Molecular mechanisms of β-cell identity loss under cellular stress in diabetes

The main hallmark in the development of both type 1 and type 2 diabetes has always been the loss of functional β-cell mass. However, studies in mouse models led to the concept of β-cell identity loss as an alternative or additional mechanism contributing to β-cell dysfunction in diabetes. During the process of β-cell identity loss, β-cells may lose their metabolic, transcriptional, and/or phenotypic features and may even, according to some mouse studies, start to resemble endocrine progenitor cells. Loss of β-cell identity can potentially lead to a decreased glucose-stimulated insulin secretion capacity. It is still largely unknown what triggers β-cell identity loss, what could be the driving factors behind this process, and whether there are targets we could focus on to somehow stop or even reverse it. The general aim of this thesis was to assess the underlying molecular mechanisms of β-cell identity loss. This thesis provides evidence that β-cell identity loss occurs to various degrees in human islets under the influence of cellular stress conditions, such as oxidative stress, endoplasmic reticulum stress, and inflammatory stress, all while having a detrimental downstream effect on β-cell function.<br>