, F.A., Tsuyuki, R.T. and Johnson, J.A. (2005) Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 28, 2345-2351.
124. Khandoudi, N., Delerive, P., Berrebi-Bertrand, I., Buckingham, R.E., Staels, B. and Bril, A. (2002) Rosiglitazone, a peroxisome proliferator-activated receptor-?, inhibits the Jun NH 2-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes 51, 1507-1514.
125. Yue, T.L., Chen, J., Bao, W., Narayanan, P.K., Bril, A., Jiang, W. et al. (2001) In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104, 2588-2594.
126. Singh, S., Loke, Y.K. and Furberg, C.D. (2007) Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. J. Am. Med. Ass. 298, 1189-1195.
127. Nissen, S.E. and Wolski, K. (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457-2471.
128. Dagenais, G.R., Gerstein, H.C., Holman, R., Budaj, A., Escalante, A. et al. (2008) Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. Diabetes Care 31, 1007-1014.
129. Home, P.D., Pocock, S.J., Beck-Nielsen, H., Curtis, P.S., Gomis, R., Hanefeld, M. et al. (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125-2135.
130. Kahn, S.E., Haffner, S.M., Heise, M.A., Herman, W.H., Holman, R.R., Jones, N.P. et al. (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427-2443.
131. Kahler, K.H., Rajan, M., Rhoads, G.G., Safford, M.M., Demissie, K., Lu, S.E. et al. (2007) Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration. Diabetes Care 30, 1689-1693.
132. King, K.A. and Levi, V.E. (2004) Prevalence of edema in patients receiving combination therapy with insulin and thiazolidinedione. Am. J. Health Pharm. 61, 390-393
133. Guan, Y., Hao, C., Cha, D.R., Rao, R., Lu, W., Kohan, D.E. et al. (2005) Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat. Med. 11, 861-866.
134. Takahashi, A., Nagashima, K., Hamasaki, A., Kuwamura, N., Kawasaki, Y., Ikeda, H. et al. (2007) Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase. Diabetes Res. Clin. Pract. 77, 343-350.
135. Turner, R. (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837-853.
136. Li, Y., Xu, W., Liao, Z., Yao, B., Chen, X., Huang, Z. et al. (2004) Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care 27, 2597-2602.
137. Morello, C.M. (2011) Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int. J. Gen. Med. 4, 827-835.
138. Franklin, K., Goldberg, R.J., Spencer, F. and Klein, W. (2004) Implications of diabetes in patients with acute coronary syndromes. Arch. Intern. Med. 164, 1457-1463.
139. Norhammar, A., Malmberg, K., Diderholm, E., Lagerqvist, B., Lindahl, B., Rydé n, L. et al. (2004) Diabetes mellitus: the major risk factor in unstable coronary artery disease even after consideration of the extent of coronary artery disease and benefits of revascularization. J. Am. Coll. Cardiol. 43, 585-591.
140. Fox, K., Alonso Garcia, M.A., Ardissino, D., Buszman, P., Camici, P.G., Crea, F. et al. (2006) Guidelines on the management of stable angina pectoris: Executive summary-The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur. Heart J. 27, 1341-1381.
141. Yusuf, S., Sleight, P., Pogue, J., Bosch, J., Davies, R. and Dagenais, G. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342, 145-153.
142. Daly, C.A., Fox, K.M., Remme, W.J., Bertrand, M.E., Ferrari, R. and Simoons, M.L. (2005) The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur. Heart. J. 26, 1369-1378.
143. McFarlane, S.I. (2009) Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev. Cardiovasc. Ther. 7, 1363-1371.
144. Mann, J.F.E., Schmieder, R.E., McQueen, M., Dyal, L., Schumacher, H., Pogue, J. et al. (2008) Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 372, 547-553.
145. Festa, A., D'Agostino, R., Hales, C.N., Mykkä nen, L. and Haffner, S.M. (2000) Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects. Diabetes Care 23, 624-628.
146. Kjekshus, J., Gilpin, E., Cali, G., Blackey, A.R, Henning, H. and Ross, J. (1990) Diabetic patients and beta-blockers after acute myocardial infarction. Eur. Heart J. 11, 43-50.
