Pancreatic injury and glucose metabolism dysfunction: The central role of inflammatory signaling and islet β-cell apoptosis

Abstract

Acute pancreatitis is an inflammatory disorder of the pancreas and is closely associated with substantial risks of long-term metabolic dysfunctions, particularly abnormal glucose metabolism and post-pancreatitis diabetes mellitus. A comprehensive understanding of the underlying molecular mechanisms is essential to inform effective clinical intervention. A recent study by Chen et al, published in World Journal of Gastroenterology, provided valuable insights by establishing that tumor necrosis factor-α can induce pancreatic β-cell apoptosis through the Bax/Bcl-2/caspase-3 pathway, revealing a direct inflammatory link to abnormal glucose metabolism following acute pancreatitis. The current commentary critically evaluated the mechanistic interplay between pancreatic injury and inflammatory signaling in the disruption of glucose homeostasis. This study analyzed the clinical implications of these pathways for early diagnosis and management of post-pancreatitis diabetes mellitus. Furthermore, the translational potential of targeting specific inflammatory mediators to preserve β-cell mass and function was discussed. Emerging therapeutic strategies aimed at mitigating pancreatic injury by regulating glucose metabolism and inflammatory responses were also evaluated. The commentary identified persistent research gaps and proposed future directions to translate mechanistic insights into improved patient outcomes.

Key Words: Acute pancreatitis; Glucose metabolism; β-cell apoptosis; Tumor necrosis factor-α; Bax/Bcl-2/caspase-3 pathway; Post-pancreatitis diabetes mellitus

Core Tip: This editorial elucidates a key mechanism through which acute pancreatitis contributes to the development of diabetes: Tumor necrosis factor-α triggers islet β-cell apoptosis via the Bax/Bcl-2/caspase-3 pathway. We underscore the central role of this inflammatory axis in post-pancreatitis diabetes mellitus and advocate for targeting tumor necrosis factor-α as a translatable strategy to preserve β-cell mass and prevent diabetes following pancreatic injury.

This editorial refers to "Tumor necrosis factor-α promotes abnormal glucose metabolism after acute pancreatitis by inducing islet β-cell apoptosis via Bax/Bcl-2/caspase-3 signaling pathway" by Chen et al, 2025; https://dx.doi.org/10.3748/wjg.v31.i47.113205.

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INTRODUCTION

Pancreatitis, including both acute pancreatitis (AP) and chronic pancreatitis, represents a spectrum of diseases characterized by pancreatic parenchymal damage, inflammation, and impaired exocrine and endocrine function. Among them, the incidence of AP is on the rise worldwide and in all age groups. Currently, more than 3 million people worldwide are affected by AP each year, making it the third leading cause of gastrointestinal-related hospitalizations[1]. AP is an inflammatory disorder primarily characterized by acute abdominal pain and elevated pancreatic enzymes[2], manifesting a broad clinical spectrum that ranges from mild, self-limiting episodes to severe systemic inflammation and life-threatening organ failure[3]. However, emerging evidence also highlights the long-term metabolic consequences of pancreatic injury. Approximately 40% of patients with AP develop abnormal glucose metabolism (AGM) during hospitalization, with a 2-2.5-fold increased risk of progressing to post-pancreatitis diabetes mellitus (PPDM) compared to the general population. PPDM is classified as type 3c diabetes mellitus (T3cDM)[4] and accounts for approximately 9.2% of all diabetes cases. It is characterized by the loss of islet cells and impaired insulin secretion due to structural pancreatic damage.

The pathogenesis of AP-associated AGM is multifactorial, involving pancreatic necrosis, local and systemic inflammation, and disruption of gut-pancreas crosstalk. It can lead to the loss of pancreatic endocrine tissue, pancreatic fibrosis and autoimmune disorders, and both insulin deficiency and insulin resistance are involved in this pathological process[5]. Among these, inflammation-driven dysfunction and apoptosis of islet β-cells have emerged as the central events. The pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, are markedly upregulated during AP and contribute to β-cell damage. With the progression of inflammation, immune cells are recruited and activated, followed by the release of inflammatory cytokines, which further aggravates pancreatic damage and promotes the development of necrosis[6]. Chen et al[7] identified a specific molecular pathway by which pancreatic injury could promote β-cell apoptosis and subsequent AGM through the TNF-α-mediated activation of the Bax/Bcl-2/caspase-3 axis. These findings not only confirmed the causal role of TNF-α in AP-associated AGM but also identified TNF-α as a potential therapeutic target.

