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Diabetes and apoptosis: lipotoxicity

  • Diabetes and Apoptosis
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Abstract

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid ‘spill over’ to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease.

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Abbreviations

T2DM:

Type 2 diabetes mellitus

CVD:

Cardiovascular disease

TG:

Triglyceride/triacylglycerol

FFA:

Free fatty acid

GLUT4:

Glucose transporter-4

NO:

Nitric oxide

AMPK:

Adenosine monophosphate-activated protein kinase

CoA:

Coenzyme-A

SREBP-1c:

Sterol regulatory element binding protein-1c

PPAR-γ2:

Peroxisome proliferator-activated receptor

ACC:

Acetyl coenzyme A carboxylase

FAS:

Fatty acid synthetase

GPAT:

Glycerol-3-phosphate acyl transferase

CPT-1:

Carnitine palmityl transferase-1

ACO:

Fatty acyl-CoA oxidase

PGC-1α:

Peroxisome proliferator-activated receptor-γ coactivator-1α

UCP-2:

Uncoupling protein-2

VLDLs:

Very low-density lipoproteins

ROS:

Reactive oxygen species

ER:

Endoplasmic reticulum

SPT-1:

Serine palmitoyl transferase

Bcl2 :

B-cell lymphoma 2

Bad:

Bcl2-antagonist of cell death

Bax:

Bcl2-associated X protein

Bid:

BH3 interacting domain death agonist

Bim:

Bcl2-like 11

NF-κB:

Nuclear factor-κB

iNOS:

Inducible nitric oxide synthase

ACS:

Acyl CoA synthase

ECM:

Extracellular matrix

FAT-ATTAC:

Fat apoptosis through targeted activation of caspase-8

FKBP:

Peptidyl-prolyl cis–trans isomerase

AICAR:

5-Amino 4-imidazolecarboxamide riboside

MCD:

Malonyl CoA decarboxylase

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Acknowledgments

We kindly thank Kate McCorkle for assistance with the figures. Our research is supported by NIH grants R01-DK55758 and R01-CA112023 (PES) and a JDRF post-doctoral fellowship 3-2008-130 (CMK).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8549, USA

    Christine M. Kusminski, Shoba Shetty, Roger H. Unger & Philipp E. Scherer

  2. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8549, USA

    Philipp E. Scherer

  3. Faculty of Medicine, Department of Cell Physiology and Metabolism, CMU, University of Geneva, 1, rue Michel Servet, 1211, Geneva 4, Switzerland

    Lelio Orci

Authors
  1. Christine M. Kusminski
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  2. Shoba Shetty
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  3. Lelio Orci
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  4. Roger H. Unger
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  5. Philipp E. Scherer
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Corresponding author

Correspondence to Philipp E. Scherer.

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Kusminski, C.M., Shetty, S., Orci, L. et al. Diabetes and apoptosis: lipotoxicity. Apoptosis 14, 1484–1495 (2009). https://doi.org/10.1007/s10495-009-0352-8

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  • DOI: https://doi.org/10.1007/s10495-009-0352-8

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