Overcoming β-Cell Dysfunction in Type 2 Diabetes Mellitus: CD36 Inhibition and Antioxidant System

Article information

Diabetes Metab J. 2025;49(1):1-12

Publication date (electronic) : 2025 January 1

doi : https://doi.org/10.4093/dmj.2024.0796

Il Rae Park ^,^*

, Yong Geun Chung ^,^*

, Kyu Chang Won

Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

Corresponding author: Kyu Chang Won https://orcid.org/0000-0001-5945-3395 Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea E-mail: kcwon@med.yu.ac.kr

*Il Rae Park and Yong Geun Chung contributed equally to this study as first authors.

Received 2024 December 6; Accepted 2024 December 24.

Abstract

Type 2 diabetes mellitus (T2DM) is marked by chronic hyperglycemia, gradually worsening β-cell failure, and insulin resistance. Glucotoxicity and oxidative stress cause β-cell failure by increasing reactive oxygen species (ROS) production, impairing insulin secretion, and disrupting transcription factors such as pancreatic and duodenal homeobox 1 (PDX-1) and musculoaponeurotic fibrosarcoma oncogene family A (MafA). Cluster determinant 36 (CD36), an essential glycoprotein responsible for fatty acid uptake, exacerbates oxidative stress and induces the apoptosis of β-cells under hyperglycemic conditions through pathways involving ceramide, thioredoxin-interacting protein (TXNIP), and Rac1-nicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated redoxosome formation. Targeting CD36 pathways has emerged as a promising therapeutic strategy. Oral hypoglycemic agents, such as metformin, teneligliptin, and pioglitazone, have shown protective effects on β-cells by enhancing antioxidant defenses. These agents reduce glucotoxicity via mechanisms such as suppressing CD36 expression and stabilizing mitochondrial function. Additionally, novel insights into the glutathione antioxidant system and its role in β-cell survival underscore its therapeutic potential. This review focuses on the key contribution of oxidative stress and CD36 to β-cell impairment, the therapeutic promise of antioxidants, and the need for further research to apply these findings in clinical practice. Promising strategies targeting these mechanisms may help preserve β-cell function and slow T2DM progression.

Keywords: CD36 antigens; Diabetes mellitus, type 2; Hyperglycemia; Insulin-secreting cells; Oxidative stress; Reactive oxygen species

KEY FIGURE

Highlights

• Glucotoxicity impairs β-cell function via oxidative stress and mitochondrial dysfunction.

• CD36 overexpression elevates oxidative stress, contributing to glucolipotoxicity.

• CD36 drives β-cell failure via ceramide-induced oxidative stress, TXNIP, and redox signals.

• Antioxidant effects of oral hypoglycemic agents help preserve β-cell function.

• Targeting CD36 and oxidative pathways can overcome β-cell dysfunction.

The Sulwon Award for Scientific Achievement is the Korean Diabetes Association’s highest scientific award and honors an individual who has excellently contributed to the progress in the field of diabetes and metabolism. The Sulwon Award is named after an emeritus professor, Eung Jin Kim, who founded Korean Diabetes Association. Prof. Kyu Chang Won received the 16th Sulwon Award at the 37th Spring Congress of Korean Diabetes Association, May 2 to 4 in 2024 at Changwon, Korea.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by persistent hyperglycemia, deteriorating β-cell function, and insulin resistance [1,2]. Among the numerous factors contributing to β-cell failure, glucotoxicity and oxidative stress have emerged as pivotal mechanisms that exacerbate β-cell dysfunction and promote apoptosis [2-4]. Chronic hyperglycemia not only impairs insulin secretion but also alters the transcriptional and post-translational regulation of key β-cell specific genes, leading to a progressive decline in pancreatic function [5]. The interactions between oxidative stress, lipid metabolism, and cellular signaling worsen these detrimental effects, creating a vicious cycle of β-cell dysfunction [2-4].

