Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. Loss of beta-cells leads to insulin insufficiency and hyperglycemia, with patients eventually requiring lifelong insulin therapy to maintain normal glycemic control. Since T1D has been historically defined as a disease of immune system dysregulation, there has been little focus on the state and response of beta-cells and how they may also contribute to their own demise. Major hurdles to identifying a cure for T1D include a limited understanding of disease etiology and how functional and transcriptional beta-cell heterogeneity may be involved in disease progression. Recent studies indicate that the beta-cell response is not simply a passive aspect of T1D pathogenesis, but rather an interplay between the beta-cell and the immune system actively contributing to disease. Here, we comprehensively review the current literature describing beta-cell vulnerability, heterogeneity, and contributions to pathophysiology of T1D, how these responses are influenced by autoimmunity, and describe pathways that can potentially be exploited to delay T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease in which loss of beta-cell mass and subsequent insulin-insufficiency leads to hyperglycemia
Functional secretory granules, increased with high fat diet Immature, highly proliferative, Wnt+ (Become flattop+) Present in non-T1D setting, glucose responsive, express maturity markers Population appears in a T1D environment, resistant to immune killing, unresponsive to glucose, express stemness markers First to respond to calcium influx, other beta-cell response based on distance from these High levels of proinsulin and ribosomes, low insulin protein content, increased in db/db mice
We propose that an understanding of beta-cell dynamics prior to, during, and after immune-cell infiltration in T1D will be vital to development of therapies that can combat T1D development, but perhaps even precede and bypass it
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease in which loss of beta-cell mass and subsequent insulin-insufficiency leads to hyperglycemia. Beta-Cell Contributions to Autoimmune Diabetes among the highest rates, with values greater than 20 per 100,000 people [4]. Following a triggering event in genetically-susceptible individuals, immune effector cells infiltrate the pancreas and activate inflammatory pathways to mediate targeted destruction of insulinproducing beta-cells. We will explore inherent beta-cell heterogeneity and vulnerabilities, contributions to the local inflammatory environment, and how the beta-cell response to metabolic stress can perpetuate disease. Shifting focus from the beta-cell as a passive target to an active participant in disease progression will help identify novel therapeutic approaches, potentially leveraging these unique beta-cell responses and susceptibilities for both treatment and prevention of T1D. The metabolic demand associated with tightly regulated insulin secretion, paired with a highly vascularized environment, reduced antioxidant defense mechanisms, and sensitivity to proinflammatory cytokines, makes beta-cells uniquely susceptible to autoimmune-mediated destruction (Figure 1)
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