KEGG   PATHWAY: ko05415
Entry
ko05415                     Pathway                                
Name
Diabetic cardiomyopathy
Description
Diabetic cardiomyopathy has been defined as left ventricular dysfunction that occurs among patients with diabetes mellitus independent of a recognized cause such as coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy broadly involves hyperglycemia, increased circulating fatty acids, and insulin resistance contributing to reactive oxygen species (ROS) generation, mitochondrial dysfunction, impaired calcium metabolism, Renin-Angiotensin System (RAS) activation, and altered substrate metabolism. These effects result in cardiac fibrosis, hypertrophy, cardiomyocyte death, contractile dysfunction, endothelial cell damage and eventually heart failure. In the process of cardiac fibrosis, cardiac fibroblasts are the final effector cell.
Class
Human Diseases; Cardiovascular disease
Pathway map
ko05415  Diabetic cardiomyopathy
ko05415

Disease
H02498  Diabetic cardiomyopathy
Orthology
K07299  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
K07191  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K00820  glutamine---fructose-6-phosphate transaminase (isomerizing) [EC:2.6.1.16]
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K12044  troponin I, cardiac muscle
K04962  ryanodine receptor 2
K05852  phospholamban
K05853  P-type Ca2+ transporter type 2A [EC:7.2.2.10]
K04684  transcription factor Sp1
K09821  angiotensinogen
K01380  renin [EC:3.4.23.15]
K01329  chymase [EC:3.4.21.39]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19722  receptor for advanced glycosylation end products
K21421  NADPH oxidase 2 [EC:1.-.-.-]
K08011  neutrophil cytosolic factor 1
K08009  cytochrome b-245, alpha polypeptide
K08010  neutrophil cytosolic factor 2
K08012  neutrophil cytosolic factor 4
K04392  Ras-related C3 botulinum toxin substrate 1
K07860  Ras-related C3 botulinum toxin substrate 2
K04166  angiotensin II receptor type 1
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K04441  p38 MAP kinase [EC:2.7.11.24]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K01398  matrix metalloproteinase-2 (gelatinase A) [EC:3.4.24.24]
K01403  matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]
K06236  collagen type I alpha
K19720  collagen type III alpha
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K06259  CD36 antigen
K07294  peroxisome proliferator-activated receptor alpha
K19523  carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21]
K00898  pyruvate dehydrogenase kinase 2/3/4 [EC:2.7.11.2]
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K06068  novel protein kinase C delta type [EC:2.7.11.13]
K17605  serine/threonine-protein phosphatase 2A activator
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K01379  cathepsin D [EC:3.4.23.5]
K18952  atypical protein kinase C zeta type [EC:2.7.11.13]
K08766  carnitine O-palmitoyltransferase 2 [EC:2.3.1.21]
K04526  insulin
K04527  insulin receptor [EC:2.7.10.1]
K16172  insulin receptor substrate 1
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67]
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K00693  glycogen synthase [EC:2.4.1.11]
K17902  TBC1 domain family member 4
K22138  mitochondrial pyruvate carrier 1
K22139  mitochondrial pyruvate carrier 2
K00161  pyruvate dehydrogenase E1 component subunit alpha [EC:1.2.4.1]
K00162  pyruvate dehydrogenase E1 component subunit beta [EC:1.2.4.1]
K03878  NADH-ubiquinone oxidoreductase chain 1 [EC:7.1.1.2]
K03879  NADH-ubiquinone oxidoreductase chain 2 [EC:7.1.1.2]
K03880  NADH-ubiquinone oxidoreductase chain 3 [EC:7.1.1.2]
K03881  NADH-ubiquinone oxidoreductase chain 4 [EC:7.1.1.2]
K03882  NADH-ubiquinone oxidoreductase chain 4L [EC:7.1.1.2]
K03883  NADH-ubiquinone oxidoreductase chain 5 [EC:7.1.1.2]
K03884  NADH-ubiquinone oxidoreductase chain 6 [EC:7.1.1.2]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2]
K03944  NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934  NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:7.1.1.2]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2]
