Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Commun Biol. 2024 Nov 9;7(1):1479. doi: 10.1038/s42003-024-07070-z.
Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond.
空腹低血糖是各种先天性代谢缺陷（IEM）的一种严重且尚未完全阐明的症状。精密切割肝切片（PCLS）代表了一种有前途的体外研究葡萄糖生成的模型。本研究定量测定了不同糖异生前体存在时人源和鼠源 PCLS 的净葡萄糖生成率。在进食的小鼠中添加二羟丙酮的切片产生的速率最高， forskolin 和二丁酰环腺苷酸进一步刺激了这一速率。此外，我们使用 C 同位素示踪，评估了糖原分解和糖异生对净葡萄糖生成随时间变化的贡献。葡萄糖 6-磷酸转运蛋白 SLC37A4 的药理学抑制显著降低了净葡萄糖生成率，并增加了乳酸分泌和糖原储存，而糖原贮积症 I 型和 Ib 型患者的 PCLS 中葡萄糖生成则完全被抑制。总之，本研究将 PCLS 确定为一种有效的体外模型，用于研究肝脏葡萄糖生成，并为其在 IEM 研究及其他领域的未来应用开辟了机会。
