Mechanisms of disease: inflammasome activation and the development of type 2 diabetes

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.

Keywords: IL-1β; T cells; adipocytes; caspase-1 apoptosis; glyburide; inflammation; macrophages; pycard.

Figure 1

NLRP3 inflammasome activation during type II diabetes. The NLRP3 inflammasome is composed of NLRP3, ASC, and procaspase-1. During type II diabetes there is increased accumulation of endogenous danger-associated molecular patterns (ceramides, free cholesterol, etc.) which are sensed by the NLRP3 inflammasome. After sensing of DAMPs, inflammasome assembly occurs by interactions in the protein domains of NLRP3 ASC and procaspase-1. This leads to caspase-1 activation and the secretion of bioactive IL-1β and IL-18, which go on to cause insulin resistance and organ dysfunction.

Figure 2

The consequences of NLRP3 inflammasome activation during type II diabetes and possible benefits of NLRP3 and IL-1 targeted therapies. NLRP3 inflammasome activation during type II diabetes results in the production of IL-1β and IL-18, which go on to cause insulin resistance and organ dysfunction in the pancreas, adipose tissue, liver, skeletal muscle, and circulation. NLRP3 and IL-1β targeted therapy may have potential to reduce local tissue inflammation and systemic inflammation resulting in systemic improvement in insulin secretion, insulin sensitivity as well as organ function.