Our group has conducted extensive research over the years to reveal the mechanisms that cause β-cell failure in T2DM, primarily focusing on the role of glucolipotoxicity and oxidative stress. Central to this pathology is cluster determinant 36 (CD36), a multifunctional glycoprotein that regulates fatty acid uptake, glucose metabolism, and inflammatory signaling in β-cells [6,7]. Its overexpression under hyperglycemic and hyperlipidemic conditions contributes to oxidative stress and metabolic dysregulation, accelerating β-cell failure [7]. Additionally, ceramide, thioredoxin-interacting protein (TXNIP), Rac1-nicotinamide adenine dinucleotide phosphate oxidase (NOX) complexes, and redoxosomes such as p66Shc amplify oxidative damage through various signaling pathways, highlighting the complex interplay of lipid and glucose toxicity in β-cell pathology [8,9].

Recent research has also revealed the protective role of the glutathione (GSH) redox pathway and the potential of oral hypoglycemic agents (OHAs), such as metformin, teneligliptin, and pioglitazone, in mitigating glucotoxicity and preserving β-cell function [10-12]. This research supports the significance of targeting oxidative stress pathways and enhancing antioxidant defenses as promising therapeutic strategies to overcome β-cell dysfunction in T2DM [10-13]. This review offers a broad overview of the mechanisms underlying glucotoxicity and oxidative stress in pancreatic β-cells, the role of CD36 and associated signaling pathways, and the therapeutic implications of antioxidant systems and pharmacological interventions.

GLUCOTOXICITY AND OXIDATIVE STRESS

Glucotoxicity refers to the impairment of β-cell function caused by sustained exposure to high glucose levels. Evidence supports the concept of glucotoxicity, as persistent hyperglycemia impairs insulin secretion, alters the expression of β-cell-specific genes, and disrupts transcription factor activity [2,14]. As hyperglycemia advances, oxidative stress in β-cells is often driven by mitochondrial reactive oxygen species (ROS) generation during chronic insulin secretion, which overwhelms the cell’s metabolic capacity [15]. Furthermore, clinical studies have demonstrated increased oxidative stress in T2DM, marked by higher concentrations of oxidative damage markers, such as 8-hydroxy-deoxyguanine, and reduced levels of antioxidants, including GSH [16,17].

When glucose enters cells, it is metabolized primarily through glycolysis and the tricarboxylic acid cycle, generating adenosine triphosphate (ATP) to meet cellular energy demands. Uniquely, in pancreas β-cells, this generated ATP closes ATP-sensitive potassium channels, leading to calcium influx and triggering insulin granule exocytosis [18]. However, the production of ATP produces ROS as a consequence of oxidative phosphorylation. Under conditions of excessive glucose availability, the cell’s metabolic capacity is overwhelmed, leading glucose to flow into alternative metabolic pathways, including glyceraldehyde autooxidation, diacylglycerol synthesis with protein kinase C activation, and hexosamine biosynthesis, which further amplify oxidative stress through excessive ROS formation [14]. This oxidative stress is particularly harmful to β-cells because they exhibit lower levels of antioxidant enzymes, including superoxide dismutase (SOD) and catalase. This limited antioxidant capacity significantly compromises their ability to counteract oxidative stress, making them especially vulnerable to glucotoxicity-induced damage [4,19].

Mitochondrial dysfunction is a key factor leading to β-cell dysfunction during glucotoxicity [20]. In T2DM, chronic hyperglycemia leads to the downregulation of crucial mitochondrial enzymes, such as pyruvate carboxylase, citrate synthase, and reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase, which are necessary for glucose-stimulated insulin secretion (GSIS) [21,22]. This disruption impairs β-cells’ ability to respond to glucose, further exacerbating insulin secretion defects. Moreover, the overproduction of mitochondrial ROS during prolonged hyperglycemia induces oxidative stress, damaging mitochondrial membranes and proteins, which amplifies cellular dysfunction [23].

