下载PDF
{"title":"Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes.","authors":"Sasanka Ramanadham, John Turk, Sushant Bhatnagar","doi":"10.1002/cphy.c220031","DOIUrl":null,"url":null,"abstract":"<p><p>Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K <sub>ATP</sub> channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca <sup>2+</sup> ] <sub>c</sub> . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca <sup>2+</sup> -independent phospholipase A <sub>2</sub> enzyme (iPLA <sub>2</sub> β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA <sub>2</sub> β reduces cAMP-mediated amplification of GSIS, the loss of iPLA <sub>2</sub> β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA <sub>2</sub> β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"13 3","pages":"5023-5049"},"PeriodicalIF":4.2000,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10809800/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Comprehensive Physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cphy.c220031","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
引用次数: 0
引用
批量引用
Abstract
Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K ATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca 2+ ] c . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca 2+ -independent phospholipase A 2 enzyme (iPLA 2 β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA 2 β reduces cAMP-mediated amplification of GSIS, the loss of iPLA 2 β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA 2 β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.
cAMP 依赖性胰岛素分泌的非规范调节及其对 2 型糖尿病的影响
糖耐量受损(IGT)和肥胖导致的胰岛素抵抗引起的β细胞功能障碍会导致 2 型糖尿病(T2D)。β细胞的葡萄糖刺激胰岛素分泌(GSIS)是通过典型途径进行的,其中包括葡萄糖代谢、ATP生成、K ATP通道失活、质膜去极化和细胞膜[Ca 2+ ]c浓度增加。然而,胰岛素的最佳分泌需要通过增加环磷酸腺苷(cAMP)信号来放大 GSIS。cAMP 效应蛋白激酶 A(PKA)和环-AMP 激活的交换因子(Epac)调节膜去极化、基因表达、胰岛素颗粒向质膜的迁移和融合,从而放大 GSIS。钙2+依赖性磷脂酶A 2酶β异构体(iPLA 2 β)在β细胞内产生的脂质信号参与了cAMP刺激的胰岛素分泌(cSIS),这一点已得到广泛认可。最近的研究发现,补体 1q like-3 (C1ql3)分泌蛋白激活的 G 蛋白偶联受体(GPCR)信号在抑制 cSIS 中的作用。在 IGT 状态下,cSIS 会减弱,β 细胞功能也会降低。有趣的是,β 细胞特异性地缺失 iPLA 2 β 可减少 cAMP 介导的 GSIS 放大,而巨噬细胞(MØ)中 iPLA 2 β 的缺失则可防止与饮食诱导肥胖(DIO)相关的葡萄糖不耐受的发生。在本文中,我们讨论了经典(葡萄糖和 cAMP)和新型非经典(iPLA 2 β 和 C1ql3)途径,以及它们在肥胖和 T2D 导致的葡萄糖不耐受受损的情况下如何影响β细胞(功能障碍)。总之,我们提供了一个视角,即在 IGT 状态下,靶向非典型通路和典型通路可能是恢复 T2D β 细胞功能的一种更全面的方法。© 2023 美国生理学会。Compr Physiol 13:5023-5049, 2023.
本文章由计算机程序翻译,如有差异,请以英文原文为准。