Apoptosis

, Volume 14, Issue 12, pp 1484–1495

Diabetes and apoptosis: lipotoxicity

Authors

  • Christine M. Kusminski
    • Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical Center
  • Shoba Shetty
    • Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical Center
  • Lelio Orci
    • Faculty of Medicine, Department of Cell Physiology and MetabolismCMU, University of Geneva
  • Roger H. Unger
    • Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical Center
    • Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical Center
    • Department of Cell BiologyUniversity of Texas Southwestern Medical Center
Diabetes and Apoptosis

DOI: 10.1007/s10495-009-0352-8

Cite this article as:
Kusminski, C.M., Shetty, S., Orci, L. et al. Apoptosis (2009) 14: 1484. doi:10.1007/s10495-009-0352-8

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.

Keywords

Diabetes Apoptosis Lipotoxicity Pancreatic β-cells Leptin Adiponectin

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

Copyright information

© Springer Science+Business Media, LLC 2009