Hyperglycemia triggers the excessive formation of ROS through several mechanisms, including glucose oxidation, which generates superoxide and hydrogen peroxide [24], as well as the activation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, a critical ROS source in β-cells that exacerbates oxidative stress and impairs GSIS [25]. These ROS activate pro-inflammatory pathways, such as nuclear factor κB (NF-κB), which stimulates the release of proinflammatory cytokines, including interleukin 1β (IL-1β) [19]. The resulting increase in peroxynitrite formation causes singlestrand DNA breaks and triggers pyroptosis, a caspase-1-dependent mechanism of programmed cell death and inflammasome formation. These processes collectively lead to a continuous decline in β-cell viability and function under glucotoxicity [25].

At the molecular level, chronic hyperglycemia disrupts the expression of essential genes and transcription factors unique to β-cells that are critical for insulin secretion. A previous study on β-transgenic carcinoma (TC)-6 cells cultured in high glucose revealed a gradual decline in insulin secretion and mRNA levels, correlated with reduced activity of the transcription factor rat insulin promoter element 3b1 (RIPE3b1) [26]. Further research identified oxidative stress as a key contributor to these alterations, as it induces the expression of small heterodimer partner, suppressing essential transcription factors for the transcription of insulin genes such as pancreatic and duodenal homeobox 1 (PDX-1) and musculoaponeurotic fibrosarcoma oncogene family A (MafA) [5,27]. Oxidative stress also promotes the nuclear translocation of forkhead box O1 (FoxO1), which disrupts PDX-1 activity and causes the cytoplasmic mislocalization of MafA [28]. Moreover, chronic hyperglycemia induces epigenetic changes that exacerbate these disruptions, such as increased DNA methylation at the PDX-1 promoter [18]. Epigenetic modifications also impair the function of antioxidant defense genes, including SOD and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby worsening β-cell dysfunction and oxidative damage [29-31].

Additionally, hyperglycemia is often associated with iron overload, which exacerbates β-cell damage through ferroptosis, an iron-mediated form of programmed cell death [32,33]. Ferroptosis is characterized by mitochondrial shrinkage and lipid peroxidation, processes that are worsened in the presence of excessive iron [33]. Studies have shown that inhibitors of ferroptosis, such as ferrostatin-1, can enhance β-cell survival in models of diabetes, such as streptozotocin (STZ)-induced diabetic mice [34].

ROLE OF CD36 IN DIABETES AND β-CELL OXIDATIVE STRESS

CD36 is a multifunctional glycoprotein central to both physiological and pathological events, such as fatty acid metabolism, glucose regulation, inflammation, and cellular signaling [35-37]. Known also as fatty acid translocase (FAT) and glycoprotein IV (GPIV), CD36 is a member of the class B scavenger receptor family [6]. It is a 53-kDa protein composed of 471 amino acids and is primarily localized to the plasma membrane [38]. Structurally, CD36 exhibits a hairpin-like topology featuring two transmembrane domains, cytoplasmic tails at the N- and C-termini, and a significant extracellular loop that facilitates the binding of ligands (Fig. 1) [39], including long-chain fatty acids, oxidized low-density lipoproteins (oxLDLs), thrombospondin-1, and apoptotic cells [40]. The cytoplasmic tails of CD36 undergo post-translational modifications such as palmitoylation, which stabilize its structure and modulate its function [36,41].

Fig. 1.

Structure and post-translational modifications of cluster determinant 36 (CD36). CD36 exhibits a hairpin-like topology consisting of two transmembrane domains, cytoplasmic tails at the N- and C-termini, and a large extracellular loop. The extracellular loop mediates ligand binding to molecules such as long-chain fatty acids and oxidized low-density lipoproteins. Key structural features include the CD36 LIMP-II Emp Sequence Homology (CLESH) domain, which facilitates fatty acid uptake, and a hydrophobic binding pocket within the extracellular region. Post-translational modifications, including palmitoylation, glycosylation, and ubiquitylation, occur on the cytoplasmic tails and extracellular domain, playing crucial roles in regulating CD36’s stability, trafficking, and ligand-binding functionality. Adapted from Moon et al. [45].

