Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand.
Am J Physiol Endocrinol Metab. 2022 Dec 1;323(6):E467-E479. doi: 10.1152/ajpendo.00401.2021. Epub 2022 Sep 21.
Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from β-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, β-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts β-cell function. This is the first study to describe a model in which the preptin-coding portion of the gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature . Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.
Preptin 是一种 34 个氨基酸的肽，来源于胰岛素样生长因子 2 的 E 肽前体，与β细胞分泌的胰岛素一起分泌。对于内源性 Preptin 对全身葡萄糖代谢的影响知之甚少。我们开发了一种新的小鼠模型，在该模型中， 基因的 Preptin 部分在所有组织中被遗传缺失，以下称为 Preptin 敲除 (KO)，并测试了以下假设：去除 Preptin 将导致胰岛素对代谢挑战的反应降低。Preptin KO 和野生型 (WT) 小鼠每周进行空腹血糖测量，在 9、29 和 44 周龄时进行腹腔内胰岛素耐量试验 (ITT)，在 45 周龄时进行口服葡萄糖耐量试验 (GTT)。与 WT 小鼠相比，雌雄 Preptin KO 小鼠的肝脏和肾脏中的 exon 2-3 mRNA 表达相似，但 exon 3-4 (Preptin) 表达无法检测到。新生血清的 Western blot 分析表明，从 KO 等位基因翻译的 pro-IGF2 的加工可能发生改变。在 47 周龄之前，雌雄 Preptin KO 小鼠的体重、体成分、β 细胞面积和空腹血糖浓度与 WT 小鼠相似。雌性 KO 小鼠在体内葡萄糖刺激后胰岛素反应能力下降。这种影响在雄性 KO 小鼠中不存在。尽管 Preptin 对葡萄糖稳态不是必需的，但结合之前的体外和离体研究结果，这些数据表明 Preptin 对 β 细胞功能有积极影响。这是第一个描述在小鼠中基因的 Preptin 编码部分被遗传缺失的模型的研究。这些小鼠在出生时没有与 KO 相关的体型减小，这表明 IGF2 功能得到维持，但我们证明了成熟 的加工方式发生了变化。雌性 KO 小鼠的葡萄糖刺激胰岛素分泌减少，而雄性的胰岛素反应与野生型没有差异。
