INSR

In nerve cells, the hormone regulates whether mitochondria are shut down or kept running. The hormone insulin controls many cellular processes and adapts them to the body's current energy supply. One of the insulin-regulated processes is the quality control of cellular power plants in neurons, Angelika Harbauer and her team at the Max Planck Institute for Biological Intelligence discovered. When sufficient energy is available in the body, insulin facilitates the elimination of defective mitochondria. When energy is scarce or when the insulin signal is interrupted, mitochondrial recycling is reduced and cells continue to use their old power plants, even potentially damaged ones. The continued operation of faulty mitochondria could affect ageing processes and neurological diseases. Nerve cells place special demands on their energy supply. Due to their extensive branching and their high energy needs, they keep a close watch on their cellular power plants, the mitochondria. The cells have to ensure that there are always sufficient mitochondria available in their long extensions, the axons, where the power plants fuel the cell's communication with its neighboring cells. This is why neurons transport mitochondria even to the cells' most remote locations. Angelika Harbauer's earlier research had shown that mitochondria carry along the blueprints of the PINK1 protein on their journey through the neuron. "PINK1 is a key protein that acts when mitochondria need to be removed because they are no longer functioning correctly," explains the Max Planck research group leader. "It can mark mitochondria for recycling and is precisely controlled by the cells." A failure to keep PINK1 in check could lead to a shortage of mitochondria, whereas the continued operation of defective cellular power plants can damage a cell. A hormone with many roles Angelika Harbauer and her team now uncovered that the hormone insulin is involved in mitochondrial quality control in neurons. Insulin is well-known for its role in regulating a cell's sugar uptake. It also controls many processes inside cells to precisely adjust them to the body's current energy supply. In the case of mitochondrial recycling, this works as follows: If sufficient energy is available, a signal is transmitted from the insulin receptor on the cell surface to the mitochondria. Here, PINK1 blueprints are stored as mRNA molecules. When the insulin signal arrives, the blueprints are released by the mitochondria and the cell can produce additional PINK1 protein. This ensures that defective mitochondria are efficiently eliminated. In case of an energy shortage, or if the insulin receptor signal is missing, the blueprints for PINK1 remain tightly bound to the mitochondria. On the one hand, the tight binding to mitochondria allows the PINK1 blueprints to hitchhike far into the nerve cells' long extensions. On the other hand, it reduces the availability of mRNA molecules for PINK1 production. PINK1 protein levels remain low and mitochondrial recycling is reduced -- even though this can lead to the continued operation of damaged power plants. "We had expected that the binding of the mRNA to the mitochondria would promote PINK1 production," says Tabitha Hees, lead author of the study. "Surprisingly, our experiments showed that this is not the case. When energy levels are low, it is apparently more favorable for the cells to produce less PINK1 protein and to continue using potentially damaged mitochondria." Interrupted signaling with implications for health and ageing A similar situation can occur when the transmission of signals from the insulin receptor to mitochondria is disturbed due to disease. Defective insulin signaling is a hallmark of diabetes and has also been observed in the brain in connection with Alzheimer's disease. It is also known that inefficient mitochondrial quality control can contribute to various neurodegenerative diseases. "Our observations add to our understanding of how cellular energy supply, ageing and neurodegenerative diseases are interrelated," says Angelika Harbauer. Next, the researchers aim to investigate what happens to the PINK1 blueprints once they are released from the mitochondria into the cell. "We are particularly interested in finding out where the PINK1 protein is made, if not at mitochondria, and how it afterwards finds its way back to mitochondria," says Tabitha Hees. Only when these two steps are taken care of, PINK1 will initiate the recycling of faulty power plants to prevent them from damaging the nerve cell.

