Review
Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy

https://doi.org/10.1016/j.bbamcr.2015.02.005Get rights and content
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Highlights

  • Insulin stimulates mitochondrial fusion in rat neonatal cardiomyocytes.

  • Myocardial insulin resistance contributes to the development of diabetic cardiomyopathy.

  • Human diabetic hearts are associated with the fragmentation of the mitochondrial network.

  • Insulin regulates myocardial autophagy.

  • Drp1 is essential for normal cardiac function regulating autophagy/mitophagy.

Abstract

Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics.

Abbreviations

DCM
Diabetic cardiomyopathy
T2DM
Type 2 diabetes mellitus
LV
Left ventricular
CAD
Coronary artery disease
HFD
High fat-diet
FA
Fatty acid
IRS1
Insulin receptor substrate 1
CIRKO
Cardiomyocyte-specific knockout of the insulin receptor
Mnf1
Dynamin-related GTPase mitofusin 1
Mnf2
Dynamin-related GTPase mitofusin 2
Opa-1
Optic atrophy protein 1
IMM
Inner mitochondrial membrane
OMM
Outer mitochondrial membrane
Fis1
Mitochondrial fission 1 protein
Drp1
Dynamin related protein 1
ROS
Reactive oxygen species
SOD
Superoxide dismutase
O-Glc-NAcylation
O-linked-β-N-acetylglucosamine modification
HF
Heart failure
mTOR
Mammalian target of rapamycin
NFκB
Nuclear factor kappa-light-chain-enhancer of activated B cells
Pink1
Serine/threonine kinase PTEN-induced putative kinase 1
Parkin
E3 ubiquitin ligase
AMPK
5′ AMP-activated protein kinase
Drp1-CKO
Cardiomyocyte-specific Drp1 knockout
T1DM
Type 1 diabetes mellitus
LAMP1
Lysosomal-associated membrane protein 1
IRS2
Insulin receptor substrate 2
CIRS12KO
Cardiomyocyte-specific deletion of both IRS1 and IRS2

Keywords

Insulin signaling
Diabetic cardiomyopathy
Mitochondrial dynamics

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