Prkar1a in the regulation of insulin secretion.
Prkar1a in the regulation of insulin secretion.
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DOI：
10.1055/s-0032-1321866
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Kirschner L
中科院分区：
文献类型：
--
作者：
Hussain MA;Stratakis C;Kirschner L
2 型糖尿病 (T2DM) 的发病率在全球范围内迅速增加，对个人生活质量以及各州医疗费用的经济负担产生了重大影响。虽然对 T2DM 发病机制的起源知之甚少，但胰腺 β 细胞葡萄糖刺激的胰岛素分泌 (GSIS) 的早期缺陷被认为是 T2DM 的标志。在葡萄糖刺激后，胰岛素以双相方式分泌，早期第一阶段胰岛素爆发，随后是第二阶段、更持续的胰岛素输出阶段。在 T2DM 早期，第一相胰岛素分泌减少，在有发展为 T2DM 风险的受试者中也是如此。使用肠促胰岛素激素胰高血糖素样肽-1 (GLP-1) 或其长效肽类似物 exendin-4 (E4) 有效治疗 T2DM，可恢复第一相并增强第二相葡萄糖刺激的胰岛素分泌。在 T2DM 人类中，肠促胰岛素作用的这种作用在 GLP-1/E4 输注后几分钟内就会发生。另一个重要的考虑因素是，肠促胰岛素激素仅在高于某个葡萄糖阈值（略高于正常葡萄糖范围）时才会增强 GSIS。这确保了肠促胰岛素激素仅在葡萄糖水平较高时刺激 GSIS，而当胰岛素水平低于某个阈值时则无效。 GLP-1 受体在胰腺 β 细胞上高度表达，其激活会刺激 2 种不同的细胞内信号传导途径：a) cAMP-蛋白激酶 A 分支和 b) cAMP-EPAC2（EPAC = 由 cAMP 激活的交换蛋白）分支。虽然 EPAC2 分支被认为介导 GLP-1 对第一相 GSIS 的影响，但 PKA 分支对于前一个分支的激活是必需的。然而，这两个分支如何相互作用和汇聚，以及它们对胰岛素分泌和胰岛素囊泡胞吐作用的影响如何协调，人们知之甚少。因此，在我们研究之初，我们对 cAMP 依赖性信号通路的细胞内相互作用知之甚少，这些信号通路在受到刺激时，会恢复 T2DM 患病 β 细胞中的葡萄糖依赖性第一阶段并增加第二阶段胰岛素分泌。
The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with significant consequences on individual quality of life as well as economic burden on states’ healthcare costs. While origins of the pathogenesis of T2DM are poorly understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is considered a hallmark of T2DM. Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase burst of insulin, which is followed by a second, more sustained phase of insulin output. First phase insulin secretion is diminished early in T2DM as well is in subjects who are at risk of developing T2DM. An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1) or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments second-phase glucose stimulated insulin secretion. This effect of incretin action occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important consideration is that incretin hormones augment GSIS only above a certain glucose threshold, which is slightly above the normal glucose range. This ensures that incretin hormones stimulate GSIS only when glucose levels are high, while they are ineffective when insulin levels are below a certain threshold. Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells, stimulates 2 distinct intracellular signaling pathways: a) the cAMP-protein kinase A branch and b) the cAMP-EPAC2 (EPAC = exchange protein activated by cAMP) branch. While the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA branch is necessary for the former branch to be active. However, how these 2 branches interplay and converge and how their effects on insulin secretion and insulin vesicle exocytosis are coordinated is poorly understood. Thus, at the outset of our studies we have a poorly understood intracellular interplay of cAMP-dependent signaling pathways, which – when stimulated – restore glucose-dependent first phase and augment second phase insulin secretion in the ailing β-cells of T2DM.
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影响因子：
7.7
作者：
Peyot ML;Pepin E;Lamontagne J;Latour MG;Zarrouki B;Lussier R;Pineda M;Jetton TL;Madiraju SR;Joly E;Prentki M
通讯作者：
Prentki M
影响因子：
15.9
作者：
VAAG, A;HENRIKSEN, JE;BECKNIELSEN, H
通讯作者：
BECKNIELSEN, H
影响因子：
15.9
作者：
WARD, WK;BOLGIANO, DC;PORTE, D
通讯作者：
PORTE, D
影响因子：
158.5
作者：
LILLIOJA, S;MOTT, DM;BOGARDUS, C
通讯作者：
BOGARDUS, C
影响因子：
168.9
作者：
Nolan, Christopher J.;Damm, Peter;Prentki, Marc
通讯作者：
Prentki, Marc