CD36 is essential for the uptake and transport of fatty acids, particularly in adipocytes, hepatocytes, and pancreatic β-cells [8,41,42]. In pancreatic β-cells, CD36 functions as a fatty acid detector, coordinating the cellular response to metabolic changes by facilitating fatty acid uptake [8,42,43]. This process impacts insulin secretion and energy homeostasis [8]. However, CD36 overexpression has been associated with β-cell failure under conditions of hyperglycemia and hyperlipidemia, contributing to glucotoxicity and lipotoxicity [7,44]. Hyperglycemic conditions induce CD36 expression, leading to elevated free fatty acid (FFA) uptake and ROS production, which impair insulin secretion and promote β-cell apoptosis [45]. Supporting this, our experimental work showed that the treatment of insulin-1 (INS-1) cells with high glucose-induced glucotoxicity, characterized by insulin suppression, reduced PDX-1 mRNA expression, loss of GSIS, increased ROS levels, and significantly elevated CD36 expression. Notably, inhibiting CD36 restored insulin secretion and reduced oxidative stress [43]. These findings emphasize CD36’s pivotal role in mediating glucotoxicity and suggest that targeting CD36 could be a potential therapeutic strategy to counteract β-cell dysfunction in diabetes [45].

Furthermore, CD36 overexpression increases oxLDL uptake, inducing a shift in mitochondrial metabolism from oxidative phosphorylation to superoxide production [45,46]. This process often involves the activation of mitogen-activated protein kinase (MAPK) family kinases, including c-Jun N-terminal kinase (JNK) and p38. Such signaling cascades contribute to insulin resistance, tissue inflammation, and metabolic dysregulation [47]. Recent evidence in pancreas β-cells suggests that CD36-mediated oxLDL uptake induces endoplasmic reticulum (ER) stress leading to dysfunction and apoptosis through JNK activation and downstream pro-apoptotic signaling [48]. Remarkably, blocking CD36 with inhibitors such as sulfo-N-succinimidyl oleate (SSO) or siRNA has been shown to alleviate ER stress and β-cell dysfunction induced by high glucose [10].

Post-translational modifications, including palmitoylation and glycosylation, have a significant regulatory impact on CD36 stability, trafficking, and function [36,41,49]. For example, palmitoylation of CD36 by palmitoyl-transferases anchors it to the plasma membrane, enabling efficient fatty acid uptake [41]. Recent evidence suggests that CD36 palmitoylation contributes to inflammation in hepatocytes, underscoring its role in non-alcoholic steatohepatitis (NASH) [7,41]. Conversely, inhibition of palmitoylation reduces CD36 stability, promotes ubiquitination, and redirects the protein for degradation. This has also been shown to reduce inflammation in liver tissues and protect against NASH and metabolic dysregulation associated with aging [7,36,41]. These effects have been shown to suppress JNK signaling, activate AMP-activated protein kinase (AMPK) pathways, and enhance fatty acid β-oxidation [41,50]. Similarly, glycosylation at specific residues within CD36’s extracellular domain influences its ligand-binding capacity and localization [49]. However, the regulatory mechanisms linking these modifications to specific metabolic outcomes require further investigation [7].

In clinical studies, soluble CD36 (sCD36) has become a promising biomarker for metabolic disorders [51]. Increased plasma sCD36 levels have been shown to correlate with insulin resistance, highlighting its utility in identifying individuals at risk of metabolic dysregulation [52]. Furthermore, increased sCD36 levels have been observed in diabetic patients with albuminuria, suggesting its relevance as a marker for diabetic vascular complications and its potential role in monitoring disease progression and complications [53,54]. Beyond its diagnostic implications, targeting CD36 has demonstrated therapeutic promise in managing metabolic and inflammatory disorders. For instance, the CD36 antagonist salvianolic acid B has been found to reduce visceral fat, improve glucose tolerance, and alleviate inflammation in animal models of obesity and insulin resistance [55]. Similarly, ezetimibe inhibits CD36 and reduces fatty acid influx, offering protective effects against β-cell dysfunction in T2DM; interestingly, supporting its protective role, a recent phase 4 clinical trial demonstrated that a combination of rosuvastatin and ezetimibe significantly improved homeostasis model assessment of β-cell function compared to rosuvastatin monotherapy [56,57]. In addition, metformin has been reported to inhibit CD36-mediated ER stress and oxidative stress, protecting against T2DM-related β-cell dysfunction [10]. Antioxidants have also been shown to reduce oxLDL uptake by suppressing CD36 expression and enhancing insulin secretion through PDX-1 activation [58].

