Diabetes and apoptosis: lipotoxicity

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.

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

“…Further stress signals, including oxidative stress and lipid peroxidation, lead to hepatocyte injury and inflammation, probably playing an important role in the transition from simple steatosis to NASH [3]. Interestingly, cell death by apoptosis may also constitute an important component of disease progression [4]. In fact, members of our team and others have already demonstrated that hepatocyte apoptosis is a prominent pathological feature in patients with NASH and NAFLD [5,6].…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Apoptotic cell death is also regarded as a terminal junction of various molecular mechanisms. It contributes to cardiac remodeling by destroying contractile units and inducing compensatory myocardial cell hypertrophy and reparative fibrosis (Kusminski, Shetty, Orci, Unger & Scherer, 2009). The rate of CM apoptosis in patients with diabetes is 85‐fold greater than that in nondiabetics (Ho, Liu, Liau, Huang & Lin‐Shiau, 2000).…”

“…However, the present study mainly focused on the effects of GLP‐1 on lipid regulation because, along with hyperglycemia, lipid accumulation and toxicity play key roles in DCM (Kusminski et al., 2009; Yang et al., 2007). The lack of glycemic control in cardiovascular disease progress in obese and T2DM patients underscores the importance of lowering cardiac steatosis in them.…”

Enhanced Metabolic Flexibility Associated with Elevated Adiponectin Levels

“…Ectopic storage of lipids in nonadipose tissue is widely accepted as a cause of metabolic dysregulation and occurs at variable degrees in obese or lipodystrophic individuals. 1 This phenomenon is commonly referred to as lipotoxicity, and a large body of literature has revealed a variety of mechanisms underlying fatty acid-induced metabolic dysregulation. 2,3 Furthermore, reduction of ectopic lipid storage has been proven successful in the prevention or reversal of metabolic disease.…”