Novel beta-cell stress protection mechanisms and modifiers of diabetes development

Understanding the mechanisms underlying endocrine pancreatic β-cell fitness, and failure in diabetes, constitutes a fundamental challenge for diabetes research since beta-cell stress and dysfunction contributes to both TID and T2D. β-cell molecular factors, or defects that compromise beta-cell stress- or glucose responses may underlie the susceptibility to diabetes. These defects
predispose to diabetes by aggravating β-cell damage in response to diabetes triggers, such as autoimmunity or metabolic stress. Since a residual β-cell mass often remain long after T1D onset, we hypothesize that the molecular players in the early phases of β-cell stress, prior to destruction of the cells, is an interesting target for preservation of their function. Mutations in the intermediate filament
keratins, are known to cause or predispose to many human liver and skin diseases, while the involvement of keratins in human diabetes or in β-cell biology are outstanding questions. In this project, we have goals, 1) to understand the cell-autonomous molecular roles of β-cell keratins using β-cell conditional keratin knockout and transgenic mice with human keratin mutations, isolated islets and β-cell cultures, and 2) to assess the association of variants in keratin gene regions to diabetes. The hypothesis and aims are based on earlier findings and preliminary data and they will focus on i) how keratins target and maintain β-cell GLUT2 at the plasma membrane, ii) participate in insulin vesicle targeting and secretion, and iii) are upregulated, modified, reorganized during β-cell stress. In addition iv) GWAS studies and computational analysis will be explored for associations between keratins and diabetes. We hypothesis that β-cell keratins and keratin-associated proteins and signalling pathways are central for β-cell fitness and involved in protection from susceptibility to β-cell injury, and hence diabetes development.