Aims/hypothesis

Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.

Methods

Our multi-disciplinary approach included hyperinsulinaemic–euglycaemic clamps in Cd36^−/− and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion.

Results

Insulin clamps showed that Cd36^−/− mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.

Conclusions/interpretation

CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism.

Trial registration

Clinicaltrials.gov NCT03012386

Data availability

The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/) under accession code GSE235988 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988).

Graphical Abstract

中文翻译：

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CD36 缺乏症患者微血管胰岛素抵抗伴肌肉葡萄糖处置增强

 目标/假设

微血管功能障碍会导致胰岛素抵抗。CD36 是一种脂肪酸转运蛋白和胰岛素信号传导调节剂，在微血管内皮细胞中含量丰富。携带 CD36 编码变体 rs3211938 的次要等位基因 （G） 的人类 CD36 表达降低 50%，并表现出内皮功能障碍。我们旨在确定 G 等位基因携带者是否对胰岛素有微血管抵抗，如果是，这如何影响葡萄糖处置。

 方法

我们的多学科方法包括 Cd36 ^{- / -} 和野生型小鼠以及 CD36 缺陷 50% 个体的高胰岛素正常血糖钳夹，以及对照对应物，以及具有/没有 CD36 耗竭的原代人源性微血管内皮细胞。

 结果

胰岛素夹显示 Cd36 ^−/− 小鼠胰岛素刺激的葡萄糖处置增强，但血管顺应性和毛细血管灌注降低。腓肠肌的活体显微镜检查显示经毛细血管胰岛素通量未改变。CD36 缺陷的人具有更好的胰岛素刺激葡萄糖处理能力，但胰岛素无反应的微血管血容量 （MBV）。CD36 耗尽的人微血管细胞显示 Akt 、内皮 NO 合酶和 NO 生成的胰岛素激活受损。因此，在 CD36 缺乏症中，微血管胰岛素抵抗与葡萄糖处置的胰岛素敏感性增强自相矛盾地相关。

结论/解释

CD36 缺乏症先前已被证明可以减少肌肉/心脏脂肪酸的摄取，而在这里我们表明它降低了血管顺应性和胰岛素增加 MBV 以优化葡萄糖和氧气输送的能力。肌肉和心脏通过转录重塑来响应这些能量挑战，为胰岛素刺激的糖酵解通量启动组织。氧输送减少激活缺氧诱导因子、生长因子的内皮释放或细胞内小囊泡可能介导这种适应。在 CD36 缺陷中靶向 NO 生物利用度可能有益于微血管系统和肌肉/心脏代谢。

 试用注册

Clinicaltrials.gov NCT03012386

 数据可用性

本研究中生成的 RNAseq 数据已存入 NCBI 基因表达综合 （www.ncbi.nlm.nih.gov/geo/） 中，登录代码为 GSE235988 （https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988）。

 图形摘要