Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications

Abstract

As a new way of programmed cell death, pyroptosis plays a vital role in many diseases. In recent years, the relationship between pyroptosis and type 2 diabetes (T2D) has received increasing attention. Although the current treatment options for T2D are abundant, the occurrence and development of T2D appear to continue, and the poor prognosis and high mortality of patients with T2D remain a considerable burden in the global health system. Numerous studies have shown that pyroptosis mediated by the NLRP3 inflammasome can affect the progression of T2D and its complications; targeting the NLRP3 inflammasome has potential therapeutic effects. In this review, we described the molecular mechanism of pyroptosis more comprehensively, discussed the most updated progress of pyroptosis mediated by NLRP3 inflammasome in T2D and its complications, and listed some drugs and agents with potential anti-pyroptosis effects. Based on the available evidence, exploring more mechanisms of the NLRP3 inflammasome pathway may bring more options and benefits for preventing and treating T2D and drug development.

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation

“…NLRP3 inflammasomes have been profoundly attributed to the pathogenic mechanisms that induce T2DM and its related complications. 49 Ding et al revealed that NLRP3 inflammasome modulates endoplasmic reticulum stress, which regulates glucose tolerance, insulin resistance, inflammation and apoptosis in adipose tissue in DM. 190 It seems that the activation of NLRP3 inflammasome leads to the maturation and the release of pro-inflammatory mediator IL-1β in the sciatic nerve of diabetic rats.…”

“… 232 Recent evidence suggests that overactivation of NLRP3 inflammasome plays an essential role in the pathogenesis of DM and its complications. 49 , 123 , 190 , 233 , 234 The NLRP3 inflammasome includes the apoptosis-associated speck-like adaptor protein (ASC), NLRP3 and pro-caspase-1. Upon activation, NLRP3 becomes ligated to ASC and then binds to pro-caspase-1.…”

Mitochondria-associated programmed cell death as a therapeutic target for age-related disease

“…In response to different stimuli, cells undergo different types of cell death, which modulates the survival of β-cells during disease progression. Apoptosis is the predominant mechanism associated with β-cell loss in Type 1 diabetes and a reduced β-cell population in Type 2 diabetes 119 – 122 . In Type 1 diabetes, β-cell failure is mediated by an immune response characterized by mononuclear and T cells interacting with antigen-presenting cells to generate a high level of inflammatory cytokines, chemokines, and other triggering factors, leading to apoptotic cell death.…”

“…A report showed that necroptosis was the previously unknown mechanism underlying β-cell death in response to islet amyloid formation. NLRP3 inflammasome-mediated pyroptosis also appears to contribute significantly to the development of Type 2 diabetes and insulin resistance 122 . The activation of the NLRP3 inflammasome can be induced by various factors, such as high glucose, fatty acids, ROS, and IAPP levels 127 , 128 .…”

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC

“…Since NLRP3 can sense pathogens and many stimuli derived from the host, abnormal NLRP3 inflammasome activation is demonstrated to be an essential driver of a series of complex human diseases, including acute kidney injury, atherosclerosis, non-alcoholic steatohepatitis (NASH), and type 2 diabetes (Li et al 2022a , b ; Wang et al 2021 ; Yang et al 2022 ; Zhao et al 2021 ), suggesting that NLPR3 inflammasome may act as a potential therapeutic target for these diseases (Chauhan et al 2020 ; Wang and Hauenstein 2020 ). Therefore, inhibiting NLRP3 inflammasome may be a promising approach for treating NLRP3-mediated inflammatory diseases (Chiazza et al 2016 ; Pappritz et al 2022 ; Swanson et al 2019 ).…”