CD36-DEPENDENT STRESS PATHWAYS: INTERPLAY OF CERAMIDE, TXNIP, AND REDOX SIGNALING IN β-CELL FAILURE

Prolonged FFA exposure induces apoptosis in human islets. Apoptosis is mediated by caspase activation, with partial involvement of non-caspase proteases and the ceramide pathway [59]. Ceramide signaling is crucial to the onset of β-cell failure in T2DM [60,61]. However, the exact mechanisms remain unclear.

In our study using INS-1 cells, we demonstrated that ceramide induces β-cell apoptosis by promoting mitochondrial dysfunction, activating NF-κB, and upregulating TXNIP, an endogenous inhibitor of thioredoxin, which disrupts redox balance and reduces insulin gene expression. Notably, we found that CD36 inhibition effectively blocked ceramide-induced NF-κB activation and TXNIP expression, restoring thioredoxin activity, insulin production, and β-cell survival [8].

Additionally, TXNIP is a critical regulator mediating ER stress, inflammation, and apoptosis in β-cells. Under ER stress, TXNIP expression is significantly increased, especially in β-cells [62]. ER stress-induced TXNIP expression contributes to β-cell apoptosis by triggering inflammasome activation and IL-1β production [62]. These result in mitochondrial dysfunction, increased ROS, and β-cell apoptosis. Our previous study demonstrated that pretreatment with the CD36 inhibitor SSO markedly restored the Akt activity and counteracted the suppressive effect of ceramide on insulin and PDX-1 mRNA expression. CD36 inhibition also reduced the apoptotic response to ceramide by suppressing cleaved caspase 3 expression. Consequently, it restored mitochondrial function, reduced oxidative stress, and preserved β-cell survival [8].

We further explored the mechanisms of β-cell dysfunction under hyperglycemic conditions. Previous research using the zucker diabetic fatty (ZDF) rat model demonstrated that hyperglycemia accelerates the Rac1-Nox-ROS-JNK1/2 signaling pathway, elevating oxidative stress, mitochondrial dysfunction, and β-cell apoptosis [63]. In our study conducted with INS-1 cells and human 1.1b4 cells, a high glucose concentration upregulated CD36 expression via Rac1-NADPH oxidase activity, inducing ROS production, mitochondria dysfunction, and cell apoptosis. Rac1 activated NADPH oxidase, generating ROS and oxidative stress. NADPH oxidase activity promoted CD36 expression and membrane localization. CD36 facilitated fatty acid uptake and resulted in mitochondrial dysfunction and β-cell failure. Furthermore, inhibition of Rac1 with NSC23766 or Rac1-siRNA suppressed NADPH oxidase activity, reduced ROS levels, downregulated CD36 expression, and preserved β-cell viability, highlighting the Rac1-CD36 axis as a potential therapeutic target for preventing glucose-induced β-cell dysfunction [64].

Our group later focused on “redoxosomes” (redox-active endosomes), first introduced in 2006 [65]. These specialized structures contain components such as the Rac-1 NOX complex, enzymes associated with ROS processing, and sensors that regulate NOX activity [63,65]. Redoxosomes represent a specific subset of signaling endosomes and play a crucial role in modulating redox-dependent effector functions by managing ROS as signaling molecules [65].

