Role of the unfolded protein response in pancreatic beta cell function and survival: implications for type 1 and type 2 diabetes

Diabetes is a disease of insufficient insulin production from pancreatic beta cells. This arises as a consequence of: 1) beta cell destruction by pro-inflammatory cytokines such as IL-1 beta, IFN-gamma, and TNF-alpha in type 1 diabetes (T1D); or 2) the failure of beta cells to cope with the development of insulin resistance and obesity in type 2 diabetes (T2D). In both cases, the mechanisms underlying beta cell failure remain unknown. The aim of this thesis is to examine possible mechanisms that contribute to beta cell dysfunction and death in T1D and T2D.This thesis examined the involvement of endoplasmic reticulum (ER) stress in cytokine-induced beta cell death. Previously, ER stress was thought to occur as a result of nitric oxide (NO) production. This thesis demonstrated for the first time that NO is not required for ER stress activation but plays an important role in the subsequent unfolded protein response (UPR) by regulating the switch from adaptive to apoptotic UPR signalling. This ability of NO to regulate UPR signalling may provide a mechanism for the decision of beta cells to undergo apoptosis rather than to adapt to ER stress for survival from cytokine attack.Cytokines also activate the major inflammation signalling regulator nuclear factor-kappaB (NF-kappaB). Research in this thesis revealed a novel crosstalk between NF-kappaB and ER stress signalling pathways involving the balance of the adaptive UPR. Preferential upregulation of ER degradation over chaperone capacity can lead to increased activity in the proteasome central to NF-kappaB activation, resulting in potentiation of cytokine-mediated NF-kappaB signalling and cell death. The interface between the UPR and NF-kappaB signalling may be important in the regulation of beta cell death in T1D.In the face of obesity-associated insulin resistance, the normal beta cell response is insulin hypersecretion, failure of which results in T2D. Mouse models of obesity with opposing diabetes disposition were utilised to study mechanisms of beta cell compensation and failure. The study is the first to show that ER stress in islets is a normal response to obesity, raising the possibility that a sustained adaptive UPR provides a molecular link between obesity-associated insulin resistance and beta cell compensation; conversely, a suppressed adaptive UPR, coupled with inflammation, oxidative stress and the loss of beta cell differentiation may underlie beta cell failure and progression to diabetes