深度聚焦类器官与3D培养论坛，OTC2024论坛合作详询：王晨 180 1628 8769     肠道是一个高度代谢的组织，但是影响肠道隐窝增殖、分化和再生的代谢程序还未完全明了。在这里，我们研究了线粒体去乙酰化酶4（SIRT4）如何影响肠道稳态。肠道SIRT4的缺失促进了肠道细胞在电离辐射（IR）后的增殖。SIRT4在小鼠肠道癌症模型中充当肿瘤抑制因子，SIRT4的丧失导致肠腺瘤中谷氨酰胺和核苷酸代谢失调。缺乏SIRT4的肠器官体在IR应激后显示出增加的增殖以及增加的谷氨酰胺摄取和转向新合成核苷酸生物合成而非回收途径的转变。抑制新合成核苷酸生物合成减少了SIRT4缺失器官体在IR后的生长优势。这项工作确立了SIRT4作为肠代谢和稳态的调节器，在DNA损伤应激的环境下，通过重新编程核苷酸代谢。这篇文章的特点主要在于以下几个方面：1. 创新性的发现：文章首次揭示了SIRT4（线粒体去乙酰化酶4）在肠道稳态和代谢调控中的关键作用，特别是在DNA损伤（如电离辐射）后的肠道再生过程中。这一发现为理解肠道代谢调控和再生提供了新的视角。2.深入的机制研究：研究不仅发现了SIRT4缺失可以促进肠道细胞的增殖，还深入探讨了其背后的代谢机制，特别是SIRT4如何通过影响谷氨酰胺和核苷酸的代谢来调节肠道细胞的行为。这为肠道疾病的代谢干预提供了可能的新靶点。3. 肠道癌症相关性：文章还探讨了SIRT4在肠道癌症发展中的作用，发现其作为肿瘤抑制因子的功能，这为癌症的预防和治疗提供了新的策略。4. 类器官模型的应用：研究利用肠类器官模型，这是一种高度相关的生物学模型，能够在体外模拟肠道的微环境和细胞行为，使研究结果更具生物学意义和临床相关性。5. 疾病干预的潜在途径：通过阐明SIRT4对肠道增殖和代谢的调节作用，研究为开发新的治疗策略提供了线索，尤其是在肠道损伤恢复和癌症治疗方面。总之，这篇文章通过研究SIRT4在肠道稳态中的作用，揭示了肠道代谢和再生的新机制，并为肠道疾病的治疗提供了新的思路和靶点。这篇文章中，类器官（organoid）模型被应用来深入研究SIRT4（线粒体去乙酰化酶4）在肠道稳态、增殖及代谢调节中的作用。具体的应用如下：1. 模拟肠道微环境：通过肠类器官模型，研究人员能够在体外复现肠道的微环境，包括细胞的三维结构、相互作用和生长条件。这允许研究人员观察SIRT4缺失对肠道细胞增殖和分化的直接影响。2. 研究DNA损伤后的肠道再生：文章中使用类器官模型来模拟电离辐射（IR）对肠道造成的损伤，并研究在这种情况下SIRT4的作用。通过对受辐射处理的肠类器官进行分析，研究人员能够观察到SIRT4缺失是如何促进肠道细胞在损伤后的增殖和再生。3. 探索代谢途径的变化：利用肠类器官模型，研究人员能够详细分析SIRT4对肠道细胞谷氨酰胺摄取和核苷酸代谢的影响。这一发现揭示了SIRT4如何通过调节肠道细胞的代谢途径来控制细胞的增殖和生存。4. 验证新的治疗靶点：通过在肠类器官模型中敲除或抑制SIRT4表达，研究人员可以评估这种改变对肠道再生能力的影响，从而验证SIRT4作为肠道疾病治疗的潜在靶点。总之，这篇文章通过在肠类器官模型中应用SIRT4的研究，提供了一种强有力的方法来研究肠道细胞在正常和病理条件下的行为，特别是在损伤后的再生过程中，从而为未来的治疗策略提供了基础。