Department of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Horm Metab Res. 2012 Sep;44(10):759-65. doi: 10.1055/s-0032-1321866. Epub 2012 Sep 5.
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.
2 型糖尿病（T2DM）的发病率在全球范围内迅速上升，对个体生活质量和国家医疗保健成本造成了重大经济负担。尽管 T2DM 的发病机制尚不清楚，但胰腺β细胞中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。在葡萄糖刺激下，胰岛素呈双相分泌，早期第一时相胰岛素分泌迅速，随后是第二时相胰岛素输出的更持续阶段。在 T2DM 以及处于发生 T2DM 风险的人群中，早期第一时相胰岛素分泌减少。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，可恢复第一时相和增强第二时相葡萄糖刺激的胰岛素分泌。这种肠促胰岛素作用在 T2DM 人类 GLP-1/E4 输注后几分钟内发生。另一个重要考虑因素是，肠促胰岛素激素仅在高于一定葡萄糖阈值时才增强 GSIS，该阈值略高于正常葡萄糖范围。这确保了肠促胰岛素激素仅在血糖水平高时刺激 GSIS，而在胰岛素水平低于一定阈值时则无效。GLP-1 受体的激活，在胰腺β细胞上高度表达，刺激 2 个不同的细胞内信号通路：a）cAMP-蛋白激酶 A 分支和 b）cAMP-EPAC2（EPAC=cAMP 激活的交换蛋白）分支。虽然 EPAC2 分支被认为介导 GLP-1 对第一时相 GSIS 的作用，但 PKA 分支对于前一分支的活性是必要的。然而，这两个分支如何相互作用和收敛，以及它们如何协调对胰岛素分泌和胰岛素囊泡胞吐作用的影响，尚不清楚。因此，在我们研究的开始，我们对 cAMP 依赖性信号通路的细胞内相互作用知之甚少，当这些信号通路被刺激时，可恢复 T2DM 患病β细胞中葡萄糖依赖性第一时相和增强第二时相胰岛素分泌。
