Inside the beta Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing beta-cells is common to virtually all forms of diabetes. Although the mechanisms underlying beta-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the beta-cell. Cellular and environmental factors contribute to beta-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and beta-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in beta-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in beta cells in the context of the animal models.