Research using INS-1 cells was conducted to investigate the mechanism of ceramide-induced redoxosome activation in pancreatic β-cells [9]. Ceramide activated Src-Vav2 signaling, leading to Rac1-mediated NADPH oxidase activation and increased ROS production, which promoted redoxosome formation. Simultaneously, JNK signaling facilitated the phosphorylation and mitochondrial translocation of p66Shc, resulting in the oxidation of peroxiredoxin-3 and mitochondrial dysfunction [9]. The protein p66Shc oxidized cytochrome c, contributing to hydrogen peroxide production. JNK and p38 activated p66Shc by phosphorylating its S36 residue [66], thus unleashing its pro-oxidant and pro-apoptotic functions [66]. CD36, a key mediator in this pathway, was activated by ceramide, amplifying oxidative stress, mitochondrial dysfunction, and β-cell apoptosis [9]. Additionally, inhibition of CD36 effectively decreased ceramide-induced JNK and p66Shc serine 36 phosphorylation, preserving mitochondrial function, enhancing antioxidant defenses (thioredoxin-2 and peroxiredoxin-3), and restoring GSIS, suggesting CD36 as a potential therapeutic target to mitigate ceramide-induced β-cell dysfunction [9].

MOLECULAR MECHANISMS OF GLUTATHIONE-MEDIATED β-CELL PROTECTION

The GSH antioxidant system is critical in maintaining pancreatic β-cell function and mitigating insulin resistance by neutralizing oxidative stress [11]. Under diabetic conditions, high glucose levels disrupt the cellular redox balance, deplete NADPH, and reduce GSH regeneration, leading to ROS accumulation and β-cell dysfunction [25]. Studies have revealed distinct molecular pathways through which the GSH system preserves β-cell integrity and insulin secretion, particularly involving mitochondrial aldehyde dehydrogenase 2 (ALDH2) and abelson (c-Abl) tyrosine kinase [67,68].

We examined the relationship between ALDH2 activation and the glucose-6-phosphate dehydrogenase (G6PD)-GSH antioxidant pathway in β-cells and found that cyclin-dependent kinase 5 is activated under hyperglycemic conditions, promoting G6PD degradation and decreasing NADPH availability [67]. This cascade suppresses GSH regeneration, exacerbates ROS production, and culminates in mitochondrial damage and β-cell death. Notably, pharmacological activation of ALDH2 using aldehyde dehydrogenase activator-1 (ALDA1) stabilized G6PD activity, restored NADPH levels, and protected mitochondrial function. This process involved the ALDH2-AMPK-sirtuin 2 (SIRT2) axis, where AMPK activation enhanced NAD+ production, promoting SIRT2-mediated β-cell survival. Further experiments highlighted the role of hydrogen sulfide as a downstream effector of ALDH2. Treatment with sodium hydrogen sulfide elevated hydrogen sulfide levels, restored ALDH2 activity, and upregulated SIRT2 and G6PD expression, thereby enhancing the GSH antioxidant response and safeguarding β-cell function. Inhibition of SIRT2 negated these protective effects, underscoring its essential role in this axis. Overall, these findings suggest that targeting the ALDH2-AMPK-SIRT2 pathway may offer a novel therapeutic approach for diabetes by preserving β-cell function and insulin secretion [67].

