402 000 euro
Understanding the mechanisms underlying beta-cell failure in diabetes constitutes a fundamental challenge for diabetes research. Beta-cell stress and dysfunction contributes to diabetes in both type 1 and type 2 diabetes. In this project, we are exploring the regulatory functions of intermediate filament keratins in pancreatic beta-cell biology under basal circumstances as well in diabetes. It is wellknown that mutations in keratins cause or predispose to many human liver and skin diseases, but the involvement of keratins in diabetes or in beta-cell biology is still insufficiently known. Our earlier research indicates that keratins participate in maintaining blood glucose regulation, beta-cell protein targeting, mitochondrial function and insulin content. Reduced keratin 8 levels moreover increases murine diabetes susceptibility, and early diabetes development is accompanied by keratin upregulation in the pancreatic beta-cells. Pancreatic keratins are thus involved in essential beta-cell functions and could comprise a novel beta-cell factor that can regulate diabetes susceptibility. This research will utilize several in vivo disease models and complementary beta-cell lines, to comprehensively examine keratin-regulated beta-cell function at a molecular level as well as on their effects on the whole organism. These methods will be combined with state-of-the-art imaging techniques and an array of biochemical methods. In this project, we will clarify the molecular mechanisms of keratins in the dynamics of insulin secretion basally, after glucose-stimulation or in chronic hyperglycaemia (diabetes). Further, we will examine the influence of keratins on beta-cell stress tolerance and diabetes suceptibility. With this research, we expect to be able to elucidate keratin-regulated molecular mechanisms and pathways that are important in beta-cell function and diabetes development. In the long term, these new insights will aid the development of disease modifying therapeutics to enhance beta-cell function and maintain insulin secretion in diabetes patients.