IP-10 secretion as a possible mechanism for beta-cell death in type 2 diabetes

• Applicant: Kathrin Maedler, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 69281175

Both type 1 and type 2 diabetes results from a decreased mass of insulin secreting beta cells in the pancreas. The underlying cause of this loss of cells is an increased rate of apoptosis, a term to describe a form of cell death that is regulated and deliberate. We showed recently, that chronically elevated blood glucose levels accelerate beta cell death. This glucose-induced apoptosis is mediated by the activation of the Fas pathway in β-cells as well as by secretion and production of the pro-inflammatory cytokine interleukin-1β (IL-β). Cytokine and chemokine secretion by macrophages infiltrating the pancreatic islets as well as by the pancreatic beta-cell itself leads to beta-cell destruction and is considered to be a main mechanism of beta-cell death and loss of function in type 1 diabetes and recently, sub-clinical inflammation has also been observed in type 2 diabetes. Mechanisms of cytokine induced beta-cell destruction have been investigated, but the actions of chemokines are widely unknown. In our preliminary results, we found that the chemokine Interferon-gamma-inducible protein-10 (IP-10) is highly secreted from cultured isolated islets from diabetic organ donors but not from healthy control islets. In the present proposal we hypothesize that IP-10 has deleterious effects on the β-cell and that IP-10 expression is an early marker of beta-cell death. We aim to protect β-cells from the IP-10 effects by blocking its specific receptor as a target to prevent β-cell apoptosis and to maintain beta-cell survival.

• DFG Programme: Independent Junior Research Groups