Complementing this, our research focused on investigated the impact of c-Abl tyrosine kinase on oxidative stress-induced β-cell dysfunction [68]. Chronic oxidative stress induces β-cell dysfunction and loss in type 1 diabetes mellitus and T2DM [15,69-71], with c-Abl activating protein kinase c delta (PKCδ) to promote DNA damage and β-cell apoptosis [72,73]. Notably, ferroptosis, a form of non-apoptotic cell death triggered by oxidative stress, is suppressed by glutathione peroxidase 4 (GPX4), which is essential for β-cell survival [74-76]. Estrogen-related receptor gamma (ERRγ) plays a critical role in regulating ROS homeostasis and mitochondrial function, and its deficiency leads to β-cell dysfunction and impaired glucose tolerance [77-80]. Based on these prior studies, we conducted a study that revealed that c-Abl activation contributes to ferroptosis-like cell death in pancreatic β-cells through the c-Abl-PKCδ pathway. Under oxidative stress conditions induced by STZ or hydrogen peroxide, activation of this pathway led to GPX4 degradation and cell death. Inhibition of c-Abl using the selective inhibitor GNF2 suppressed GPX4 degradation, restored the GSH balance, and enhanced β-cell survival. Additionally, GNF2 treatment upregulated ERRγ and glutaminase 1 (GLS1), improving the GSH/glutathione disulfide (GSSG) ratio and promoting insulin secretion. Further experiments with ERRγ agonists demonstrated increased GPX4 stability, while ERRγ inhibition counteracted the protective effects of cAbl inhibition, promoting cell death. These findings highlight the critical role of c-Abl and ERRγ in regulating the GSH antioxidant system under oxidative stress, suggesting that pancreatic islet survival could be promoted in diabetes by targeting this pathway [68].

Together, these studies provide compelling evidence that the GSH antioxidant system is vital for maintaining β-cell function and combating oxidative stress in diabetes. By elucidating the mechanisms underlying the ALDH2-AMPK-SIRT2 axis and the c-Abl-PKCδ pathway, they offer promising therapeutic targets to enhance β-cell survival, improve insulin secretion, and mitigate insulin resistance in diabetes management [67,68].

ANTIOXIDANT MECHANISMS OF CURRENT DIABETES MEDICATIONS: INSIGHTS FROM METFORMIN, TENELIGLIPTIN, AND PIOGLITAZONE

We investigated the mechanisms by which diabetes medications protect against β-cell glucotoxicity through their antioxidant properties. Previous studies have shown that treatment with troglitazone in diabetic animal models preserves PDX-1 DNA binding activity and insulin gene expression, suggesting its potential as a strategy to mitigate glucotoxicity [81]. In our in vivo studies, we explored the antioxidant-mediated β-cell-protective mechanisms of metformin, teneligliptin, and pioglitazone [10-12].

Teneligliptin is a third-generation dipeptidyl peptidase-4 (DPP-4) inhibitor that has been proven to enhance blood glucose control and stabilize β-cell function while also being associated with a low risk of hypoglycemia [82,83]. Metformin is the most commonly used medication for T2DM, and its efficacy has also been well-established. However, whether these two drugs contribute to β-cell preservation is under debate, and their mechanisms remain unclear [10,12]. Therefore, based on previous studies, we researched the mechanisms by which they contribute to β-cell preservation.

Furthermore, we studied how metformin alleviates oxidative and ER stress to suppress CD36 expression in rat islets exposed to high glucose [10]. Metformin was found to restore insulin and Pdx-1 expression, improve GSIS, reduce ROS production, and block CD36 expression induced by ER stressors and high glucose. Additionally, metformin-induced CD36 inhibition reduced fatty acid influx and ROS production, thereby decreasing apoptosis in high glucose-treated β-cells [12]. Furthermore, additional research revealed that teneligliptin enhances the expression and activity of the SIRT1 protein via ubiquitin-specific protease 22 (USP22), promoting SIRT3-mediated deacetylation of peroxiredoxin 3 (PRDX3), which inhibits PRDX3 hyperoxidation and strengthens mitochondrial antioxidant defenses. This study demonstrated that teneligliptin acts as a negative regulator of PRDX3 acetylation through USP22-mediated SIRT1 activation [12].

