Proteomic identification of carboxypeptidase E connects lipid-induced beta-cell apoptosis and dysfunction in type 2...

Type 2 diabetes occurs when the endocrine pancreas can no longer secrete enough insulin to maintain glucose and lipid homeostasis. This is likely due to cumulative defects in beta-cell fate and function, as well as insulin resistance. A number of recent studies, including ones from our group, have used unbiased proteomic, genomic and genetic approaches to unravel the mechanisms by which hyperlipidemia causes beta-cell apoptosis and dysfunction. It is clear from these studies and others, that there are multiple pathways by which fatty acids such as palmitate can lead to beta-cell dysfunction and death. In the present article, we highlight the role for dysfunction in the ER and secretory pathway in the toxic effects of free fatty acids. Recent work has shown that the rapid degradation of carboxypeptidase E plays a significant role in beta-cell death in response to the free fatty acid palmitate. These newly identified targets of beta-cell lipotoxicity present novel avenues for research and therapeutic intervention.