In this editorial, we comment on the article by Zhang et al. Diabetes mellitus is a chronic disorder associated with several complications like cardiomyopathy, neuropathy, and retinopathy. Diabetes prevalence is increasing worldwide. Multiple diabetes medications are prescribed based on individual patients’ needs. However, the exact mechanisms by which many of these drugs exert their pro-tective effects remain unclear. Zhang et al elucidates molecular mechanisms undelaying cardioprotective effect of the dipeptidyl peptidase-IV inhibitor, teneligliptin. Briefly, teneligliptin alleviates the activation of NOD-like receptor protein 3 inflammasome, a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Suppression of NOD-like receptor protein 3 inflammasome activity reduces the expression of cytokines, oxygen radicals and inflammation. These findings highlight teneligliptin as an anti-diabetic cardioprotective reagent.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia. DM increases the risk of microvascular and macrovascular complications including heart disease, retinopathy, neuropathy, and nephropathy. DM is a global health crisis affecting an estimated 425 million individuals worldwide[1]. Diabetic cardiomyopathy (DCM) is a serious complication of DM that affects approximately 12% of patients with DM and leads to heart failure and death[2]. DCM is a chronic progressive myopathy characterized by ventricular chamber dilation and myocyte hypertrophy, leading to impaired systolic function and heart failure[3]. The exact mechanisms underlying DCM are not fully understood; however, chronic hyperglycemia is believed to play a role. One critical pathway implicated in DCM development is the NOD-like receptor protein 3 (NLRP3) inflammasome. The NLRP3 inflammasome is a multiprotein complex that activates inflammatory responses. Recent studies have demonstrated that NLRP3 inflammasome activation contributes to DCM by promoting inflammation and cell death in the heart[4,5].

In the context of glucose homeostasis, dipeptidyl peptidase-4 (DDP-4) plays a key role in the regulation of incretin hormones, including glucagon, glucagon-like peptide (GLP)-1, GLP-2, and gastric inhibitory peptide[6]. These incretins are secreted into the bloodstream and stimulate postprandial insulin secretion and peripheral glucose uptake. The inactivation of these incretins via dipeptidyl peptidase-4 (DPP-4) digestion is essential for maintaining glucose homeostasis[7]. In DM characterized by impaired incretin function, DPP-4 inhibition is a therapeutic strategy to enhance incretin activity and improve glycemic control.

DPP-4 inhibitors or gliptins are a class of oral antihyperglycemic drugs that suppress DDP-4 activity, leading to elevated and sustained incretin levels[8]. Several gliptins, including sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin, have been approved for clinical use in Western countries to manage type 2 DM management[9]. Teneligliptin, anagliptin, and trelagliptin are gliptins approved in some Asian markets, but are not yet widely available globally[10]. Omarigliptin was initially used in Japan and is currently undergoing further evaluation in clinical trials[11,12].

Although extensive research has established the efficacy of DPP-4 inhibitors in the management of DM, a comprehensive comparison of all the available gliptins is beyond the scope of this editorial. Here, we focus specifically on the article by Zhang et al[13] published in the recent issue of the World Journal of Diabetes (PMID: 38680706, DOI: 10.4239/wjd.v15.i4.724) elucidating the potential therapeutic role of teneligliptin in DCM and its unique characteristics compared to other established gliptins.

Teneligliptin is an orally administered medication belonging to the class of DPP-4 inhibitors. Compared to other DPP4 inhibitors, teneligliptin is relatively cost-effective and economical for patients[14]. Although it shares similar efficacy and safety profiles with other gliptins, teneligliptin exerts unique pharmacokinetic and pharmacodynamic properties owing to its distinct chemical structure. Classified as a class III DPP-4 inhibitor, teneligliptin exhibits a stronger binding affinity to the enzyme than other class II gliptins[15]. This strong binding is attributed to the formation of an additional subsidized bond with DPP-4, potentially leading to more extensive and longer-lasting DPP-4 inhibition[16,17]. However, large-scale clinical trials are needed to investigate whether this translates into significant advantages in glycemic control compared to other gliptins. While a recent meta-analysis suggested favorable efficacy and acceptable safety of teneligliptin compared to other DDP-4 inhibitors, further well-designed clinical trials are warranted to definitively confirm these findings[18]. Interestingly, recent research has suggested that teneligliptin may have additional benefits beyond glycemic control. Previous studies have reported that teneligliptin exerts anti-inflammatory and protective effects on myocardial and neuronal cells[19-22]. These findings suggest that teneligliptin is a potential therapeutic agent for the management of DCM.