This editorial aimed to contextualize the findings, published in World Journal of Gastroenterology, by Chen et al[7] within the broader landscape of pancreatic injury and glucose metabolism dysfunction. This study first discussed the clinical epidemiological links between AP and AGM or PPDM, followed by the molecular mechanisms underlying inflammation-mediated β-cell damage, while focusing on the Bax/Bcl-2/caspase-3 pathway. Moreover, the potential therapeutic approaches targeting inflammatory signaling, as well as the current challenges and future research directions, were also explored.

CLINICAL ASSOCIATION BETWEEN PANCREATIC INJURY AND GLUCOSE METABOLISM DYSFUNCTION

The link between pancreatic injury and glucose metabolism abnormalities is well established, with AP emerging as a key risk factor for incident diabetes. Although hyperglycemia in AP was historically dismissed as a transient stress response, one study has redefined it as a critical precursor to diabetes of the exocrine pancreas[8]. This view is supported by Charley et al[9], who highlighted the potential for irreversible β-cell injury rather than temporary dysfunction, while another paper emphasized that this persisting complication remains significantly under-recognized in clinical practice[10]. Numerous population-based cohort studies have consistently demonstrated that AP survivors carry a significantly elevated risk of developing new-onset diabetes compared to age-matched controls (Figure 1)[7,11,12]. For instance, Lee et al[11] analyzed data from 3187 patients with AP in Taiwan, with a median follow-up of 5 years, and reported a 2.1-fold increased risk of diabetes. Similarly, a national population-based study of Taiwan by Shen et al[12] involving 2966 patients with AP showed a 2.5-fold higher incidence of new-onset diabetes, with the risk further amplified in the patients with recurrent AP. A meta-analysis by Das et al[13] estimated that 15%-40% of patients with AP developed PPDM within five years of their index episode.

Figure 1 Clinical association and risk factors between pancreatic injury and glucose metabolism dysfunction. Clinical association and key risk factors between pancreatic injury, represented by acute pancreatitis, and glucose metabolism dysfunction. Acute pancreatitis exacerbates glucose metabolism disorders through factors such as body mass index, disease severity, recurrence frequency, and lung injury, with short-term manifestations of abnormal glucose metabolism and long-term progression to post-pancreatitis diabetes mellitus (classified as type 3c diabetes mellitus) (created in BioRender). All data derived from clinical cohort studies or meta-analyses, key data sources including Chen et al[7], Lee et al[11], and Shen et al[12]. AGM: Abnormal glucose metabolism; AP: Acute pancreatitis; BMI: Body mass index; DM: Diabetes mellitus; GI: Glycemic index; HR: Hazard ratio; OR: Odds ratio; PPDM: Post-pancreatitis diabetes mellitus.

Numerous clinical factors modulate the risk of AP-associated AGM, as identified by Chen et al[7]. Their retrospective analysis of 369 patients with AP suggested that the body mass index (BMI), AP severity grade, recurrence frequency, and presence of lung injury were independently associated with the development of AGM. The patients with severe AP or recurrent episodes exhibited a higher likelihood of AGM, likely reflecting more extensive pancreatic damage and sustained inflammatory responses. Importantly, the AP-associated AGM frequently progressed to overt PPDM, a subtype of T3cDM that is clinically and patho-physiologically different from type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM)[14]. T3cDM is characterized by exocrine pancreatic dysfunction, such as steatorrhea, reduced β-cell mass, and impaired insulin secretion, with comparatively minimal insulin resistance relative to T2DM. Unlike type 1 diabetes mellitus, PPDM typically lacks autoimmune markers, such as anti-glutamic acid decarboxylase antibodies. Owing to the overlap in clinical manifestations with T1DM and T2DM, the clinical diagnosis of T3cDM remains challenging. Meanwhile, T3cDM is frequently accompanied by multiple metabolic disorders, including insufficient pancreatic endocrine and exocrine function as well as abnormal nutritional status, which also renders its clinical management highly difficult. These differences underscore the necessity for tailored diagnostic and therapeutic strategies for AP survivors[15]. However, PPDM remains poorly diagnosed in clinical practice and is often misclassified as T2DM. This underscores the importance of recognizing AP as a risk factor for glucose metabolism dysfunction and implementing long-term metabolic monitoring in this patient population.

