Signaling molecules in diabetes: search for potential targets in intrinsic pathways for prediction and intervention in diabetes

Type 1 diabetes (T1D) is caused by the destruction of insulin-secreting beta-cells (b-cells) of the islets of Langerhans and is described by a metabolic disorder characterized by severe insulin deficiency and hyperglycemia that lead to long-term complications. T1D is caused by an autoimmune response whose onset is attributed to inherited genetic factors and external triggers. Insight into the molecular control mechanisms in b-cells and the molecular pathophysiology of diabetes has laid the foundation for the paradigm for T1D prevention which envisages the application of strategies that support the maintenance of appropriate b-cell numbers by suppressing the cytotoxic cell signaling initiated in insulitis and preventing the activation of cell death pathways. This project will study T1D on several levels: (i) established and novel T1D-associated genetic polymorphisms in the Serbian population; (ii) aspects of b-cell physiology that deal with their responses to the local effect of tissue-intrinsic signaling by chemokine CXCL12 and its role in determining islet fate; (iii) the long-term effects of T1D and changes of HMGB1 expression in the liver, and whether HMGB1, through a paracrine-like effect, exacerbates diabetes-related liver dysfunction, and (iv) consequently, molecular targets for potential antioxidative interventions with natural substances will be identified and the molecular mechanisms underlying the activities of these preparations will be examined.