, Volume 14, Issue 12, pp 1484–1495 | Cite as

Diabetes and apoptosis: lipotoxicity

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


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.


Diabetes Apoptosis Lipotoxicity Pancreatic β-cells Leptin Adiponectin 



Type 2 diabetes mellitus


Cardiovascular disease




Free fatty acid


Glucose transporter-4


Nitric oxide


Adenosine monophosphate-activated protein kinase




Sterol regulatory element binding protein-1c


Peroxisome proliferator-activated receptor


Acetyl coenzyme A carboxylase


Fatty acid synthetase


Glycerol-3-phosphate acyl transferase


Carnitine palmityl transferase-1


Fatty acyl-CoA oxidase


Peroxisome proliferator-activated receptor-γ coactivator-1α


Uncoupling protein-2


Very low-density lipoproteins


Reactive oxygen species


Endoplasmic reticulum


Serine palmitoyl transferase


B-cell lymphoma 2


Bcl2-antagonist of cell death


Bcl2-associated X protein


BH3 interacting domain death agonist


Bcl2-like 11


Nuclear factor-κB


Inducible nitric oxide synthase


Acyl CoA synthase


Extracellular matrix


Fat apoptosis through targeted activation of caspase-8


Peptidyl-prolyl cis–trans isomerase


5-Amino 4-imidazolecarboxamide riboside


Malonyl CoA decarboxylase



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).


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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

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