Blood glucose regulation is a tightly controlled process governed by specialized cells within the pancreatic islets of Langerhans. Among these, beta cells play a critical role by secreting insulin in response to rising blood glucose levels. In diabetes mellitus, beta cell dysfunction or loss leads to elevated blood sugar. A key driver of this dysfunction is chronic endoplasmic reticulum (ER) stress and impaired unfolded protein response (UPR). In type 1 diabetes, stressed beta cells are targeted by the immune system. In type 2 diabetes, prolonged high blood glucose and fatty acid levels induce ER stress, leading to insulin resistance and beta cell failure.
Given the alarming rise in diabetes worldwide, new therapeutic strategies are urgently needed to protect, revitalize and regenerate beta cells, the liver and other affected tissues by alleviating cellular stress. Our earlier studies identified the ER-resident, unconventional growth factor MANF as a critical regulator of ER stress and a key determinant of beta cell survival, proliferation, and function in both human and mouse islets. More recently, we demonstrated that transgenic MANF expression in beta cells protects and promotes their regeneration in a mouse model of T1D by reducing cellular stress, inflammation and immunogenicity, highlighting its therapeutic potential.
Our research focuses on growth factors and small-molecule compounds that protect and regenerate beta cells by targeting cellular stress pathways and epigenetic regulation, specifically N6-methyladenosine (m6A) RNA methylation. We employ primary cells, established cell lines, genetically modified mice, and diabetes mouse models, integrating transcriptomic, genomic, cellular and molecular biology approaches to uncover the mechanisms underlying diabetes pathogenesis.
Looking ahead, we aim to investigate the therapeutic roles of MANF-mimetic small molecules and METTL3/14 methyltransferase activators to protect and regenerate beta cells and other tissues impaired in T1D and T2D, using both cellular systems and in vivo models. In those models, we continue to explore the mechanism of MANF action.