Diabetes Metab J.  2020 Apr;44(2):222-233. 10.4093/dmj.2020.0053.

The Role of CD36 in Type 2 Diabetes Mellitus: β-Cell Dysfunction and Beyond

• Moon JS
• Karunakaran U
• Suma E
• Chung SM
• Won KC

• KMID: 2502403
• DOI: http://doi.org/10.4093/dmj.2020.0053

Abstract

Impaired β-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving β-cell function, it is essential to understand the cause and mechanisms about the progression of β-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of β-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic β-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic β-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.

Keyword

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

Figure

• 

  Fig. 1 Cluster determinant 36 (CD36) structure and post-translational modifications. CD36 has two transmembrane domains and two small cytoplasmic tails that contain four palmitoylation sites. The C-terminus contains two ubiquitylation sites and the N-terminal transmembrane domain contains two motifs (G12xxxG16xxxA20 and A20xxG23) that are responsible for dimerization. The large extracellular loop contains 10 N-linked glycosylation sites and two phosphorylation sites. There are two binding entrance in extracellular domain: the one is hydrophobic pocket bind with a variety of ligands, and the other is for fatty acid transport. CLESH, CD36, LIMP-2, Emp sequence homology.

• 

  Fig. 2 Cluster determinant 36 (CD36)-induced signal transduction and damage in pancreatic β-cells, and its mechanisms. Binding of a variety of ligands to CD36 on the plasma membrane initiates the assembly of a redoxosome (Src-Rac1-nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) complex. Redoxosome activation induces c-Jun N-terminal kinases (JNK) activation, thereby leading to p66Shc mediated mitochondrial peroxiredoxin-3 oxidation via thioredoxin-2 downregulation. Moreover, this complex activates nuclear factor κB (NF-κB) which in turn contributes to the impaired mitochondrial defense leads to pancreatic β-cell failure. Besides future studies are warranted to examine the relationship between CD36 and nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing protein 3 (NLRP3) inflammasome activation in the pancreatic β-cell dysfunction and failure. Activation of CD36 signaling by oxidized low-density lipoprotein (OX-LDL) initiates the activation of the signalosome complex and inflammatory programs such as the production of reactive oxygen species (ROS) and p66Shc contribute to the pathogenic pathway that links to β-cell dysfunction and failure. GTP, guanosine triphosphate; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; TXNIP, thioredoxin-interacting protein.

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