INFLAMMATION-MEDIATED ISLET Β-CELL DAMAGE: THE CENTRAL ROLE OF TNF-Α

Pancreatic injury triggers a robust systemic inflammatory response, characterized by the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Among these mediators, TNF-α plays a crucial role in the AP pathogenesis and subsequent development of metabolic complications. One study has shown that TNFα can mediate pancreatic βcell apoptosis through TNFR1associated apoptotic factors, TNFR1-associated death domain protein, Fas receptor-associated intracellular protein with death domain (FADD), and FADD-like interleukin-1beta-converting enzyme, and TNFinduced ceramide production may be involved in this apoptotic pathway[16].

Chen et al[7] demonstrated significantly elevated TNF-α levels both in vitro [lipopolysaccharide (LPS)-induced 266-6 acinar cell model] and in vivo (sodium taurocholate-induced AP mouse model). In vitro, the conditioned media (rich in TNF-α) from LPS-treated acinar cells inhibited the proliferation of MIN-6 β-cells, reduced insulin secretion, and increased apoptosis. In vivo, the AP mice exhibited elevated serum TNF-α levels, which were correlated with β-cell apoptosis and impairment of glucose tolerance. These findings are consistent with previous reviews of experimental AP models, in which TNF-α neutralization was associated with reduced pancreatic injury and improved survival[17]. Furthermore, Gezginci-Oktayoglu and Bolkent[18] reported that TNF-α could induce β-cell apoptosis in hyperglycemic rats via the Ras signaling pathway, further supporting a direct role for TNF-α in β-cell dysfunction.

The mechanisms by which TNF-α can mediate β-cell damage are multifaceted. TNF-α can bind to its receptors, TNF receptor (TNFR) 1/TNFR2, on β-cells, triggering downstream signaling cascades that promote apoptosis and inhibit insulin secretion. Chen et al[7] identified the Bax/Bcl-2/caspase-3 axis as a key mediator of TNF-α-induced β-cell apoptosis. They found that TNF-α could upregulate Bax and caspase-3 expression while downregulating Bcl-2 in both MIN-6 cells and mouse pancreatic tissues, thus resulting in increased β-cell apoptosis. This was consistent with the study by Khadrawy et al[19], who demonstrated that modulating the Bcl-2/Bax/caspase-3 pathway could protect β-cells in diabetic rats.

Beyond directly inducing β-cell apoptosis, TNF-α can impair insulin secretion by disrupting glucose-stimulated insulin secretion. According to a previous report, treatment with IL1β and interferon-gamma resulted in reduced numbers of insulin granules and mitochondria, whereas TNF-α caused more severe damage to these organelles. Meanwhile, only TNF-α significantly inhibited glucose-stimulated insulin secretion, while IL-1β and interferon-gamma exerted no such effect[20]. Collectively, these data indicated that TNF-α might serve as a central mediator of AP-induced glucose metabolism dysfunction by targeting β-cell survival and function through the Bax/Bcl-2/caspase-3 pathway.

BAX/BCL-2/CASPASE-3 PATHWAY: A CRITICAL REGULATOR OF Β-CELL APOPTOSIS IN AP

The Bax/Bcl-2/caspase-3 pathway is a conserved apoptotic signaling cascade. In the context of pancreatic injury, the activation of this pathway by TNF-α and other pro-inflammatory cytokines drives β-cell loss and subsequent impairment of glucose metabolism.

Chen et al[7] provided compelling in vitro and in vivo evidence demonstrating that AP could activate the Bax/Bcl-2/caspase-3 pathway in β-cells. In their LPS-induced AP cell model, MIN-6 cells exposed to conditioned media from inflamed acinar cells exhibited increased Bax and caspase-3 expression, decreased Bcl-2 expression, and enhanced apoptosis. Similarly, the pancreatic tissues from sodium taurocholate-induced AP mice exhibited upregulated Bax and caspase-3 levels and downregulated Bcl-2 levels, with these alterations being more pronounced in severe AP compared to mild AP. These findings are also consistent with reports that an increased Bax/Bcl-2 ratio reflects a pro-apoptotic shift under inflammatory conditions[21].