这篇文章的创新之处主要体现在以下几个方面：1. SIRT4与肠道稳态的新联系：文章首次发现并阐明了SIRT4（线粒体去乙酰化酶4）在调节肠道细胞增殖和稳态中的关键作用，尤其是在DNA损伤后的肠道再生过程。这一发现扩展了我们对肠道细胞代谢调控及其再生能力的理解，为肠道生物学领域提供了新的见解。2. 深入解析SIRT4调控肠道代谢的机制：该研究不仅揭示了SIRT4的缺失促进肠道增殖的现象，而且深入探讨了SIRT4如何通过调控谷氨酰胺和核苷酸代谢影响肠道细胞的行为。这种对肠道代谢深层机制的解析，为未来的代谢疾病治疗提供了新的思路。3. 类器官（Organoid）模型的创新应用：本文通过使用肠类器官模型进行研究，该模型能够在体外模拟肠道的微环境和细胞行为，提供了一种研究肠道生物学和代谢调控的高效和实用工具。这种模型的应用为肠道研究提供了更为直观和精确的实验平台。4. 肠道癌症发展的新见解：文章探讨了SIRT4在肠道癌症中的作用，并发现它作为一种肿瘤抑制因子，参与调控肠道细胞的代谢和增殖。这为肠道癌症的预防和治疗提供了新的视角和潜在靶点。5.为肠道疾病治疗提供新策略：通过明确SIRT4在肠道细胞代谢和增殖中的作用，这项研究不仅为理解肠道疾病的发病机制提供了新的知识，还为开发针对性的治疗方法提供了科学依据。总的来说，这篇文章通过其对SIRT4在肠道细胞代谢和增殖调控中作用的研究，为肠道生物学、代谢调控及相关疾病的治疗提供了新的视角和方法，体现了显著的创新性。END深度聚焦类器官与3D培养论坛，OTC2024论坛合作详询：王晨 180 1628 8769戳“阅读原文”立即领取限量免费参会名额!

3月21日，诺和诺德宣布欧洲药品管理局人用医药产品委员会（CHMP）通过了一项积极的意见，建议批准Awiqli（每周一次基础胰岛素icodec）用于治疗成人糖尿病。icodec是诺和诺德在口服胰岛素OI338的基础上设计的一款超长效胰岛素制剂，人体内半衰期长达196h。其核心设计在于：①将18C长链脂肪酸替换为20C长链脂肪酸，提高分子与人血清白蛋白的结合亲和力；②将B链16位Tyr（酪氨酸）替换为His（组氨酸），降低分子对人胰岛素受体的亲和力。该产品也已在美国和中国递交上市申请（见：每周1次！诺和诺德超长效胰岛素icodec申报上市）。CHMP的积极意见是基于ONWARDS临床试验项目的结果。该项目包括6项IIIa期全球临床试验，研究了每周一次的基础胰岛素icodec的有效性和安全性，涉及4000多名1型或2型糖尿病患者，其中包括一项真实世界研究。与接受每日基础胰岛素治疗相比，每周一次的基础胰岛素治疗可使2型糖尿病患者取得更好的降糖效果（通过HbA1c的变化来测量）和血糖水平维持在推荐范围内的时间。在之前未接受过胰岛素治疗的2型糖尿病患者中，每周1次基础胰岛素治疗组和对照组的临床显著性或严重低血糖的总体观察率低于1例/患者年。在1型糖尿病患者中，每周一次的基础胰岛素icodec在降低HbA1c方面显示出非劣效性，严重或临床显著低血糖的估计率有统计学显著性增高。在整个项目中，每周一次的基础胰岛素icodec具有良好的安全性和耐受性。除了单药icodec和icodec+胰岛素以外，诺和诺德也开发了icodec+司美格鲁肽组合疗法（见：每周1次胰岛素+司美格鲁肽！诺和诺德启动新降糖组合疗法首个III期研究）。Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。精彩预告↑长按识别二维码 / 扫码即可报名↑