HTD4010 肽中的 INGAP-PP 结构修饰增强了其对大鼠胰岛基因表达和胰岛素分泌的影响。

IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Peptides Pub Date : 2024-01-10 DOI:10.1016/j.peptides.2024.171148
Macarena Algañarás, Carolina L. Román, Juan J. Gagliardino, Bárbara Maiztegui, Luis E. Flores
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引用次数: 0

摘要

2 型糖尿病(T2D)的特征是外周胰岛素抵抗以及由于 β 细胞质量和功能的逐渐丧失而导致的胰岛素分泌改变。目前,大多数抗糖尿病药物都旨在解决胰岛素分泌受损和/或胰岛素抵抗问题,只有基于 GLP-1 的制剂有助于阻止 β 细胞质量的下降。HTD4010是一种对INGAP-PP的氨基酸序列进行了两种修饰(N端乙酰化和Asn13被Ala取代)的多肽,它具有更高的血浆稳定性,可以作为改善T2D患者β细胞质量和功能的药物候选方案。在本研究中,我们发现在正常大鼠胰岛培养基中加入比 INGAP-PP 低 100 倍剂量的 HTD4010,能够以与原始肽相同的方式调节胰岛素对葡萄糖的分泌,以及与胰岛功能、胰岛素和瘦素细胞内通路、新生、凋亡和炎症反应相关的关键基因的表达。我们的研究结果证实了 HTD4010 对 β 细胞功能和参与维持 β 细胞质量的因子基因表达的积极影响。虽然还必须在糖尿病前期和 T2D 动物模型中进行新的检测才能得出结论,但我们的结果非常令人鼓舞,这表明在未来的临床试验中,以比 INGAP-PP 低 100 倍的剂量使用 HTD4010 可以最大限度地减少其副作用。
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Structural modifications of INGAP-PP present in HTD4010 peptide potentiate its effect on rat islet gene expression and insulin secretion.

Type 2 diabetes (T2D) is characterized by peripheral insulin resistance and altered insulin secretion due to a progressive loss of β-cell mass and function. Today, most antidiabetic agents are designed to resolve impaired insulin secretion and/or insulin resistance, and only GLP-1-based formulations contribute to stopping the decline in β-cell mass. HTD4010, a peptide carrying two modifications of the amino acid sequence of INGAP-PP (N-terminus acetylation and substitution of Asn13 by Ala) showed greater plasma stability and could be a good candidate for proposal as a drug that could improve β cell mass and function lost in T2D. In the present study, we showed that HTD4010 included in the culture media of normal rat islets at a dose 100 times lower than that used for INGAP-PP was able to modulate, in the same way as the original peptide, both insulin secretion in response to glucose and the expression of key genes related to insular function, insulin and leptin intracellular pathways, neogenesis, apoptosis, and inflammatory response. Our results confirm the positive effect of HTD4010 on β-cell function and gene expression of factors involved in the maintenance of β-cell mass. Although new assays in animal models of prediabetes and T2D must be performed to be conclusive, our results are very encouraging, and they suggest that the use of HTD4010 at a dose 100 times lower than that of INGAP-PP could minimize its side effects in a future clinical trial.

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来源期刊
Peptides
Peptides 医学-生化与分子生物学
CiteScore
6.40
自引率
6.70%
发文量
130
审稿时长
28 days
期刊介绍: Peptides is an international journal presenting original contributions on the biochemistry, physiology and pharmacology of biological active peptides, as well as their functions that relate to gastroenterology, endocrinology, and behavioral effects. Peptides emphasizes all aspects of high profile peptide research in mammals and non-mammalian vertebrates. Special consideration can be given to plants and invertebrates. Submission of articles with clinical relevance is particularly encouraged.
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