Additionally, we revealed that pioglitazone prevents high glucose-induced pancreatic β-cell dysfunction by activating the AMPK-GLS1 axis via the GSH antioxidant system [11]. Pioglitazone not only contributes to improving and preserving β-cell function as an insulin sensitizer but also reduces major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality [84-88]. In this study, pioglitazone was found to selectively protect against β-cell dysfunction caused by high glucose by activating the AMPK-GLS1 axis, stabilizing GLS1 through heat shock protein 75 (HSP75)/tumor necrosis factor receptor-associated protein 1 (TRAP1), and increasing the GSH/GSSG ratio to enhance mitochondrial function and antioxidant defense while reducing maladaptive ER stress and promoting adaptive UPR through a peroxisome proliferator-activated receptor γ (PPARγ)-independent mechanism [11]. Therefore, this study confirms that pioglitazone activates AMPK, which counteracts high glucose effects by stabilizing GLS1 through HSP75/TRAP1, suggesting that GLS1 stability may protect against β-cell dysfunction via the GSH antioxidant system [11].

The synthesis of the above studies revealed that each of the abovementioned anti-diabetic agents acts on oxidative stress pathways to prevent cell damage caused by oxidative processes, thereby playing a role in preserving β-cell function (Fig. 2). Metformin acts as a CD36 inhibitor, while pioglitazone inhibits ROS production by activating the AMPK-GSH mechanism. Finally, teneligliptin contributes to inhibiting mitochondrial PRDX3, thereby reducing mitochondrial H₂O₂ production, and this mechanism helps prevent β-cell apoptosis [10-12].

Fig. 2.

Cluster determinant 36 (CD36)-mediated oxidative stress pathways and therapeutic strategies in β-cell dysfunction. Ceramide- induced CD36 activation triggers Src-Vav2-Rac1 signaling, leading to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and reactive oxygen species (ROS) production. ROS further activates the c-Jun N-terminal kinase (JNK)-p66Shc pathway and upregulates thioredoxin-interacting protein (TXNIP), which inhibits thioredoxin, resulting in mitochondrial dysfunction and apoptosis. CD36 inhibitors (e.g., metformin, ezetimibe), pioglitazone, and teneligliptin mitigate these effects by suppressing ROS production, enhancing antioxidant defenses, and stabilizing mitochondrial function. GTP, guanosine triphosphate; NOX, NADPH oxidase; PRDX3, peroxiredoxin 3; TXRN2, thioredoxin reductase 2; PTP, permeability transition pore.

CONCLUSIONS

Pancreatic β-cell dysfunction remains a cornerstone of T2DM pathophysiology, driven by complex interactions between glucotoxicity, oxidative stress, and lipid metabolism. Chronic hyperglycemia exacerbates oxidative damage by increasing ROS production, activating pro-inflammatory pathways, and disrupting β-cell-specific transcription factors. CD36 has emerged as a critical mediator in this process, linking fatty acid uptake to oxidative stress, ER stress, and apoptotic signaling, thereby accelerating β-cell failure.

Advances in understanding the molecular pathways linking CD36, ceramide signaling, and oxidative stress have identified novel therapeutic targets, such as TXNIP, Rac1-NOX complexes, and redoxosomes. Furthermore, the antioxidant properties of OHAs such as metformin, teneligliptin, and pioglitazone highlight their potential to alleviate glucotoxicity and improve β-cell survival through mechanisms independent of their primary glucose-lowering effects.

As our understanding of these intricate pathways deepens, it becomes increasingly evident that therapeutic strategies focusing on reducing oxidative stress, enhancing antioxidant defenses, and targeting key mediators such as CD36 hold promise for preserving β-cell function and preventing diabetes progression. It is recommended that future research validate these findings through clinical trials and explore personalized approaches to optimize β-cell protection, ultimately improving outcomes for T2DM patients.

Notes

CONFLICTS OF INTEREST

Kyu Chang Won has been honorary editors of the Diabetes & Metabolism Journal since 2020. He was not involved in the review process of this article. Otherwise, there was no conflict of interest.

FUNDING

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) RS-2023-00208709 (to Kyu Chang Won) and a grant from the Korea government’s Institute of Information and Communications Technology Planning & Evaluation (IITP) (RS-2022-II220965), Development of diabetes patient’s healthcare digital twin technology based on continuous lifelog variables.

Acknowledgements

None

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