Abstract
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.
Highlights
Autoimmune Type 1 DiabetesAutoimmune type 1 diabetes (T1D) mellitus ( referred to as type 1A diabetes) results from insulin deficiency due to autoimmune-mediated destruction of pancreatic beta cells [1]
Other islet endocrine cell hormones were reported in the InsulinLow cells, including somatostatin, ghrelin and pancreatic polypeptide, indicating that InsulinLow cells are not arising exclusively from alpha-to-beta interconversion [116]. Do these cells arise during the asymptomatic stages and play a causal role in type 1 diabetes (T1D) pathogenesis, or are they a later consequence of the metabolic effects of and sub-optimal glycemic control? Additional studies are clearly necessary to delineate the origins of InsulinLow cells in T1D pancreata and determine whether insulin production and beta cell identity can be restored to these cells in T1D patients
Beta cell unfolded protein response (UPR), senescence, proinsulin processing defects and identity changes are all avenues with strong potential for developing long term preventive approaches for those at risk of T1D onset. These states may even be just the tip of the iceberg, as there is no reason to suppose that there are no other forms of beta cell dysfunction yet to be discovered in T1D
Summary
Autoimmune type 1 diabetes (T1D) mellitus ( referred to as type 1A diabetes) results from insulin deficiency due to autoimmune-mediated destruction of pancreatic beta cells [1]. T1D incidence has been increasing worldwide for the past few decades [3,4], and while it has a long-standing reputation as a pediatric disease, more recently an increasing number of young adults have been diagnosed [1,3]. Long-term diabetes-related complications such as nephropathy, neuropathy and retinopathy may be observed earlier in their lifetimes [1]. In addition to ongoing clinical care for those living with the disease, there is an urgent need to better understand T1D pathogenesis and develop preventive therapies and treatments
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