K03937  NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:7.1.1.2]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:1.3.5.1]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:1.3.5.1]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:7.1.1.8]
K00412  ubiquinol-cytochrome c reductase cytochrome b subunit
K00413  ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414  ubiquinol-cytochrome c reductase core subunit 1
K00415  ubiquinol-cytochrome c reductase core subunit 2
K00416  ubiquinol-cytochrome c reductase subunit 6
K00417  ubiquinol-cytochrome c reductase subunit 7
K00418  ubiquinol-cytochrome c reductase subunit 8
K00419  ubiquinol-cytochrome c reductase subunit 9
K00420  ubiquinol-cytochrome c reductase subunit 10
K02262  cytochrome c oxidase subunit 3
K02256  cytochrome c oxidase subunit 1 [EC:7.1.1.9]
K02261  cytochrome c oxidase subunit 2
K02263  cytochrome c oxidase subunit 4
K02264  cytochrome c oxidase subunit 5a
K02265  cytochrome c oxidase subunit 5b
K02266  cytochrome c oxidase subunit 6a
K02267  cytochrome c oxidase subunit 6b
K02268  cytochrome c oxidase subunit 6c
K02270  cytochrome c oxidase subunit 7a
K02271  cytochrome c oxidase subunit 7b
K02272  cytochrome c oxidase subunit 7c
K02273  cytochrome c oxidase subunit 8
K02132  F-type H+-transporting ATPase subunit alpha
K02133  F-type H+-transporting ATPase subunit beta [EC:7.1.2.2]
K02136  F-type H+-transporting ATPase subunit gamma
K02134  F-type H+-transporting ATPase subunit delta
K02135  F-type H+-transporting ATPase subunit epsilon
K02126  F-type H+-transporting ATPase subunit a
K02127  F-type H+-transporting ATPase subunit b
K02128  F-type H+-transporting ATPase subunit c
K02138  F-type H+-transporting ATPase subunit d
K02137  F-type H+-transporting ATPase subunit O
K02131  F-type H+-transporting ATPase subunit 6
K02125  F-type H+-transporting ATPase subunit 8
K05862  voltage-dependent anion channel protein 1
K15040  voltage-dependent anion channel protein 2
K15041  voltage-dependent anion channel protein 3
K05863  solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K09565  peptidyl-prolyl isomerase F (cyclophilin D) [EC:5.2.1.8]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K13242  nitric-oxide synthase, endothelial [EC:1.14.13.39]
K00134  glyceraldehyde 3-phosphate dehydrogenase (phosphorylating) [EC:1.2.1.12]
K24070  poly [ADP-ribose] polymerase 1 [EC:2.4.2.30]
K00036  glucose-6-phosphate 1-dehydrogenase [EC:1.1.1.49 1.1.1.363]
K00383  glutathione reductase (NADPH) [EC:1.8.1.7]
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K04388  TGF-beta receptor type-2 [EC:2.7.11.30]
K04500  mothers against decapentaplegic homolog 2
K23605  mothers against decapentaplegic homolog 3
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K01283  peptidyl-dipeptidase A [EC:3.4.15.1]
Compound
C00001  H2O
C00002  ATP
C00005  NADPH
C00006  NADP+
C00022  Pyruvate
C00024  Acetyl-CoA
C00027  Hydrogen peroxide
C00031  D-Glucose
C00043  UDP-N-acetyl-alpha-D-glucosamine
C00051  Glutathione
C00076  Calcium cation
C00085  D-Fructose 6-phosphate
C00092  D-Glucose 6-phosphate
C00095  D-Fructose
C00118  D-Glyceraldehyde 3-phosphate
C00127  Glutathione disulfide
C00162  Fatty acid
C00165  Diacylglycerol
C00195  N-Acylsphingosine
C00236  3-Phospho-D-glyceroyl phosphate
C00318  L-Carnitine
C00352  D-Glucosamine 6-phosphate
C00369  Starch
C00533  Nitric oxide
C00546  Methylglyoxal
C00704  Superoxide
C00794  D-Sorbitol
C00873  Angiotensin I
C02135  Angiotensin II
C02843  Long-chain acyl-CoA
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06156  alpha-D-Glucosamine 1-phosphate
C16844  Hydroxyl radical
C21011  [Protein]-N(epsilon)-(carboxymethyl)lysine
C21012  [Protein]-N(epsilon)-(carboxyethyl)lysine
C21013  [Protein]-pyrraline
C21014  [Protein]-pentosidine
C22310  Fructose 3-phosphate
C22311  3-Deoxyglucosone
Reference
PMID:30443826
  Authors
Riehle C, Bauersachs J
  Title
Of mice and men: models and mechanisms of diabetic cardiomyopathy.
