Significance and molecular mechanisms of uncoupling protein 2 during insulin secretion in pancreatic ß-cells

• Applicant: Dr. Martin Jastroch
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2009 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 148993919

Type 2 diabetes is not only one of the leading causes of death, but it also increases the risk for other chronic diseases. In order to treat this malfunction, we have to increase our understanding of the fundamental molecular aspects of insulin secretion from the pancreatic β-cell controlling blood glucose levels. Recently, it has been demonstrated that mitochondrial uncoupling protein 2 (UCP2) controls β-cell insulin secretion. Although significant studies demonstrated a key role of UCP2 in the regulation of insulin secretion in pancreatic β-cells, the molecular mechanisms of UCP2 function and its regulation are not understood.This research proposal aims to understand UCP2 protein mechanisms and how they can be regulated in the INS1 β-cell. In contrast to previous in vitro studies, the effect of UCP2 activators/inhibitors will be tested and monitored in situ by using life imaging and novel sophisticated high-throughput technologies in cellular bioenergetics. Mutational studies based on a comprehensive bioinformatical alignment of all known UCP2 sequences combined with functional modulator interaction will identify crucial protein motifs and therefore potential therapeutical targets. Finally, effectors of UCP2 function will be tested in isolated β-islets of animal models, including UCP2 knockout mice and obesity-induced diabetic phenotypes.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Martin Brand