Abstract
Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.
Highlights
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia resulting from a defect in insulin secretion, insulin sensitivity, or both
Inflammation plays a pivotal role in the development of chronic complications of DM, both microvascular and macrovascular, and in DM-related metabolic disorders such as non-alcoholic fatty liver disease (NAFLD)
The clinical and experimental data discussed in this review highlight the role of systemic and local chronic low-grade inflammation as a key etiological process leading to chronic complications of DM
Summary
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia resulting from a defect in insulin secretion, insulin sensitivity, or both. A growing number of studies on the pathogenesis of diabetic complications have focused on the involvement of multi-protein scaffolding complexes, termed inflammasomes, that coordinate the inflammatory response These components of the innate immune system are signaling platforms that, once assembled, lead to caspase-1 activation and the processing of pro-IL-1β and pro-IL-18 to their mature bioactive forms [11,12], as well as to gasdermin D-mediated pyroptosis [13], an inflammatory form of programmed cell death. Given that different DAMPs have been reported to induce different control mechanisms of inflammasome assembly and activation, including mitochondrial dysfunction, endoplasmic reticulum stress, and lysosomal rupture, [40], the specific DAMP-induced mechanisms will be discussed in the paragraphs regarding each chronic complication of DM
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