Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of ¹³C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-¹³C] glucose under conditions where GSIS was not affected (2–8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.

胰腺 β 细胞因长期暴露于过高的葡萄糖浓度而变得不可逆转，并且在受损时失去进行葡萄糖刺激的胰岛素分泌 (GSIS) 的能力。β 细胞不能控制葡萄糖摄取，因此它们很容易受到葡萄糖可用性增加时产生的过量代谢物的内源性毒性的影响。为了处理多余的燃料，β 细胞具有特定的代谢途径，但对这些途径知之甚少。我们使用稳定同位素解析 NMR 方法来研究导致 β 细胞功能障碍的早期代谢事件，在增加燃料压力下对 β 细胞代谢进行研究。该方法基于最近描述的¹³C 代谢组学通过溶解动态核极化 (dDNP) 与信号增强 NMR 相结合。在 GSIS 不受影响的条件下（2-8 小时），葡萄糖反应性 INS-1 β 细胞与浓度增加的 [U- ¹³ C] 葡萄糖一起孵育。我们发现丙酮酸和 DHAP 是对增加燃料压力反应最强烈的代谢物。发现燃料过剩的两个主要分歧途径，甘油脂/脂肪酸代谢和多元醇途径，不仅以不变的速率运行，而且数量相似。