Gurlo Tatyana, Prakash Thazha P, Wang Zhongying, Archang Maani, Pei Lina, Rosenberger Madeline, Pirie Elaine, Lee Richard G, Butler Peter C
Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
IONIS Pharmaceuticals, Carlsbad, CA, United States.
Front Mol Biosci. 2023 Feb 6;10:1096286. doi: 10.3389/fmolb.2023.1096286. eCollection 2023.
Insulin resistance is the major risk factor for Type 2 diabetes (T2D). In vulnerable individuals, insulin resistance induces a progressive loss of insulin secretion with islet pathology revealing a partial deficit of beta cells and islet amyloid derived from islet amyloid polypeptide (IAPP). IAPP is co-expressed and secreted with insulin by beta cells, expression of both proteins being upregulated in response to insulin resistance. If IAPP expression exceeds the threshold for clearance of misfolded proteins, beta cell failure occurs exacerbated by the action of IAPP toxicity to compromise the autophagy lysosomal pathway. We postulated that suppression of IAPP expression by an IAPP antisense oligonucleotide delivered to beta cells by the GLP-1 agonist exenatide (eGLP1-IAPP-ASO) is a potential disease modifying therapy for T2D. While eGLP1-IAPP-ASO suppressed mouse IAPP and transgenic human IAPP expression in mouse islets, it had no discernable effects on IAPP expression in human islets under the conditions studied. Suppression of transgenic human IAPP expression in mouse islets attenuated disruption of the autophagy lysosomal pathway in beta cells, supporting the potential of this strategy.
胰岛素抵抗是2型糖尿病（T2D）的主要危险因素。在易感个体中，胰岛素抵抗会导致胰岛素分泌逐渐丧失，胰岛病理显示β细胞部分功能缺陷以及由胰岛淀粉样多肽（IAPP）衍生的胰岛淀粉样变。IAPP与胰岛素由β细胞共同表达和分泌，这两种蛋白质的表达都会因胰岛素抵抗而上调。如果IAPP的表达超过错误折叠蛋白清除的阈值，β细胞功能衰竭会因IAPP毒性作用而加剧，从而损害自噬溶酶体途径。我们推测，通过胰高血糖素样肽-1激动剂艾塞那肽（eGLP1-IAPP-ASO）将IAPP反义寡核苷酸递送至β细胞来抑制IAPP表达，是一种治疗T2D的潜在疾病修饰疗法。虽然eGLP1-IAPP-ASO抑制了小鼠胰岛中的小鼠IAPP和转基因人IAPP表达，但在所研究的条件下，它对人胰岛中的IAPP表达没有明显影响。抑制小鼠胰岛中转基因人IAPP的表达可减轻β细胞自噬溶酶体途径的破坏，支持了该策略的潜力。