147. Malmberg, K., Herlitz, J., Hjalmarson, A. and Ryden, L. (1989) Effects of metoprolol on mortality and late infarction in diabetics with suspected acute myocardial infarction. Retrospective data from two large studies. Eur. Heart. J. 10, 423-428.
148. Shekelle, P.G., Rich, M.W., Morton, S.C., Atkinson, C.S.W., Tu, W., Maglione, M. et al. (2003) Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J. Am. Coll. Cardiol. 41, 1529-1538.
149. Funck-Brentano, C. (2006) Beta-blockade in CHF: from contraindication to indication. Eur. Heart J. 8 (Suppl C), 19-27.
150. Afzal, N., Ganguly, P.K., Dhalla, K.S., Pierce, G.N., Singal, P.K. and Dhalla, N.S. (1988) Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 37, 936-942.
151. Xu, G., Chen, J., Jing, G. and Shalev, A. (2012) Preventing ß-cell loss and diabetes with calcium channel blockers. Diabetes 61, 848-856.
152. Noto, H., Goto, A., Tsujimoto, T. and Noda, M. (2013) Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. Diabetes Metab. Syndr. Obes. 6, 257-261.
153. Lamarche, B. (1998) Fasting insulin and apolipoprotein b levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 279, 1955.
154. Baigent, C., Keech, A., Kearney, P.M., Blackwell, L., Buck, G., Pollicino, C. et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 1267-1278.
155. Cholesterol Treatment Trialists' (CTT) (2008) Collaborators. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371, 117-125.
156. Van Linthout, S., Riad, A., Dhayat, N., Spillmann, F., Du, J., Dhayat, S. et al. (2007) Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia 50, 1977-1986.
157. Dai, Q.M., Lu, J. and Liu, N.F. (2011) Fluvastatin attenuates myocardial interstitial fibrosis and cardiac dysfunction in diabetic rats by inhibiting over-expression of connective tissue growth factor. Chin. Med. J. (Engl.) 124, 89-94
158. Grieve, D.J., Cassidy, R.S. and Green, B.D. (2009) Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? Br. J. Pharmacol. 157, 1340-1351.
159. Hirata, K., Kume, S., Araki, S., Sakaguchi, M., Chin-Kanasaki, M., Isshiki, K. et al. (2009) Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem. Biophys. Res. Commun. 380, 44-49.
160. Zinman, B., Gerich, J., Buse, J.B., Lewin, A., Schwartz, S., Raskin, P. et al. (2009) LEAD-4 Study Investigators. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 32, 1224-1230.
161. Nauck, M., Frid, A., Hermansen, K., Shah, N.S., Tankova, T., Mitha, I.H. et al. (2009) LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 32, 84-90.
162. Timmers, L., Henriques, J.P.S., de Kleijn, D.P.V., DeVries, J.H., Kemperman, H., Steendijk, P. et al. (2009) Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J. Am. Coll. Cardiol. 53, 501-510.
163. Bose, A.K., Mocanu, M.M., Carr, R.D. and Yellon, D.M. (2005) Glucagon like peptide-1 is protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc. Drugs Ther. 19, 9-11.
164. DeNicola, M., Du, J., Wang, Z., Yano, N., Zhang, L., Wang, Y. et al. (2014) Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium. Am. J. Physiol. Endocrinol. Metab. 307, E630-E643.
165. Liu, Q., Anderson, C., Broyde, A., Polizzi, C., Fernandez, R., Baron, A. et al. (2010) Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc. Diabetol. 9, 76.
166. Bugger, H. and Abel, E.D. (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57, 660-671.
167. Robinson, E., Cassidy, R.S., Tate, M., Zhao, Y., Lockhart, S., Calderwood, D. et al. (2015) Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Res. Cardiol. 110, 20.
168. Younce, C.W., Burmeister, M.A. and Ayala, J.E. (2013) Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am. J. Physiol. Cell Physiol. 304, C508-C518.
169. Wang, D., Luo, P., Wang, Y., Li, W., Wang, C., Sun, D. et al. (2013) Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes 62, 1697-1708.