Importantly, Chen et al[7] demonstrated that the inhibition of TNF-α with pomalidomide, a thalidomide analog possessing anti-inflammatory and immunomodulatory properties, reversed the activation of the Bax/Bcl-2/caspase-3 pathway. The pomalidomide treatment reduced TNF-α levels, decreased Bax and caspase-3 expression, restored Bcl-2 levels, and attenuated β-cell apoptosis in the AP cell models. This was accompanied by improvements in insulin secretion and glucose tolerance, thereby highlighting the therapeutic potential of targeting this pathway. Stephens et al[22] showed that TNF-α-induced apoptosis in NIT-1 cells involves FADD-dependent death signaling and downstream caspase activation. In addition, Tsai et al[23] reported that pomalidomide could suppress cerulein-induced AP in mice by inhibiting TNF-α secretion, thereby further validating the utility of TNF-α inhibitors in pancreatic injury.

Notably, not only TNF-α but also other AP-associated pro-inflammatory cytokines and stressors can activate the Bax/Bcl-2/caspase-3 pathway. For example, IL-1β, another key cytokine upregulated in AP, can trigger the same pathway in β-cellsvia the mitogen-activated protein kinases/nuclear factor kappa B (NF-κB) signaling pathway. Mehmeti et al[24] showed that exposure of pancreatic β-cells to pro-inflammatory cytokines altered the expression of Bcl-2 family members, thereby promoting a pro-apoptotic shift and activation of the intrinsic apoptotic pathway. Therefore, the Bax/Bcl-2/caspase-3 axis might serve as a convergence point for multiple apoptotic signals in β-cells during pancreatic injury, making it an attractive therapeutic target.

THERAPEUTIC OPPORTUNITIES TARGETING INFLAMMATORY SIGNALING AND Β-CELL SURVIVAL

The identification of TNF-α and the Bax/Bcl-2/caspase-3 pathway as key mediators of AP-associated AGM has opened new avenues for therapeutic intervention. Targeting these pathways may prevent or reverse β-cell damage, thus reducing the AGM and PPDM risk in AP survivors.

TNF-α inhibitors

Chen et al[7] demonstrated that pomalidomide, an immunomodulatory agent that suppresses TNF-α production, could effectively reduce β-cell apoptosis and improve insulin secretion in AP models. Tsai et al[23] previously showed that pomalidomide could suppress cerulein-induced AP in mice by inhibiting the production of TNF-α and IL-6, leading to reduced pancreatic edema and necrosis. These preclinical data suggest that TNF-α inhibitors can be repurposed to prevent metabolic complications associated with AP.

Targeting the Bax/Bcl-2/caspase-3 pathway

The direct modulation of the Bax/Bcl-2/caspase-3 pathway represents another promising strategy to protect β-cell apoptosis. Caspase-3 inhibitors, such as Z-DEVD-FMK, could reduce β-cell apoptosis, showing promising effects in preclinical models of diabetes. Additionally, Khadrawy et al[19] reported that taxifolin, a natural flavonoid, could modulate the Bcl-2/Bax/caspase-3 pathway, protecting against β-cell damage in diabetic rats. This suggests that natural compounds might be developed as adjunctive therapies.

Anti-inflammatory strategies beyond TNF-α

The inflammatory response of AP involves a complex cytokine network, suggesting that targeting multiple inflammatory mediators may be more effective than a single therapy[25]. The levels of numerous cytokines (such as IL-6, TNF-α, IL-15, IL-17, and monocyte chemoattractant protein-1) are significantly correlated with the severity of early-stage AP[26,27]. This provides a theoretical basis for combined immunotherapy. Notably, the recombinant IL-1 receptor antagonist anakinra has been evaluated in a phase I/II clinical trial in Sanfilippo syndrome, demonstrating an acceptable safety and tolerability profile and supporting the feasibility of IL-1-targeted strategies for controlling systemic inflammation[28]. IL-1β plays a central role in the inflammatory cascade response and can exacerbate cell damage through pathways, such as the NF-κB signaling pathway. Therefore, the combination of TNF-α inhibitors and IL-1β inhibitors might provide synergistic protection for pancreatic β cells and others. Furthermore, certain traditional Chinese medicines have been shown to suppress the production of various pro-inflammatory factors by targeting upstream regulatory factors of inflammatory signals, such as NF-κB, NLR family pyrin domain containing 3, and Gasdermin D, thereby alleviating the pathological damage and apoptosis of pancreatic tissue[29]. A recent review by Zaman and Gorelick[30] discussed emerging therapies for AP that can target these pathways, emphasizing their potential for improving both acute and long-term outcomes in AP.