To explore the potential therapeutic effects of teneligliptin on DCM and delineate the associated molecular mechanisms, Zhang et al[13] conducted a study on streptozotocin-induced diabetes in mice. In this study, one group of diabetic mice was treated with teneligliptin (30 mg/kg) and the other group served as a control. Notably, teneligliptin treatment alleviated the myocardial hypertrophy phenotype observed in streptozotocin-induced diabetic mice, improved heart function parameters, and reduced the cardiomyocyte damage markers (creatine kinase-MB, aspartate transaminase, and lactate dehydrogenase). Mechanistically, the study revealed that teneligliptin inhibited NADPH oxidase 4 and NLRP3 inflammasome activation and the subsequent release of reactive oxygen species and interleukin 1β – key inflammatory molecules - in diabetic mice.

To strengthen these findings, Zhang et al[13] conducted additional experiments using isolated primary mouse car-diomyocytes. These cells were exposed to high glucose (HG) conditions mimicking the diabetic environment, with or without teneligliptin treatment. Notably, HG exposure triggered NLRP3 inflammasome activation in cardiomyocytes. Teneligliptin treatment effectively suppresses NLRP3 inflammasome activation in these cells. Moreover, teneligliptin significantly reduced the levels of creatine kinase-MB, aspartate transaminase, and lactate dehydrogenase in HG-treated cardiomyocytes, suggesting that it protected against cell damage.

Interestingly, this study also revealed that the beneficial effects of teneligliptin on cardiomyocytes were mediated by the activation of activated protein kinase (AMPK), a cellular energy sensor that plays a crucial role in maintaining metabolic homeostasis. Researchers have found that teneligliptin increases the levels of phosphorylated AMPK, an activated form, in cardiomyocytes exposed to HG levels. Furthermore, blocking AMPK signaling using compound C, a specific inhibitor, abolished the protective effects of teneligliptin[13]. These findings suggested that AMPK activation is a key mechanism underlying the cardioprotective effects of teneligliptin.

This preclinical study provides compelling insights into the potential use of teneligliptin in DCM. This study suggests that teneligliptin may exert its effects through the inhibition of NADPH oxidase 4 and the NLRP3 inflammasome, and the activation of AMPK, all of which are key players in reactive oxygen species formation and inflammation[13]. To translate these findings into clinical applications, further research is needed to validate these mechanisms in human patients with DCM, and to elucidate the precise pathways through which teneligliptin influences AMPK and NLRP3 signaling for a complete understanding of its therapeutic potential.

While teneligliptin effectively lowers hemoglobin A1c, still need to be clarify the direct trophic effects on β-cell function and mass restoration, or its potential immunomodulatory effects during and after drug administration. This is a crucial aspect, as it could pave the way for type 1 DM intervention trials aimed at better disease management and prevention.

Because teneligliptin is a relatively new DPP-4 inhibitor studied primarily in Asian populations, large-scale multi-ethnic trials are warranted. These trials should assess the effectiveness of teneligliptin compared to other DPP-4 in-hibitors, both as monotherapy and in combination therapy with other DM medications. Additionally, studies should identify the genetic and/or clinical factors influencing patient responses to teneligliptin, enabling personalized treatment approaches, and assessing the causative factors for rare side effects reported with DPP-4 inhibitors. Exploring the potential benefits of teneligliptin in high-risk populations, such as prediabetics and those with metabolic syndrome, is also of interest, considering the current limited focus on patients with DM in clinical trials.

Long-term follow-up studies utilizing proteomics and metabolomics are necessary to understand the impact of tene-ligliptin on long-term complications such as neuropathy, nephropathy, and liver disease. Finally, we believe that the involvement of international societies and organizations would be highly beneficial. This collaboration could lead to the implementation of guidelines and a consensus for safer use of teneligliptin and other DPP-4 therapies in managing DM and its associated complications.

Zhang et al[13] suggested that teneligliptin, a drug for diabetes, may have therapeutic potential in DCM; however, further research is required. In mice, teneligliptin improves heart function and reduces damage markers, potentially by inhibiting inflammatory pathways. Human trials are necessary to confirm these findings and determine the optimal dose of teneligliptin for DCM. Addressing these future directions will bridge the gap between this preclinical study and clinical applications, allowing researchers to explore the full potential of teneligliptin for DCM and potentially broaden diabetes management.