Pleiotropic actions of IL-1 signaling on β-cell function and glucose homeostasis.

  • Author / Creator
    Hajmrle, Catherine
  • Significant research efforts have been devoted to understanding the role of aberrant immune function in the pathophysiology of metabolic disease. In this context, the proinflammatory cytokine IL-1β has emerged as a pleiotropic regulator of glucose homeostasis. The diabetogenic consequences of IL-1 signaling have been examined extensively, with persistent IL-1 signaling inducing β-cell apoptosis, secretory dysfunction, and resulting in the dysregulation of glucose homeostasis. In contrast to its cytotoxic effects, however, the mechanisms underlying the anti-diabetic actions of IL-1β are relatively unknown. The present work challenges the widely-accepted view that the glucoregulatory effects of IL-1β are primarily diabetogenic. The studies presented here elucidate a novel role of IL-1 signaling in the maintenance glucose homeostasis. Furthermore, this thesis demonstrates that the insulinotropic effects IL-1β are duration-dependent, with anti-diabetic actions predominating under conditions of acute IL-1 signaling. The present studies also confirm the cytotoxic actions of persistent IL-1 signaling on β-cell viability and demonstrate that the post-translational modifier SUMO1 abrogates these effects. Findings of the current thesis shed light on the relatively understudied aspects of IL-1β, both by establishing the necessity of IL-1 signaling in the regulation of glucose homeostasis and by implicating IL-1β as a mediator of islet compensation. These studies provide insights into potential mechanisms and environments regulating the pleiotropic effects of this cytokine and suggest that with strategic targeting of this pathway, the modulation of IL-1 signaling may emerge as a highly effective therapy in the treatment of type 2 diabetes

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  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.