Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Ann N Y Acad Sci. 2010 Nov;1212:41-58. doi: 10.1111/j.1749-6632.2010.05802.x. Epub 2010 Oct 29.
Type 2 diabetes occurs due to a relative deficit in β-cell mass or function. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), and gastrin are gastrointestinal hormones that are secreted in response to nutrient intake, regulating digestion, insulin secretion, satiety, and β-cell mass. In this review, we focus upon β-cell mass regulation. β-cell mass expands through β-cell proliferation and islet neogenesis; β-cell mass is lost via apoptosis. GLP-1 and GIP are well-studied gastrointestinal hormones and influence β-cell proliferation, apoptosis, and islet neogenesis. CCK regulates β-cell apoptosis and mitogenesis, and gastrin stimulates islet neogenesis. GLP-1 and GIP bind to G protein-coupled receptors and regulate β-cell mass via multiple signaling pathways. The protein kinase A pathway is central to this process because it directly regulates proliferative and anti-apoptotic genes and transactivates several signaling cascades, including Akt and mitogen-activated protein kinases. However, the signaling pathways downstream of G protein-coupled CCK receptors that influence β-cell mass remain unidentified. Gastrointestinal hormones integrate nutrient signals from the gut to the β-cell, regulating insulin secretion and β-cell mass adaptation.
2 型糖尿病的发生是由于β细胞质量或功能相对不足所致。胰高血糖素样肽 1（GLP-1）、葡萄糖依赖性胰岛素释放肽（GIP）、胆囊收缩素（CCK）和胃泌素是响应营养摄入而分泌的胃肠激素，调节消化、胰岛素分泌、饱腹感和β细胞质量。在这篇综述中，我们重点关注β细胞质量的调节。β细胞质量通过β细胞增殖和胰岛新生而扩大；β细胞质量通过细胞凋亡而丧失。GLP-1 和 GIP 是研究充分的胃肠激素，它们影响β细胞增殖、凋亡和胰岛新生。CCK 调节β细胞凋亡和有丝分裂，胃泌素刺激胰岛新生。GLP-1 和 GIP 与 G 蛋白偶联受体结合，通过多种信号通路调节β细胞质量。蛋白激酶 A 通路是这一过程的核心，因为它直接调节增殖和抗凋亡基因，并转激活包括 Akt 和丝裂原激活蛋白激酶在内的几个信号级联。然而，影响β细胞质量的 G 蛋白偶联 CCK 受体下游的信号通路仍未确定。胃肠激素将来自肠道的营养信号整合到β细胞中，调节胰岛素分泌和β细胞质量适应。
