Assessment of endocrine molecular entities targeted by inflammation that are involved in the onset of autoimmune diabetes.

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by pancreatic beta cells demise due to the attack of self-lymphocyte repertoire. We aim to identify molecular entities targeted by the autoimmune assault to pancreatic beta cells that are causally related to T1D progression. The proinflammatory biological niche in which beta cells are immersed during the autoimmune insult promotes deep phenotypical changes crucial for the pathogenic process. These changes lead mainly to beta cell fitness impairment, cell cycle intervention and apoptosis triggering. By using the Microarray technology we identified a series of genes the expression of which is altered in the islet endocrine cells prior to diabetes onset in the NOD (Non Obese Diabetic) mice. One of those genes encodes for cyclin D3 that triggers cell cycle progression through G1 phase towards the S phase. Cyclin D3 can also bind certain transcription factors and activate inflammation process and development of the T cells (NFκB, GATA). The cyclin D3 promoter has binding sequences to NFκB a transcription factor linked to the action of T1D-related proinflammatory cytokines such as IL-1beta and TNFalpha. We found that cyclin D3 is the only D-type cyclin the expression of which is regulated by inflammation in NOD endocrine islet cells. Moreover we found that cyclin D3 protects beta cells against cytokine-induced apoptosis and is required for proper beta cell function. Moreoever, we observed that CDK11, another cell-cycle related gene that interacts with cyclin D3, is also regulated by inflammation in endocrine islet cells. We have assessed whether there is a causal relationship between the coordinated differential expression of both genes during the insulitic assault and diabetes onset