Key Takeaways & Executive Findings
- •• NLRP3 inflammasome-mediated pyroptosis is a key mechanism in the pathogenesis of type 2 diabetes mellitus. • Aerobic exercise effectively inhibits NLRP3-related pathways, reducing pancreatic β-cell pyroptosis and improving insulin sensitivity. • Resistance exercise, hypoxic exercise, Tai Chi, and Yijinjing also exhibit potential in regulating pyroptosis for diabetes management. • Exercise offers a multi-targeted approach for preventing and treating type 2 diabetes mellitus by modulating pyroptosis.
Abstract
BACKGROUND: Pyroptosis, a pro-inflammatory form of programmed cell death, plays a key role in innate immunity. However, its excessive activation can induce the body's inflammatory response and the development of disease, e.g., pancreatic β-cell pyroptosis is closely associated with the pathogenesis of type 2 diabetes mellitus. Recent studies suggest that exercise may suppress β-cell pyroptosis, thereby offering potential benefits for the prevention and management of type 2 diabetes mellitus and its complications. Nevertheless, the precise mechanisms underlying the interplay among β-cell pyroptosis, type 2 diabetes mellitus, and exercise remain unclear. OBJECTIVE: To review a series of pyroptosis pathways and the molecular mechanisms of pancreatic β-cell pyroptosis and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the pathophysiological process of type 2 diabetes mellitus, and to summarize the effects and potential mechanisms of different exercise modalities in regulating the pyroptosis of pancreatic β-cells and preventing and controlling type 2 diabetes mellitus, thereby providing theoretical and practical guidance for the prevention and control of type 2 diabetes mellitus and for the intervention of exercise. METHODS: A systematic literature search was conducted in CNKI, VIP, WanFang, Google Scholar, Web of Science, and PubMed for relevant literature published from January 2000 to April 2025. High-quality studies on exercise regulation of pyroptosis in the prevention and treatment of type 2 diabetes mellitus were screened. Based on explicit inclusion and exclusion criteria, the quality of the literature was assessed and integrated, and finally 57 articles were analyzed and summarized. RESULTS AND CONCLUSION: ① NLRP3 inflammasome-mediated pyroptosis plays an important role in the development and progression of type 2 diabetes mellitus; ② Various exercise interventions, especially aerobic exercise, can effectively improve pancreatic β-cell damage and enhance insulin sensitivity by inhibiting NLRP3-related pathways and reducing inflammatory responses; ③ Tai Chi, Yijinjing, resistance exercise, and hypoxic exercise also show certain regulatory potential. In summary, exercise intervenes in pyroptosis through multiple pathways, providing theoretical support and practical directions for new targets in the prevention and treatment of type 2 diabetes mellitus.
1. Introduction
Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion and/or utilization, with complex etiologies. Unhealthy lifestyles and lack of physical activity (sedentary behavior) remain major causes and risk factors for the development of diabetes and its complications. Despite the availability of various pharmacological and non-pharmacological treatments, the incidence of complications continues to rise with the duration of diabetes. In China, the number of diabetes patients has been increasing steadily; according to the first Chinese Diabetes Map, the prevalence of diabetes has increased nearly 20-fold over the past 40 years, imposing a huge health and economic burden on patients. In summary, diabetes and its prevention and treatment have become one of the major public health issues globally in the 21st century.
Pyroptosis is a form of programmed cell death distinct from apoptosis and necrosis, but sharing similarities with both. Specifically, it is triggered by the activation of inflammasomes (mainly NLRP3 inflammasome), caspases, and the gasdermin protein family, leading to cell membrane blebbing, swelling, lysis, and rupture, as well as the release of pro-inflammatory contents. Pyroptosis promotes the release of pro-inflammatory cytokines such as interleukin-1β and interleukin-18, thereby recruiting immune cells and participating in innate immunity to protect the host from pathogens. However, pyroptosis is a double-edged sword; excessive or aberrant activation can cause chronic inflammation. In recent years, increasing evidence has shown that pyroptosis (especially aberrant NLRP3 activation) is closely associated with many diseases characterized by cell death and inflammation, particularly metabolic diseases such as diabetes and obesity, as well as cardiovascular diseases. This suggests that inhibiting pyroptosis may offer a new angle for the prevention and treatment of diabetes.
Exercise, as a preventive and therapeutic measure, has been proven to be a key and effective strategy, in addition to pharmacological intervention, for alleviating and improving diabetes and its complications. Meanwhile, many recent studies have demonstrated that exercise can effectively counteract pancreatic β-cell pyroptosis and improve the body's inflammatory state, thereby preventing and ameliorating diabetes and its complications. For example, aerobic exercise can inhibit the expression of inflammatory factors (such as IL-1β and IL-18) and promote the release of anti-inflammatory cytokines, thereby protecting β-cell function.
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Zhao Yanan, Cao Liquan, Tan Sijie (2026). A new perspective on exercise for the prevention and treatment of type 2 diabetes mellitus: pyroptosis. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21430
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Frequently Asked Questions
What is pyroptosis and how does it relate to type 2 diabetes?
Pyroptosis is a pro-inflammatory form of programmed cell death mediated by inflammasomes, particularly NLRP3. In type 2 diabetes, excessive pyroptosis of pancreatic β-cells leads to their destruction and reduced insulin secretion, contributing to disease progression.
How does exercise help prevent or treat type 2 diabetes?
Exercise, especially aerobic exercise, can inhibit NLRP3 inflammasome activation and reduce pyroptosis of pancreatic β-cells, thereby preserving β-cell function and improving insulin sensitivity. It also reduces systemic inflammation, which is beneficial for diabetes management.
What types of exercise are effective in modulating pyroptosis?
Aerobic exercise has been most extensively studied and shown to be effective. Resistance exercise, hypoxic exercise, and traditional mind-body exercises like Tai Chi and Yijinjing also demonstrate potential in regulating pyroptosis and improving metabolic health.
What are the key molecular mechanisms linking exercise to pyroptosis inhibition?
Exercise modulates the NLRP3 inflammasome pathway, reducing the activation of caspase-1 and the cleavage of gasdermin D, thereby decreasing the release of IL-1β and IL-18. It also enhances antioxidant defenses and reduces oxidative stress, which can trigger pyroptosis.
Is exercise a viable alternative to medication for type 2 diabetes?
Exercise is not a replacement for medication but is a crucial adjunct therapy. It can improve glycemic control, reduce cardiovascular risk factors, and may help reduce the required medication dosage. Always consult healthcare professionals for personalized advice.
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