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Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes

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Abstract

Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ARBs:

Angiotensin receptor blockers

ADA:

American Diabetes Association

AGEs:

Advanced glycation end-products

AMPK:

AMP-activated protein kinase

AT1R:

Angiotensin II type I receptor

C/EBP:

CCAAT/enhancer binding protein

CAN:

Cardiac autonomic neuropathy

CRP:

C-reactive protein

CVD:

Cardio vascular diseases

DG:

Diacyl glycerol

DM:

Diabetes mellitus

eNOS:

Endothelial nitric oxide synthase

ERR:

Estrogen-related nuclear receptors

ET-1:

Endothelin-1

FAT/CD36:

Fatty acid translocase

FetA:

Fetuin-A

FFA:

Free fatty acid

Glut4:

Glucose transporter 4

HDL:

High-density lipoprotein

HO-1:

Heme oxygenase-1

ICAM-1:

Intracellular adhesion molecule-1

IL-6:

Interleukin-6

IR:

Insulin resistance

IR-β:

Insulin receptor β

IRS-1:

Insulin receptor substrate-1

JNK:

Janus kinase

STAT:

Signal transducer and activator of transcription

LCFA:

Long-chain fatty acid

LDL:

Low-density lipoprotein

LPL:

Lipoprotein lipase

MAPK:

Mitogen-activated protein kinase

MCP-1:

Macrophage chemo attractant protein-1

mTOR:

Mammalian target of rapamycin

NADP:

Nicotinamide adenine dinucleotide phosphate

NEFA:

Non-esterified fatty acid

NFAT:

Nuclear factor of activated T cells

NFκ-B:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NO:

Nitric oxide

NOXs:

NADPH oxidases

NRF1:

Nuclear respiratory factor 1

OXPHO:

Oxidative phosphorylation

PAI-1:

Plasminogen activator inhibitor-1

PFK2:

Phosphofructokinase 2

PGC-1α:

PPAR-γ coactivator 1α

PH:

Pleckstrin homology

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

PKB/Akt:

Protein kinase B

PPARs:

Peroxisome proliferator-activated receptors

PTEN:

Phosphatase and tensin homolog

PTP1B:

Protein tyrosine phosphatase 1B

ROS:

Reactive oxygen species

SHIP:

SH2-containing inositol 5′-phosphatase

SOCS:

Suppressors of cytokine signaling

SREBP:

Sterol regulatory element binding protein

TAG:

Triacyl glycerol

Tfam A:

Mitochondrial transcription factor A

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

UCP:

Uncoupling protein

VAT:

Visceral adipose tissue

VEGF:

Vascular endothelial growth factor

VLDL:

Very low-density lipoprotein

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Acknowledgments

Prof. Sarita Gupta was a visiting scientist in Institute of Cardiovascular Sciences. Nathalia Bernardes and Danielle da Silva Dias were exchange students, under the Canada-Brazil Training program. Dr. Pawan Singal is the holder of the Dr. Naranjan S. Dhalla Chair in Cardiovascular Research supported by St. Boniface Hospital and Research Foundation.

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Correspondence to Sarita Gupta.

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Patel, T.P., Rawal, K., Bagchi, A.K. et al. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Heart Fail Rev 21, 11–23 (2016) doi:10.1007/s10741-015-9515-6

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Keywords

  • Insulin resistance
  • CVD
  • Dyslipidemia
  • Metabolic syndrome
  • Oxidative stress
  • Inflammation