Abstract
Over the recent past, the importance of aberrant immune cell activation as one of the contributing mechanisms to the development of insulin-resistance and type 2 diabetes (T2D) has been recognized. Among the panoply of pro-inflammatory cytokines that are linked to chronic metabolic diseases, new data suggests that interleukin-1β (IL-1β) may play an important role in initiating and sustaining inflammation-induced organ dysfunction in T2D. Therefore, factors that control secretion of bioactive IL-1β have therapeutic implications. In this regard, the identification of multiprotein scaffolding complexes, “inflammasomes,” has been a great advance in our understanding of this process. The secretion of bioactive IL-1β is predominantly controlled by activation of caspase-1 through assembly of a multiprotein scaffold, “inflammasome” that is composed of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) ASC (apoptosis associated speck-like protein containing a CARD) and procaspase-1. The NLRP3 inflammasome appears to be an important sensor of metabolic dysregulation and controls obesity-associated insulin resistance and pancreatic beta cell dysfunction. Initial clinical “proof of concept” studies suggest that blocking IL-1β may favorably modulate factors related to development and treatment of T2D. However, this potential therapeutic approach remains to be fully substantiated through phase-II clinical studies. Here, we outline the new immunological mechanisms that link metabolic dysfunction to the emergence of chronic inflammation and discuss the opportunities and challenges of future therapeutic approaches to dampen NLRP3 inflammasome activation or IL-1β signaling for controlling type 2 diabetes.
Highlights
With a disease rate of 8.3% and cost of $174 billion, there is no debate that diabetes is a highly prevalent and costly lifelong disease (Dall et al, 2010; Centers for Disease Control and Prevention, 2011)
Whereas type 1 diabetes is characterized by autoimmune destruction of pancreatic islets, Type 2 diabetes (T2D) has been described as an autoinflammatory disorder, characterized first by insulin resistance in peripheral tissues followed by beta cell failure, including decreased islet size and insulin production (McGonagle and McDermott, 2006)
T2D is clearly associated with obesity, and clinical progression of this disease has been linked to chronic low-grade inflammation due to activation of immune cells
Summary
With a disease rate of 8.3% and cost of $174 billion, there is no debate that diabetes is a highly prevalent and costly lifelong disease (Dall et al, 2010; Centers for Disease Control and Prevention, 2011). The underlying clinical rationale to identify the immunological triggers of metabolically driven inflammation has been to develop approaches to therapeutically target the immune sensors and break the feed-forward cycle of organ dysfunction and development of diabetes. Despite overwhelming evidence in favor of TNF having a critical role in regulating inflammation and insulin-action (Hotamisligil et al, 1993, 1994a,b, 1995; Hotamisligil and Spiegelman, 1994; Peraldi et al, 1996; Uysal et al, 1997; Liu et al, 1998), the translation of basic research findings with TNF targeted neutralization approaches to diabetes care in humans has had disappointing results with both acute www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
