Shibao Cyndya A, Peche Vivek S, Pietka Terri A, Samovski Dmitri, Williams Ian M, Abumrad Naji N, Gamazon Eric R, Goldberg Ira J, Wasserman David H, Abumrad Nada A
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Division of Nutritional Sciences and Obesity Research, Washington University School of Medicine, St Louis, MO, USA.
Diabetologia. 2025 Mar;68(3):662-675. doi: 10.1007/s00125-024-06292-4. Epub 2024 Nov 6.
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.
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.
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.
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 ).
目的/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调节因子，在微血管内皮细胞中大量存在。携带CD36编码变体rs3211938次要等位基因（G）的人，其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存在微血管对胰岛素的抵抗，以及如果存在，这如何影响葡萄糖的处置。
我们的多学科方法包括对Cd36小鼠和野生型小鼠，以及50% CD36缺乏的个体及其对照进行高胰岛素-正常血糖钳夹试验，此外还对有/无CD36缺失的原代人源微血管内皮细胞进行试验。
胰岛素钳夹试验表明，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。腓肠肌活体显微镜检查显示跨毛细血管胰岛素通量未改变。CD36缺乏的人胰岛素刺激的葡萄糖处置较好，但微血管血容量（MBV）对胰岛素无反应。CD36缺失的人微血管细胞显示Akt、内皮型一氧化氮合酶和一氧化氮生成的胰岛素激活受损。因此，在CD36缺乏的情况下，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/解读：先前已表明CD36缺乏会降低肌肉/心脏脂肪酸摄取，而在此我们表明它会降低血管顺应性以及胰岛素增加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应对这些能量挑战，使组织为胰岛素刺激的糖酵解通量做好准备。氧气输送减少激活缺氧诱导因子、内皮生长因子释放或小细胞内囊泡可能介导这种适应性变化。针对CD36缺乏时的一氧化氮生物利用度进行干预可能有益于微血管以及肌肉/心脏代谢。
Clinicaltrials.gov NCT03012386 数据可用性：本研究中生成的RNAseq数据已存入NCBI基因表达综合数据库（www.ncbi.nlm.nih.gov/geo/），登录号为GSE235988（https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988）。
