Apoptosis

, Volume 14, Issue 12, pp 1484–1495

Diabetes and apoptosis: lipotoxicity

  • Christine M. Kusminski
  • Shoba Shetty
  • Lelio Orci
  • Roger H. Unger
  • Philipp E. Scherer
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

DiabetesApoptosisLipotoxicityPancreatic β-cellsLeptinAdiponectin

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

Authors and Affiliations

  • Christine M. Kusminski
    • 1
  • Shoba Shetty
    • 1
  • Lelio Orci
    • 3
  • Roger H. Unger
    • 1
  • Philipp E. Scherer
    • 1
    • 2
  1. 1.Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Cell BiologyUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Faculty of Medicine, Department of Cell Physiology and MetabolismCMU, University of GenevaGeneva 4Switzerland