Traub Shuyang, Meier Daniel T, Schulze Friederike, Dror Erez, Nordmann Thierry M, Goetz Nicole, Koch Norina, Dalmas Elise, Stawiski Marc, Makshana Valmir, Thorel Fabrizio, Herrera Pedro L, Böni-Schnetzler Marianne, Donath Marc Y
Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, 1211 Geneva, Switzerland.
Cell Rep. 2017 Mar 28;18(13):3192-3203. doi: 10.1016/j.celrep.2017.03.005.
Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.
胰腺α细胞可能不仅将胰高血糖素原加工成胰高血糖素，还加工成胰高血糖素样肽-1（GLP-1）。然而，旁分泌GLP-1对β细胞功能的生物学意义仍不清楚。我们使用α细胞消融和α细胞特异性GLP-1缺乏的小鼠，研究了局部产生的胰岛素分泌刺激因子对β细胞功能和葡萄糖稳态的影响。正常情况下，肠道GLP-1可补偿α细胞来源的GLP-1的缺乏。然而，随着衰老和代谢应激，葡萄糖耐量受损。使用二肽基肽酶-4（DPP-4）抑制剂西他列汀可部分挽救这种情况，但给予胰高血糖素则无效。在来自这些小鼠的分离胰岛中，葡萄糖刺激的胰岛素分泌严重受损，外源性GLP-1或胰高血糖素可挽救胰岛素分泌。这些数据突出了α细胞来源的GLP-1在代谢应激期间对葡萄糖稳态的重要性，并可能影响2型糖尿病中全身性GLP-1激动剂与通过DPP-4抑制剂稳定局部α细胞来源的GLP-1的临床应用。
