Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in β-Cells
Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in β-Cells
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DOI：
10.2337/db19-0944
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发表时间：
2020-06-01
期刊：
影响因子：
7.7
通讯作者：
Eliasson, Lena
中科院分区：
文献类型：
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作者：
Nagao, Mototsugu;Esguerra, Jonathan L. S.;Eliasson, Lena
肥胖是2型糖尿病（T2D）的危险因素；然而，并不是所有的肥胖者都会患上这种疾病。在本研究中，我们旨在探讨T2D和非T2D （ND）供者胰岛胰岛素分泌能力差异的原因，特别是肥胖供者（BMI >= 30 kg/m(2)）。肥胖t2dm供体胰岛胰岛素分泌减少，β细胞胞吐减少，脂肪酸转位酶CD36表达升高。我们验证了CD36是降低胰岛素分泌能力的关键分子的假设。事实上，CD36过表达导致胰岛素分泌减少，胞吐受损，颗粒对接减少。同时伴有胞外蛋白SNAP25、STXBP1和VAMP2的表达减少，这可能是因为CD36诱导了胰岛素受体底物（IRS）蛋白的下调，抑制了胰岛素信号磷脂酰肌醇3-激酶/AKT通路，增加了转录因子fox01的核定位。CD36抗体处理人β细胞系endoc - β H1后，IRS1和胞外蛋白水平升高，颗粒对接改善，胰岛素分泌增强。我们的研究结果表明，肥胖T2D供体的β细胞有功能失调的胞吐，可能是由于CD36表达差异所代表的脂质处理异常。因此，CD36可能是限制与肥胖相关的T2D中β细胞功能的关键分子。
Obesity is a risk factor for type 2 diabetes (T2D); however, not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI >= 30 kg/m(2)). Islets from obese donors with T2D had reduced insulin secretion, decreased beta-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human beta-cell line EndoC-beta H1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that beta-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit beta-cell function in T2D associated with obesity.