170. Shigeta, T., Aoyama, M., Bando, Y.K., Monji, A., Mitsui, T., Takatsu, M. et al. (2012) Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. Circulation 126, 1838-1851.
171. Noyan-Ashraf, M.H., Abdul Momen, M., Ban, K., Sadi, A.M., Zhou, Y.Q., Riazi, A.M. et al. (2009) GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 58, 975-983.
172. Ye, Y., Qian, J., Castillo, A.C., Ling, S., Ye, H., Perez-Polo, J.R. et al. (2013) Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 304, H131-H141.
173. Giorgino, F., Leonardini, A. and Laviola, L. (2013) Cardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials. Ann. N.Y. Acad. Sci. 1281, 36-50.
174. Robinson, E., Tate, M., Lockhart, S., McPeake, C., O'Neill, K.M., Edgar, K.S. et al. (2016) Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling. Cardiovasc. Diabetol. 15, 65.
175. Ban, K., Noyan-Ashraf, M.H., Hoefer, J., Bolz, S.-S., Drucker, D.J. and Husain, M. (2008) Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340-2350.
176. Giacco, F., Du, X., Carratú, A., Gerfen, G.J., D'Apolito, M., Giardino, I. et al. (2015) GLP-1 cleavage product reverses persistent ros generation after transient hyperglycemia by disrupting an ros-generating feedback loop. Diabetes 64, 3273-3284.
177. Picatoste, B., Ramírez, E., Caro-Vadillo, A., Iborra, C., Ares-Carrasco, S., Egido, J. et al. (2013) Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms. PLoS ONE 8, e78330
178. Nikolaidis, L.A., Elahi, D., Hentosz, T., Doverspike, A., Huerbin, R., Zourelias, L. et al. (2004) Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 110, 955-961.
179. Lønborg, J., Vejlstrup, N., Kelbæk, H., Bøtker, H.E., Kim, W.Y., Mathiasen, A.B. et al. (2012) Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur. Heart J. 33, 1491-1499.
180. Scirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B. et al. (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369, 1317-1326.
181. White, W.B., Cannon, C.P., Heller, S.R., Nissen, S.E., Bergenstal, R.M., Bakris, G.L. et al. (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369, 1327-1335.
182. Marso, S., Daniels, G., Brown-Frandsen, K., Kristensen, P., Mann, J.F., Nauck, M.A. et al. (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311-322.
183. Marsenic, O. (2009) Glucose control by the kidney: an emerging target in diabetes. Am. J. Kidney Dis. 53, 875-883.
184. Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S. et al. (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117-2128.
185. Nagareddy, P.R., Murphy, A.J., Stirzaker, R.A., Hu, Y., Yu, S., Miller, R.G. et al. (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17, 695-708.
186. Tahara, A., Kurosaki, E., Yokono, M., Yamajuku, D., Kihara, R., Hayashizaki, Y. et al. (2013) Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur. J. Pharmacol. 715, 246-255.
187. Panchapakesan, U., Pegg, K., Gross, S., Komala, M.G., Mudaliar, H., Forbes, J. et al. (2013) Effects of SGLT2 inhibition in human kidney proximal tubular cells-renoprotection in diabetic nephropathy? PLoS ONE 8, e54442.
188. Osorio, H., Coronel, I., Arellano, A., Pacheco, U., Bautista, R., Franco, M. et al. (2012) Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid. Med. Cell Longev. 2012, 542042.
189. Abassi, Z., Leor, J., Landa, N., Younis, F., Hollander, K., Mayoux, E. et al. (2016) Empagliflozin exerts cardio- and nephro- protective effects in Cohen-Rosenthal diabetic hypertensive rats. J. Hypertens 34 (Suppl 1), e58-e59.
190. Ceriello, A., Genovese, S., Mannucci, E. and Gronda, E. (2015) Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 3, 929-930.
191. Papazafiropoulou, A., Papanas, N., Pappas, S., Maltezos, E. and Mikhailidis, D.P. (2015) Effects of oral hypoglycemic agents on platelet function. J. Diabetes Complicat. 29, 846-51.