Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
Endocrinology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
Front Endocrinol (Lausanne). 2020 May 13;11:258. doi: 10.3389/fendo.2020.00258. eCollection 2020.
Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD- (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagoninsulin cells and insulin ductal cells arose during treatment. experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.
1 型糖尿病是一种由胰岛素产生β细胞破坏引起的自身免疫性疾病。理想的免疫疗法应将自身免疫反应的阻断与功能性靶细胞群的恢复结合起来。为了开发新的 1 型糖尿病治疗方法，以促进β细胞群的恢复，我们进行了基于系统生物学的药物再定位分析，以确定商业上可用的化合物的β细胞再生潜力。药物再定位是一种用于确定批准药物新用途的策略，这些用途超出了医疗适应证的范围。获得了 28 种非同义重新定位候选药物的列表，并选择了 16 种药物作为 1 型糖尿病治疗候选药物，涉及胰腺β细胞再生。进一步筛选出安全性差的药物。最后，我们选择利拉鲁肽，因为它对新生、α细胞的转分化和/或现有β细胞的复制具有预测疗效值。利拉鲁肽是胰高血糖素样肽-1 的类似物，用于 2 型糖尿病患者。利拉鲁肽在 1 型糖尿病免疫缺陷 NOD-（NSG）小鼠中进行了测试。利拉鲁肽显著改善了糖尿病 NSG 小鼠的血糖水平。在治疗过程中，由于β细胞数量的增加，β细胞质量显著增加。停药后，这两个参数都降低了。有趣的是，在治疗过程中出现了胰岛双激素胰高血糖素胰岛素细胞和胰岛素导管细胞。实验表明，在正常血糖条件下，用利拉鲁肽培养的胰岛中胰岛素和胰高血糖素基因表达增加。这些结果表明β细胞替代，包括转分化和新生，是辅助因素，并支持利拉鲁肽在 1 型糖尿病中恢复β细胞群的作用。了解这种药物的作用机制在这种自身免疫性疾病中可能具有潜在的临床意义。