  Journal
Basic Res Cardiol 114:2 (2018)
DOI:10.1007/s00395-018-0711-0
Reference
PMID:24462787
  Authors
Huynh K, Bernardo BC, McMullen JR, Ritchie RH
  Title
Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways.
  Journal
Pharmacol Ther 142:375-415 (2014)
DOI:10.1016/j.pharmthera.2014.01.003
Reference
PMID:28231848
  Authors
Lorenzo-Almoros A, Tunon J, Orejas M, Cortes M, Egido J, Lorenzo O
  Title
Diagnostic approaches for diabetic cardiomyopathy.
  Journal
Cardiovasc Diabetol 16:28 (2017)
DOI:10.1186/s12933-017-0506-x
Reference
PMID:32080423
  Authors
Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L
  Title
Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence.
  Journal
Nat Rev Cardiol 17:585-607 (2020)
DOI:10.1038/s41569-020-0339-2
Reference
PMID:31212580
  Authors
Zamora M, Villena JA
  Title
Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy.
  Journal
Int J Mol Sci 20:E2833 (2019)
DOI:10.3390/ijms20112833
Reference
PMID:29605388
  Authors
Palomer X, Pizarro-Delgado J, Vazquez-Carrera M
  Title
Emerging Actors in Diabetic Cardiomyopathy: Heartbreaker Biomarkers or Therapeutic Targets?
  Journal
Trends Pharmacol Sci 39:452-467 (2018)
DOI:10.1016/j.tips.2018.02.010
Reference
PMID:28439258
  Authors
Mishra PK, Ying W, Nandi SS, Bandyopadhyay GK, Patel KK, Mahata SK
  Title
Diabetic Cardiomyopathy: An Immunometabolic Perspective.
  Journal
Front Endocrinol (Lausanne) 8:72 (2017)
DOI:10.3389/fendo.2017.00072
Reference
PMID:28177068
  Authors
Chong CR, Clarke K, Levelt E
  Title
Metabolic Remodeling in Diabetic Cardiomyopathy.
  Journal
Cardiovasc Res 113:422-430 (2017)
DOI:10.1093/cvr/cvx018
Reference
PMID:11742414
  Authors
Brownlee M
  Title
Biochemistry and molecular cell biology of diabetic complications.
  Journal
Nature 414:813-20 (2001)
DOI:10.1038/414813a
Reference
PMID:32821697
  Authors
Gollmer J, Zirlik A, Bugger H
  Title
Established and Emerging Mechanisms of Diabetic Cardiomyopathy.
  Journal
J Lipid Atheroscler 8:26-47 (2019)
DOI:10.12997/jla.2019.8.1.26
Reference
PMID:17592090
  Authors
Boudina S, Abel ED
  Title
Diabetic cardiomyopathy revisited.
  Journal
Circulation 115:3213-23 (2007)
DOI:10.1161/CIRCULATIONAHA.106.679597
Reference
PMID:29109032
  Authors
Varma U, Koutsifeli P, Benson VL, Mellor KM, Delbridge LMD
  Title
Molecular mechanisms of cardiac pathology in diabetes - Experimental insights.
  Journal
Biochim Biophys Acta Mol Basis Dis 1864:1949-1959 (2018)
DOI:10.1016/j.bbadis.2017.10.035
Reference
PMID:23147391
  Authors
Mandavia CH, Aroor AR, Demarco VG, Sowers JR
  Title
Molecular and metabolic mechanisms of cardiac dysfunction in diabetes.
  Journal
Life Sci 92:601-8 (2013)
DOI:10.1016/j.lfs.2012.10.028
Reference
PMID:21626163
  Authors
Falcao-Pires I, Leite-Moreira AF
  Title
Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment.
  Journal
Heart Fail Rev 17:325-44 (2012)
DOI:10.1007/s10741-011-9257-z
Reference
PMID:27148064
  Authors
Westermeier F, Riquelme JA, Pavez M, Garrido V, Diaz A, Verdejo HE, Castro PF, Garcia L, Lavandero S
  Title
New Molecular Insights of Insulin in Diabetic Cardiomyopathy.
  Journal
Front Physiol 7:125 (2016)
DOI:10.3389/fphys.2016.00125
Reference
PMID:33276047
  Authors
Randhawa VK, Dhanvantari S, Connelly K
  Title
How Diabetes and Heart Failure Modulate Each Other and Condition Management.
  Journal
Can J Cardiol S0828-282X(20)31115-6 (2020)
DOI:10.1016/j.cjca.2020.11.014
Reference
PMID:31641426
  Authors
Athithan L, Gulsin GS, McCann GP, Levelt E
  Title
Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date.
