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.
Citations
Citations to this article as recorded by
Small‐Molecule Sarco/Endoplasmic Reticulum Ca2+‐ATPase Activators Reverse Methylglyoxal‐Induced Inhibition through Nonantioxidant Mechanisms Carlos Cruz‐Cortés, Silvia Micháliková, Petronela Rezbáriková, L. Michel Espinoza‐Fonseca, Jana Viskupičová ChemMedChem.2026;[Epub] CrossRef
Bone Marrow Mesenchymal Stromal Cells and Their Derived Extracellular Vesicles Protect Pancreatic Beta‐TC‐6 Cells From Hypoxia‐Induced Injury via miR‐539‐3p‐Mediated Downregulation of CD36 Expression Na Lin, Yaoyao Liang, Minying Tang, Fei Liu, Liuyan Chen, Lvying Wu, Yunfeng Fu, Zhuoyu Li, Lingfeng Zhu, Jin Chen, Yuelin Zhang Stem Cells International.2026;[Epub] CrossRef
Potential Involvement of PI3K/AKT Signaling Pathway in the Protective Effects of Rhinacanthus nasutus Against Diabetic Nephropathy-Induced Oxidative Stress Junyu Liu, Yehao Lin, Xudong Yi, Min Zhang, Pharkphoom Panichayupakaranant, Joseph Buhagiar, Haixia Chen Antioxidants.2026; 15(2): 252. CrossRef
Amylin and parameters of carbohydrate and lipid metabolism in patients with type 2 diabetes mellitus in the Azerbaijani population Z.G. Akhmedova, D.I. Kagramanova INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine).2026; 22(1): 35. CrossRef
Advanced Studies in Molecular and Metabolic Mechanisms of Diabetes: Pathogenic Crosstalk, Biomarkers, and Translational Therapeutics Iliyana Sazdova, Hristo Gagov, Nikola Hadzi-Petrushev, Marina Konaktchieva, Rossitza Konakchieva, Mitko Mladenov Applied Sciences.2026; 16(6): 3027. CrossRef
Chlorogenic acid and gallic acid synergistically reduce hyperglycemia and hyperlipidemia in diabetic BALB/c mice Mudassir Hassan, Muhammad Ali, Javaria Altaf, Faisal Saeed Awan Scientific Reports.2026;[Epub] CrossRef
Effects of prolonged exposure to 2.45 GHz electromagnetic fields on mouse health over a 5-month period Zhichun Lv, Yunqiang Wu, Ke Zhao, Jingjing Li, Huiying Gao, Xiongwei Zhao, Siyu Li, Anyu Xu, Jingfei Li, Yuyang Cai, Shensi Xiang, Hui Chen, Ronghua Yin, Miao Yu, Xiaoming Yang, Changyan Li Ecotoxicology and Environmental Safety.2026; 315: 120106. CrossRef
CD36 serves as a potential drug-target to alleviate inflammation in atherosclerosis via leonurine-mediated blockade of its activation pocket Ge Lin, Ai-Qiu Chi, Sheng-Yang Cai, Ya-Meng Zhang, Yu-Chen Ren, Xu Lu, Chen Sun, Xue-Pan Mu, Igor Ying Zhang, Jing-Wei Weng, Meng-Yao Li, Ying Chen, Yi Zhun Zhu, Bei-Bei Tao, Yi-Chun Zhu Free Radical Biology and Medicine.2026; 251: 256. CrossRef
Biochemical Mechanisms of Cellular Stress Adaptation in the Pathogenesis of Chronic Diseases Joanna Lemanowicz, Sylwester M. Kloska, Anetta Siwik-Ziomek, Paweł Kołaczyk, Urszula Wnuk Lipińska, Anna Kloska Molecules.2026; 31(9): 1381. CrossRef
Mitochondrial dysfunction–driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications Satyam Yadav, Gautam Kumar, Sumit Kumar, Khadga Raj Aran, Sourabh Kosey Molecular Biology Reports.2026;[Epub] CrossRef
Compensated But Failing: Early β‐Cell Dysfunction Under Normoglycemia in Children and Adolescents With Overweight and Obesity Paulina Correa‐Burrows, Estela Blanco, Raquel Burrows Diabetes/Metabolism Research and Reviews.2026;[Epub] CrossRef
Targeting PGC-1α by miRNA-374 Simultaneously Improve β-Cell Dysfunction and Suppress Hepatic Glucose Overproduction Ji-Won Kim, Joonyub Lee, Young-Hye You, Chan-Hee Oh, Heon-Seok Park, Eun Young Lee, Seung-Hwan Lee, Seung-Hyun Ko, Ji-Ho Park, Kun-Ho Yoon Diabetes & Metabolism Journal.2026; 50(3): 535. CrossRef
Network pharmacology and experimental approaches to elucidate the mechanism of Niruryadi Gulika in protecting pancreatic β-cells in Type 2 diabetes Rajappan Chandra Satish Kumar, Chittaranjan Das, Dhayalan Kalavathy GokulRaj, Murali Krishna Prasad, Mothishwaran Bhuvaneshwaran, Kunka Mohanram Ramkumar In Silico Research in Biomedicine.2026; 2: 100366. CrossRef
