Beta cell ER stress and the UPR in T1D

Type 1 diabetes (T1D) results from insulin insufficiency owing to near complete destruction of insulin-producing pancreatic β-cells by an autoimmune process. Over the last decade, the active participation of pancreatic β-cells in their own autoimmune destruction and the impact of aberrant stress responses to T1D disease progression have gained considerable attention.

Early studies demonstrated that β-cells exposed to pro-inflammatory cytokines have significantly increased endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).  ER stress initiates the unfolded protein response (UPR), which operates through inositol-requiring protein-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor-6 (ATF6), all of which are localized in the ER membrane and respond to stress by relaying signals from the ER to the cytoplasm and nucleus. While the UPR initially attempts to mitigate ER stress, if the stress is prolonged or severe, it switches from being a pro-adaptive to a pro-apoptotic response

We and other laboratories showed that ER stress and dysregulated UPR were present in β-cells of mouse models of T1D and patients with T1D.  In our earlier studies, we provided the first direct link between the ER stress and T1D and showed that mitigation of β-cell ER stress with a chemical chaperone, TUDCA can prevent T1D in preclinical models (Engin et al., Sci Transl Med 2013). TUDCA is currently in Phase II clinical trials for individuals with new-onset T1D.

Over the past 10 years, studies from our lab have focused on dissecting the function of the specific UPR mediators in β-cells in T1D. Specifically, work from our lab demonstrated that during early stages of disease stress-induced transient dedifferentiation of β-cells could alter the diabetogenic activity of immune cells and protect NOD mice against T1D (Lee et al., Cell Metab 2020). In a follow-up study, we showed that under chronic stress conditions β-cells undergo transcriptional and translational reprogramming that induce a high degree of adaptive plasticity (Chen et al., Nat Commun 2022). Our laboratory’s recent work provided the first evidence for a link between the UPR and β-cell senescence/immune surveillance  in T1D (Lee et al., Cell Metab 2023). 

We use genetic mouse models of the UPR, human islets, mouse cell lines along with a sophisticated toolbox of genetic, biochemical, pharmacological, immunological protocols as well as cutting-edge single cell -omics and imaging to probe the role of stress responses in β-cells during the initiation and progression of T1D.