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      The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

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          Abstract

          CD36 is a multiligand receptor contributing to glucose and lipid metabolism, immune response, inflammation, thrombosis, and fibrosis. A wide range of tissue expression includes cells sensitive to metabolic abnormalities associated with metabolic syndrome and diabetes mellitus (DM), such as monocytes and macrophages, epithelial cells, adipocytes, hepatocytes, skeletal and cardiac myocytes, pancreatic β-cells, kidney glomeruli and tubules cells, pericytes and pigment epithelium cells of the retina, and Schwann cells. These features make CD36 an important component of the pathogenesis of DM and its complications, but also a promising target in the treatment of these disorders. The detrimental effects of CD36 signaling are mediated by the uptake of fatty acids and modified lipoproteins, deposition of lipids and their lipotoxicity, alterations in insulin response and the utilization of energy substrates, oxidative stress, inflammation, apoptosis, and fibrosis leading to the progressive, often irreversible organ dysfunction. This review summarizes the extensive knowledge of the contribution of CD36 to DM and its complications, including nephropathy, retinopathy, peripheral neuropathy, and cardiomyopathy.

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          Most cited references181

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          Diabetic neuropathy

          The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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            Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.

            Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells.
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              CD36 is a sensor of diacylglycerides.

              Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria, fungi and protozoa. The breadth of the ligand repertoire seems unusual, even if one considers that TLR2 may form heteromers with TLRs 1 and 6 (ref. 12), and it is likely that additional proteins serve as adapters for TLR2 activation. Here we show that an N-ethyl-N-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the R-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36(obl) macrophages readily detect S-MALP-2, PAM(2)CSK(4), PAM(3)CSK(4) and zymosan, revealing that some--but not all--TLR2 ligands are dependent on CD36. Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                11 August 2020
                August 2020
                : 9
                : 8
                : 1877
                Affiliations
                Department of Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; carmon12@ 123456gmail.com
                Author notes
                Author information
                https://orcid.org/0000-0001-8109-7112
                https://orcid.org/0000-0003-1561-346X
                Article
                cells-09-01877
                10.3390/cells9081877
                7465275
                32796572
                69daa488-49ba-4eb6-a0c8-1830922fb86c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 July 2020
                : 09 August 2020
                Categories
                Review

                cardiomyopathy,hyperglycemia,fatty acids,inflammation,insulin resistance,lipotoxicity,nephropathy,neuropathy,oxidative stress,retinopathy

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