Diabetes Metab J.  2025 Jan;49(1):1-12. 10.4093/dmj.2024.0796.

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

• Park IR
• Chung YG
• Won KC

• KMID: 2563264
• DOI: http://doi.org/10.4093/dmj.2024.0796

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.

Keyword

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

Figure

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  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].

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  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.

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