Metformin beyond Glycemic Control: New Mechanistic Insights and Expanding Therapeutic Horizons Eugene Han, Jung Ho Nam, Insuk Lee, Cheol Ryong Ku, Yong-ho Lee Diabetes & Metabolism Journal.2026; 50(3): 435. CrossRef
Molecular mechanisms and structure—activity relationships of natural polysaccharides in ameliorating type 2 diabetes mellitus: a comprehensive review Ying Zhou, Ruodi Yang, Qingfeng Wang, Jiaxin Li, Yufeng Yang, Yan Shi, Juntong Liu Frontiers in Nutrition.2026;[Epub] CrossRef
Cholesterol, high-density lipoprotein, and glucose (CHG) index and incident impaired fasting glucose in Chinese adults: a retrospective longitudinal cohort study Duo Yang, Renzhe Lin, Sen Li, Shujun Ye, Zitian Luo, Huankai Zhang, Si Wu, Longsheng Zhang Frontiers in Nutrition.2026;[Epub] CrossRef
Risk factors for carotid plaque in type 2 diabetes mellitus: The need for more extensive data Xing-Yun Yang, Jia-Hui Zhao, Shi-Song Wang, Cun-Yi Zou World Journal of Diabetes.2026;[Epub] CrossRef
The efficacy and safety of Chaihu guizhi ganjiang tang for type 2 diabetes mellitus: a systematic review and meta-analysis Quan Zhang, Yujie Ouyang, Shurui He, Chunguang Xie, Xiaoxu Fu Frontiers in Pharmacology.2026;[Epub] CrossRef
Allosteric Modulation of Mitochondrial Complex I By Succinylation of NDUFV2 Subunit Under Hyperglycemic Conditions: Implications for Ros-Mediated Β-Cell Apoptosis in Type 2 Diabetes Zainab Nasser Hussein Jurnal MIPA dan Pembelajarannya.2026; 6(6): 1. CrossRef
The Role of Platelets in the Pathogenesis of Diabetes Mellitus and Comorbid Conditions E. V. Kirienkova, A. G. Goncharov, V. V. Shupletsova, A. A. Komar, R. M. Tursunov, L. S. Litvinova Cell and Tissue Biology.2026; 20(6): 605. CrossRef
Curcumin modulates the adipose FBN1–Asprosin axis and improves metabolic dysfunction in a rat model of type 2 diabetes Abdolvahed Safarzaei, Hamid Hafezinouri, Hamed Fanaei Metabolism Open.2026; 32: 100500. CrossRef
Polygonatum sibiricum polysaccharides enhance pancreatic β-cell function in diabetic zebrafish by mitigating mitochondrial oxidative damage via the AMPK-SIRT1 pathway Fan Lin, Wenjing Yu, Ping Li, Shuyao Tang, Yitong Ouyang, Liya Huang, Di Wu, Shaowu Cheng, Zhenyan Song Frontiers in Nutrition.2025;[Epub] CrossRef
Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats Milena Cremer de Souza, Maria Luisa Gonçalves Agneis, Karoliny Alves das Neves, Matheus Ribas de Almeida, Geórgia da Silva Feltran, Ellen Mayara Souza Cruz, João Paulo Ferreira Schoffen, Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva International Journal of Molecular Sciences.2025; 26(10): 4652. CrossRef
From Glucotoxicity to Lung Injury: Emerging Perspectives on Diabetes-Associated Respiratory Complications Hongmei Yu, Jie Liu, Xiaojuan He Lung.2025;[Epub] CrossRef
Quercetin as an Anti-Diabetic Agent in Rodents—Is It Worth Testing in Humans? Tomasz Szkudelski, Katarzyna Szkudelska, Aleksandra Łangowska International Journal of Molecular Sciences.2025; 26(15): 7391. CrossRef
Preclinical Evaluation of 2-Aminobenzothiazole Derivatives: In Silico, In Vitro, and Preliminary In Vivo Studies as Diabetic Treatments and Their Complications Natalia Reyes-Vallejo, Miguel Valdes, Adelfo Reyes-Ramírez, Juan Andres Alvarado-Salazar, Alejandro Cruz, Erik Andrade-Jorge, Jessica Elena Mendieta-Wejebe Molecules.2025; 30(16): 3427. CrossRef
Metal organic frameworks (MOFs) synthesis and their use as a loading agent in oxidative stress-based diseases Muhammad Saqib Saif, Sana Batool, Yusra Majeed, Asadullah, Tuba Tariq, Li Haitao, Yanjun Duan, Ghazala Mustafa, Murtaza Hasan Journal of Environmental Chemical Engineering.2025; 13(5): 118725. CrossRef
Synergism of Synthetic Sulfonamides and Natural Antioxidants for the Management of Diabetes Mellitus Associated with Oxidative Stress Ancuța Dinu (Iacob), Luminita-Georgeta Confederat, Ionut Dragostin, Ionela Daniela Morariu, Dana Tutunaru, Oana-Maria Dragostin Current Issues in Molecular Biology.2025; 47(9): 709. CrossRef