  Journal
World J Diabetes 10:490-510 (2019)
DOI:10.4239/wjd.v10.i10.490
Reference
PMID:21111987
  Authors
Murarka S, Movahed MR
  Title
Diabetic cardiomyopathy.
  Journal
J Card Fail 16:971-9 (2010)
DOI:10.1016/j.cardfail.2010.07.249
Reference
PMID:25085967
  Authors
Thomas CM, Yong QC, Rosa RM, Seqqat R, Gopal S, Casarini DE, Jones WK, Gupta S, Baker KM, Kumar R
  Title
Cardiac-specific suppression of NF-kappaB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.
  Journal
Am J Physiol Heart Circ Physiol 307:H1036-45 (2014)
DOI:10.1152/ajpheart.00340.2014
Reference
PMID:28236380
  Authors
Brahma MK, Pepin ME, Wende AR
  Title
My Sweetheart Is Broken: Role of Glucose in Diabetic Cardiomyopathy.
  Journal
Diabetes Metab J 41:1-9 (2017)
DOI:10.4093/dmj.2017.41.1.1
Reference
PMID:18829990
  Authors
Singh VP, Le B, Khode R, Baker KM, Kumar R
  Title
Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis.
  Journal
Diabetes 57:3297-306 (2008)
DOI:10.2337/db08-0805
Reference
PMID:18296558
  Authors
Singh VP, Baker KM, Kumar R
  Title
Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production.
  Journal
Am J Physiol Heart Circ Physiol 294:H1675-84 (2008)
DOI:10.1152/ajpheart.91493.2007
Reference
PMID:26678809
  Authors
Jia G, DeMarco VG, Sowers JR
  Title
Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.
  Journal
Nat Rev Endocrinol 12:144-53 (2016)
DOI:10.1038/nrendo.2015.216
Reference
PMID:18309108
  Authors
Kim JA, Wei Y, Sowers JR
  Title
Role of mitochondrial dysfunction in insulin resistance.
  Journal
Circ Res 102:401-14 (2008)
DOI:10.1161/CIRCRESAHA.107.165472
Reference
PMID:30170598
  Authors
Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuniga FA
  Title
Association between insulin resistance and the development of cardiovascular disease.
  Journal
Cardiovasc Diabetol 17:122 (2018)
DOI:10.1186/s12933-018-0762-4
Reference
PMID:31269778
  Authors
Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A
  Title
Molecular Dysfunction and Phenotypic Derangement in Diabetic Cardiomyopathy.
  Journal
Int J Mol Sci 20:E3264 (2019)
DOI:10.3390/ijms20133264
Reference
PMID:24307101
  Authors
Joshi M, Kotha SR, Malireddy S, Selvaraju V, Satoskar AR, Palesty A, McFadden DW, Parinandi NL, Maulik N
  Title
Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria.
  Journal
Mol Cell Biochem 386:233-49 (2014)
DOI:10.1007/s11010-013-1861-x
Reference
PMID:29867137
  Authors
Knapp M, Tu X, Wu R
  Title
Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy.
  Journal
Acta Pharmacol Sin 40:1-8 (2019)
DOI:10.1038/s41401-018-0042-6
Reference
PMID:16487830
  Authors
Asbun J, Villarreal FJ
  Title
The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy.
  Journal
J Am Coll Cardiol 47:693-700 (2006)
DOI:10.1016/j.jacc.2005.09.050
Reference
PMID:32024054
  Authors
Levick SP, Widiapradja A
  Title
The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function.
  Journal
Int J Mol Sci 21:E970 (2020)
DOI:10.3390/ijms21030970
Related
pathway
ko00010  Glycolysis / Gluconeogenesis
ko00020  Citrate cycle (TCA cycle)
ko00190  Oxidative phosphorylation
ko00520  Amino sugar and nucleotide sugar metabolism
ko03320  PPAR signaling pathway
ko04071  Sphingolipid signaling pathway
ko04150  mTOR signaling pathway
ko04210  Apoptosis
ko04260  Cardiac muscle contraction
ko04350  TGF-beta signaling pathway
ko04614  Renin-angiotensin system
ko04910  Insulin signaling pathway
ko04930  Type II diabetes mellitus
ko04931  Insulin resistance
ko04933  AGE-RAGE signaling pathway in diabetic complications
ko04940  Type I diabetes mellitus
LinkDB

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