Streckel Elisabeth, Braun-Reichhart Christina, Herbach Nadja, Dahlhoff Maik, Kessler Barbara, Blutke Andreas, Bähr Andrea, Übel Nicole, Eddicks Matthias, Ritzmann Mathias, Krebs Stefan, Göke Burkhard, Blum Helmut, Wanke Rüdiger, Wolf Eckhard, Renner Simone
Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany.
Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany.
J Transl Med. 2015 Feb 25;13:73. doi: 10.1186/s12967-015-0431-2.
The glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. However, efficacy and safety of liraglutide in adolescents has not been systematically investigated. Furthermore, possible pro-proliferative effects of GLP1R agonists on the endocrine and exocrine pancreas need to be further evaluated. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass.
Two-month-old GIPR(dn) transgenic pigs were treated daily with liraglutide (0.6-1.2 mg per day) or placebo for 90 days. Glucose homeostasis was evaluated prior to and at the end of the treatment period by performing mixed meal and intravenous glucose tolerance tests (MMGTT and IVGTT). Finally animals were subjected to necropsy and quantitative-stereological analyses were performed for evaluation of alpha- and beta-cell mass, beta-cell proliferation as well as acinus-cell proliferation.
MMGTT at the end of the study revealed 23% smaller area under the curve (AUC) for glucose, a 36% smaller AUC insulin, and improved insulin sensitivity, while IVGTT showed a 15% smaller AUC glucose but unchanged AUC insulin in liraglutide- vs. placebo-treated animals. Liraglutide led to marked reductions in body weight gain (-31%) and food intake (-30%) compared to placebo treatment, associated with reduced phosphorylation of insulin receptor beta (INSRB)/insulin-like growth factor-1 receptor beta (IGF1RB) and protein kinase B (AKT) in skeletal muscle. Absolute alpha- and beta-cell mass was reduced in liraglutide-treated animals, but alpha- and beta-cell mass-to-body weight ratios were unchanged. Liraglutide neither stimulated beta-cell proliferation in the endocrine pancreas nor acinus-cell proliferation in the exocrine pancreas, excluding both beneficial and detrimental effects on the pig pancreas.
Although plasma liraglutide levels of adolescent transgenic pigs treated in our study were higher compared to human trials, pro-proliferative effects on the endocrine or exocrine pancreas or other liraglutide-related side-effects were not observed.
胰高血糖素样肽-1受体（GLP1R）激动剂利拉鲁肽可改善成年2型糖尿病患者的血糖控制并减轻体重。然而，利拉鲁肽在青少年中的疗效和安全性尚未得到系统研究。此外，GLP1R激动剂对内分泌和外分泌胰腺可能的促增殖作用需要进一步评估。我们研究了利拉鲁肽对β细胞中表达显性负性葡萄糖依赖性促胰岛素多肽受体（GIPR(dn)）的青春期猪的影响，这导致了一种糖尿病前期状态，包括葡萄糖耐量受损、胰岛素分泌减少和功能性β细胞量的逐渐减少。
对2月龄的GIPR(dn)转基因猪每天给予利拉鲁肽（0.6 - 1.2毫克/天）或安慰剂，持续90天。在治疗期开始前和结束时，通过进行混合餐和静脉葡萄糖耐量试验（MMGTT和IVGTT）评估葡萄糖稳态。最后对动物进行尸检，并进行定量立体分析以评估α细胞和β细胞量、β细胞增殖以及腺泡细胞增殖。
研究结束时的MMGTT显示，与安慰剂治疗的动物相比，利拉鲁肽治疗的动物葡萄糖曲线下面积（AUC）小23%，胰岛素AUC小36%，胰岛素敏感性提高；而IVGTT显示葡萄糖AUC小15%，但胰岛素AUC无变化。与安慰剂治疗相比，利拉鲁肽导致体重增加（-31%）和食物摄入量（-30%）显著降低，这与骨骼肌中胰岛素受体β（INSRB）/胰岛素样生长因子-1受体β（IGF1RB）和蛋白激酶B（AKT）的磷酸化减少有关。利拉鲁肽治疗的动物中α细胞和β细胞的绝对量减少，但α细胞和β细胞量与体重的比值未改变。利拉鲁肽既未刺激内分泌胰腺中的β细胞增殖，也未刺激外分泌胰腺中的腺泡细胞增殖，排除了对猪胰腺的有益和有害影响。
尽管我们研究中治疗的青春期转基因猪的血浆利拉鲁肽水平高于人体试验，但未观察到对内分泌或外分泌胰腺的促增殖作用或其他利拉鲁肽相关的副作用。
