Emerging Roles for A20 in Islet Biology and Pathology

Abstract

A20 is most characteristically described in terms relating to inflammation and inflammatory pathologies. The emerging understanding of inflammation in the etiology of diabetes mellitus lays the framework for considering a central role for A20 in this disease process. Diabetes mellitus is considered a major health issue, and describes a group of common metabolic disorders pathophysiologically characterized by hyperglycemia. Within islets of Langherhans, the endocrine powerhouse of the pancreas, are the insulin-producing pancreatic β-cells.Loss of β-cell mass and function to inflammation and apoptosis is a major contributing factor to diabetes. Consequently, restoring functional β-cell mass via transplantation represents a therapeutic option for diabetes. Unfortunately, transplanted islets also suffers from loss of β-cell function and mass fueled by a multifactorial inflammatory cycle triggered by islet isolation prior to transplantation, the ischemic environment at transplantation as well as allogeneic or recurrent auto-immune responses. Activation of the transcription factor NF-κB is a central mediator of inflammatory mediated β-cell dysfunction and loss. Accordingly, a plethora of strategies to block NF-κB activation in islets and hence limit β-cell loss have been explored, with mixed success. We propose that the relatively poor efficacy of NF-κB blockade in β-cells is due to concommittant loss of the important, Nf-κB regulated anti-apoptotic and anti-inflammatory protein A20. A20 has been identified as a β-cell expressed gene, raising questions about its role in β-cell development and function, and in β-cell related pathologies. Involvement of apoptosis, inflammation and NF-κB activation as β-cell factors contributing to the pathophysiology of diabetes, coupled with the knowledge that β-cells express the A20 gene, implies an important role for A20 in both normal β-cell biology as well as β-cell related pathology. Genome wide association studies (GWAS) linking single nucleotide polymorphisms in the A20 gene with the occurrence of diabetes and its complications support this hypothesis. In this chapter we review data supporting the role of A20 in β-cell health and disease. Furthermore, by way of their specialized function in metabolism, pancreatic β-cells also provide opportunities to explore the biology of A20 in scenarios beyond inflammation.