A Study on Acylation-Regulated Membrane Proteins Involved in Insulin Exocytosis

胰岛素胞吐作用中酰化调节膜蛋白的研究

• 批准号: 13671151
• 负责人: KOMATSU Mitsuhisa
• 金额: $ 2.18万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671151/
• 关键词: insulin release; secretion; acylation; cAMP; Ca2+; type 2 diabetes; アシル化; 膵β細胞; 膵ベータ細胞; 細胞内Ca^<2+>濃度

Insulin release from pancreatic β-cell is regulated by multiple distinct mechanisms, which are mutually related. Among various insulin secretagogues, glucose is the most powerful and important one. Glucose is known to stimulate insulin release via KATP channel-dependent and -independent mechanisms. Molecular basis for the KATP channel-dependent mechanism has relatively well established. Our research purpose is, therefore, to elucidate the mechanisms of KATP channel-independent pathways. Before this research was started, we and others had obtained considerable amount of evidence that support an involvement of glucose-induced changes in lipid signaling cascades in the KATP channel-independent ones. In particular, protein acylation was implicated as an underlying molecular event in nutrient-induced insulin secretion. In this research period, we have extensively challenged to identify the β-cell proteins that acylated by nutrient such as glucose. Finally, we identified rapidly turning over … More palmitoylated (one form of acylation) 24-kDa proteins from isolated rat pancreatic islets (Endocrinology 144 : 5232-5241, 2003). Knowing that the 24 kDa proteins are targets for nutrient stimuli in the β-cell, we are now trying to reveal nature of the proteins and to study functional roles of the proteins in controlling insulin release under various conditions. Another aspect of the fruits in this research period is that we successfully demonstrate previously unknown effect of CAMP in stimulus-secretion coupling in the β-cell. We found that (1) : cAMP increased readily releasable pool of insulin granules irrespective of the presence or absence of Ca2+, and it induced Ca2+-independent, time-dependent potentiation of subsequent insulin release (Endocrinology 143 : 4203-4209, 2002), (2) ; given cellular cAMP is increased, glucose does trigger insulin release under the condition where glucose is not capable to elevate cytosolic free Ca2+ concentration (Diabetes 51 : S29-S32, 2002). These findings improved our understandings of mechanisms of insulin release. In future, we will approach to mechanisms of impaired insulin secretion in patients with type 2 diabetes by extending our knowledge of the mechanisms of insulin secretion Less

胰腺β细胞的胰岛素释放受多种不同的相互关联的机制调控。在各种胰岛素分泌剂中，葡萄糖是最强大、最重要的一种。已知葡萄糖通过KATP通道依赖性和非依赖性机制刺激胰岛素释放。KATP通道依赖机制的分子基础已经较为完善。因此，我们的研究目的是阐明KATP通道无关通路的机制。在这项研究开始之前，我们和其他人已经获得了相当多的证据，支持葡萄糖诱导的脂质信号级联变化参与了与KATP通道无关的脂质信号级联。特别是，蛋白质酰化被认为是营养诱导胰岛素分泌的潜在分子事件。在这一研究阶段，我们已经广泛地挑战了识别被营养物质（如葡萄糖）酰化的β细胞蛋白。最后，我们从分离的大鼠胰岛中发现了更多的棕榈酰化（一种酰化形式）24-kDa蛋白（内分泌学144:5232-5241,2003）。已知24kda蛋白是β细胞中营养刺激的靶标，我们现在正试图揭示蛋白质的性质，并研究蛋白质在各种条件下控制胰岛素释放的功能作用。本研究成果的另一个方面是，我们成功地证明了CAMP在β细胞中刺激-分泌偶联中的先前未知的作用。我们发现(1)：无论Ca2+的存在与否，cAMP都增加了胰岛素颗粒的易释放池，并诱导了随后的Ca2+独立的、时间依赖性的胰岛素释放增强（内分泌学143:4203-4209,2002），(2)；在细胞cAMP升高的情况下，葡萄糖确实会触发胰岛素释放，而葡萄糖不能提高胞质游离Ca2+浓度（Diabetes 51: S29-S32, 2002）。这些发现提高了我们对胰岛素释放机制的理解。在未来，我们将通过扩大我们对胰岛素分泌机制的了解来探讨2型糖尿病患者胰岛素分泌受损的机制

项目成果

Primacy of beta-cell dysfunction in the development of hyperglycemia: a study in the Japanese general population.

• DOI: 10.1016/j.metabol.2004.02.024
• 发表时间: 2004-07
• 期刊: Metabolism: clinical and experimental
• 作者: M. Katakura;M. Komatsu;Yoshihiko Sato;K. Hashizume;T. Aizawa

Pancreatic B-Cel, a Unique Fuel Sensor. (K Daksshinamurti and J Zempleni, eds) In Nurients and Cell Signaling

Pancreatic B-Cel，一种独特的燃料传感器。

• 发表时间: 2005
• 作者: Yamada S;Komatsu M et al.;Komatsu M et al.;Komatsu M
• 通讯作者: Komatsu M

Katakura M et al.: "Prospective analysis of mortality, morbidity, and risk factors in elderly diabetic, Nagano study"Diabetes Care. 26. 638-644 (2003)

Katakura M 等人：“长野研究，老年糖尿病死亡率、发病率和危险因素的前瞻性分析”糖尿病护理。

Yamada S, Komatsu M et al.: "Nutrient modulation of palmitoylated 24KDa protein in rat pancreatic islets"Endocrinology. 144. 5232-5241 (2003)

Yamada S、Komatsu M 等人：“大鼠胰岛中棕榈酰化 24KDa 蛋白的营养调节”内分泌学。

Yamada S, Komatsu M et al.: "Time-dependent stimulation of insulin exocytosis by 3 : 5'-cyclic adenosine monophosphate in the rat islet β-cell"Endocrinology. 143. 4203-4209 (2002)

Yamada S、Komatsu M 等人：“大鼠胰岛 β 细胞中 3:5-环单磷酸腺苷对胰岛素胞吐作用的时间依赖性刺激”内分泌学 143. 4203-4209 (2002)