Targeting the stress responses 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). 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, suggesting that enhancing ER adaptive capacity and mitigating stress can improve β-cell function and survival. Consistent with this, in our earlier studies we reported that alleviating ER stress via a chemical chaperone, tauroursodeoxycholic acid (TUDCA), could prevent diabetes in preclinical models. Indeed, TUDCA is now under Phase II clinical trials for new-onset T1D patients.

Our laboratory generated genetic models to investigate the function of the β-cell UPR in a preclinical T1D model, NOD mice. Using an IRE1α β-cell-specific deletion mouse model, my lab made the striking discovery that loss of IRE1α in β-cells, prior to islet immune infiltration, leads to a transient β-cell dedifferentiation, which allows β-cells to escape immune-mediated destruction. In another collaborative study, we identified how adaptation to chronic ER stress induces pancreatic β-cell plasticity. More recently, we discovered that deletion of β-cell ATF6 in NOD mice prior to insulitis generates a p21-driven early senescence phenotype and alters β-cell secretome to induce recruitment of M2 macrophages to the islets. Consequently, M2 macrophages promote anti-inflammatory responses and immunesurveillance that cause resolution of islet inflammation, removal of terminally senesced β-cells, reduction of β-cell apoptosis, and prevention of T1D.

Our laboratory utilizes genetic mouse models of the UPR, along with a sophisticated toolbox of genetic, biochemical, and pharmacological protocols, single cell -omics to probe the role of stress responses, and interorganellar communication in β-cells during the initiation and progression of T1D.