Metabolic monitoring and early intervention

Beyond pharmacological interventions, the early detection and monitoring of glucose metabolism dysfunction in AP survivors are critical. Current guidelines recommend diabetes screening in patients with AP at the time of discharge and during follow-up; however, adherence remains suboptimal. The risk factors for AGM identified by Chen et al[7], including BMI, AP severity, recurrence frequency, and lung injury, provide a framework for risk stratification, allowing clinicians to prioritize monitoring in high-risk individuals. Lifestyle interventions, such as weight loss, dietary modification, and physical activity, might also reduce AGM risk by improving insulin sensitivity and reducing inflammatory burden. Thiruvengadam et al[31] reported that after AP, the statin use was associated with a lower risk of diabetes, suggesting that lipid-lowering therapy could be a complementary strategy in high-risk patients.

CHALLENGES AND FUTURE DIRECTIONS

Despite significant advances in understanding the link between AP and glucose metabolism dysfunction, there are still several challenges remaining.

First, the study by Chen et al[7] is a single-center retrospective analysis, which might exhibit a selection bias. Future research should include multi-center, prospective cohort studies with long-term follow-up to validate the correlations among TNF-α, β-cell apoptosis, AGM, or PPDM. These studies should also incorporate additional functional metabolic assessments in addition to fasting blood glucose and hemoglobin A1c.

Second, the limited follow-up duration in Chen et al’s study[7] restricts the understanding of the long-term clinical implications. Longer follow-up periods in future studies are necessary to clarify the natural course of AP-associated glucose metabolism dysfunction and the long-term efficacy of interventions.

Third, the AP mouse model used only male mice with a small sample size. Given known sex differences in inflammatory responses and glucose metabolism, the generalizability of the findings may be limited. Future preclinical studies should include both male and female animals to more comprehensively reflect clinical reality.

Fourth, while Chen et al’s study[7] focused on the Bax/Bcl-2/caspase-3 pathway, the upstream and downstream components of TNF-α networks, such as β-cell apoptosis mediated by TNFR1/TNFR2 or the interplay between NF-κB/mitogen-activated protein kinases and apoptotic pathways, were not explored. Further investigation is required to fully delineate these complex signaling cascades and their contributions to AP-associated AGM.

Finally, translating preclinical findings to clinical practice remains a considerable challenge. Although TNF-α inhibitors and caspase inhibitors have demonstrated efficacy in animal models, their safety and effectiveness in patients with AP require validation through large-scale clinical trials. Additionally, the optimal timing of therapy (whether during the acute phase or follow-up) and duration of therapy remain uncertain, requiring a careful balance of efficacy and adverse effects, such as infection risk associated with immunosuppression.

Furthermore, the poor diagnosis of PPDM presents an urgent clinical issue. The current diagnostic criteria are vague, leading to frequent misclassification with T2DM. The development of PPDM-specific biomarkers, such as pancreatic exocrine function tests or β-cell mass imaging techniques, is crucial to improve diagnostic accuracy and facilitate targeted therapeutic strategies.

CONCLUSION

Pancreatic injury, particularly AP, is closely associated with glucose metabolism dysfunction, including AGM and PPDM. Chen et al[7] confirmed that elevated TNF-α levels could promote islet β-cell apoptosis via the Bax/Bcl-2/caspase-3 pathway; this process was correlated with the severity of inflammation. Notably, pomalidomide could effectively attenuate TNF-α-induced apoptosis and reverse changes in the dysregulation of key apoptotic proteins, highlighting its therapeutic potential in AP-associated AGM.

Clinically, recognizing AP as a risk factor for diabetes is essential, and long-term metabolic monitoring of AP survivors should be implemented. Risk stratification based on BMI, AP severity, recurrence, and presence of organ injury can help identify patients at the highest risk of AGM or PPDM. The combination of pharmacological interventions targeting TNF-α or the Bax/Bcl-2/caspase-3 pathway with lifestyle modifications may reduce β-cell damage and improve metabolic outcomes.

Future studies should prioritize multi-center prospective validation studies, exploration of upstream and downstream signaling mechanisms, and translational clinical trials to improve the long-term prognosis of AP survivors and reduce the disease burden of diabetes associated with pancreatic injury.