Diabetes and apoptosis: lipotoxicity.
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.
Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
Christine M
CM
Kusminski
Shoba
S
Shetty
Lelio
L
Orci
Roger H
RH
Unger
Philipp E
PE
Scherer
D000818:Animals; D017209:Apoptosis; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology; D050356:Lipid Metabolism; D008055:Lipids / Q000633:toxicity*; D008099:Liver / Q000503:physiopathology
D008055:Lipids