Organelle Dysfunction in Type 1 Diabetes

Autoimmune-mediated β-cell destruction is the major cause of type 1 diabetes (T1D), yet the precise molecular mechanisms by which β-cells contribute to their own demise in T1D pathogenesis remain poorly understood. Pancreatic β-cells undergo significant physiological endoplasmic reticulum (ER) stress during insulin synthesis, requiring an effective adaptive response mediated by the unfolded protein response (UPR). However, under chronic ER stress conditions induced by pathological conditions, such as T1D, adaptive pro-survival UPR fails to establish cellular homeostasis and may elicits apoptosis.

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.

Furthermore, our lab recently reported that elimination of the key UPR gene, serine/threonine-protein kinase/endoribonuclease (IRE1), from the β-cells of a T1D mouse model (NOD mice), leads to protection from T1D by an unprecedented mechanism pertinent to transient β-cell dedifferentiation. To follow up on our intriguing initial reports, it is critical to elucidate the molecular mechanisms by which the UPR regulates β-cell death and survival in T1D. Progress in this area could lead to the development of novel and effective non-immune based therapeutic approaches for T1D.

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