Glucolipotoxicity promotes the capacity of the glycerolipid/NEFA cycle supporting the secretory response of pancreatic beta cells,Diabetologia

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Glucolipotoxicity promotes the capacity of the glycerolipid/NEFA cycle supporting the secretory response of pancreatic beta cells
Diabetologia ( IF 8.4 ) Pub Date : 2022-01-12 , DOI: 10.1007/s00125-021-05633-x
Lucie Oberhauser _{1,

2} , Cecilia Jiménez-Sánchez _{1,

2} , Jesper Grud Skat Madsen ₃ , Dominique Duhamel _{1,

2} , Susanne Mandrup ₃ , Thierry Brun _{1,

2} , Pierre Maechler _{1,

2}

Affiliation

Aims/hypothesis

Chronic exposure of pancreatic beta cells to high glucose and fatty acids has been proposed to induce glucolipotoxicity. However, contradictory results suggest adaptations of the beta cells, which might be instrumental for partial preservation of the secretory response. In this context, we delineated the expression pattern of genes related to lipid pathways along with fat storage/mobilisation during glucose-stimulated insulin secretion.

Methods

Insulin-secreting cells were cultured for 3 days at different glucose concentrations (5.5, 11.1, 25 mmol/l) without or with BSA-complexed 0.4 mmol/l palmitate and oleate. Then, transcriptomic analyses of lipid pathways were performed in human islets by RNA-Seq and in INS-1E cells and rat islets by quantitative RT-PCR. Storage of fat was assessed in INS-1E cells by electron microscopy and Bodipy staining, which was also used for measuring lipid mobilisation rate. The secretory response was monitored during acute 15 mmol/l glucose stimulation using online luminescence assay for INS-1E cells and by radioimmunoassay for rat islets.

Results

In human islets, chronic exposure to palmitate and oleate modified expression of a panel of genes involved in lipid handling. Culture at 25 mmol/l glucose upregulated genes encoding for enzymes of the glycerolipid/NEFA cycle and downregulated receptors implicated in fatty acid signalling. Similar results were obtained in INS-1E cells, indicating enhanced capacity of the glycerolipid/NEFA cycle under glucotoxic conditions. Exposure to unsaturated C18:1 fatty acid favoured intracellular lipid accumulation in a glucose-dependent way, an effect also observed with saturated C16:0 fatty acid when combined with the panlipase inhibitor Orlistat. After the glucolipotoxic culture, intracellular fat mobilisation was required for acute glucose-stimulated secretion, particularly in oleate-treated cells under glucotoxic culture conditions. The lipid mobilisation rate was governed chiefly by the levels of stored fat as a direct consequence of the culture conditions rather than energetic demands, except in palmitate-loaded cells.

Conclusions/interpretation

Glucolipotoxic conditions promote the capacity of the glycerolipid/NEFA cycle thereby preserving part of the secretory response. The cycle of fat storage/mobilisation emerges as a mechanism helping the beta cell to cope with glucotoxic conditions.

Graphical abstract

中文翻译：

糖脂毒性促进甘油脂/NEFA循环的能力，支持胰腺β细胞的分泌反应

目标/假设

已经提出胰腺β细胞长期暴露于高葡萄糖和脂肪酸以诱导糖脂毒性。然而，矛盾的结果表明β细胞的适应性，这可能有助于部分保存分泌反应。在这种情况下，我们描述了与脂质途径相关的基因的表达模式以及葡萄糖刺激的胰岛素分泌过程中的脂肪储存/动员。

方法

胰岛素分泌细胞在不同葡萄糖浓度（5.5、11.1、25 mmol/l）下培养 3 天，不含或含 BSA 复合的 0.4 mmol/l 棕榈酸盐和油酸盐。然后，通过 RNA-Seq 在人类胰岛中以及通过定量 RT-PCR 在 INS-1E 细胞和大鼠胰岛中进行脂质途径的转录组学分析。通过电子显微镜和 Bodipy 染色评估 INS-1E 细胞中的脂肪储存，这也用于测量脂质动员率。在急性 15 mmol/l 葡萄糖刺激期间，使用 INS-1E 细胞的在线发光测定和大鼠胰岛的放射免疫测定监测分泌反应。

结果

在人类胰岛中，长期暴露于棕榈酸和油酸会改变一组参与脂质处理的基因的表达。25 mmol/l 葡萄糖培养上调编码甘油脂/NEFA 循环酶的基因和下调涉及脂肪酸信号传导的受体。在 INS-1E 细胞中获得了类似的结果，表明在糖毒性条件下甘油脂/NEFA 循环的能力增强。暴露于不饱和 C18:1 脂肪酸以葡萄糖依赖性方式促进细胞内脂质积累，当与泛脂肪酶抑制剂奥利司他联合使用时，饱和 C16:0 脂肪酸也观察到这种效应。糖脂毒性培养后，急性葡萄糖刺激的分泌需要细胞内脂肪动员，特别是在糖毒性培养条件下油酸处理的细胞中。