Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
Diabetes Obes Metab. 2018 Sep;20 Suppl 2(Suppl 2):127-136. doi: 10.1111/dom.13381.
The islet of Langerhans plays a key role in glucose homeostasis through regulated secretion of the hormones insulin and glucagon. Islet research has focused on the insulin-secreting β-cells, even though aberrant glucagon secretion from α-cells also contributes to the aetiology of diabetes. Despite its importance, the mechanisms controlling glucagon secretion remain controversial. Proper α-cell function requires the islet milieu, where β- and δ-cells drive and constrain α-cell dynamics. The response of glucagon to glucose is similar between isolated islets and that measured in vivo, so it appears that the glucose dependence requires only islet-intrinsic factors and not input from blood flow or the nervous system. Elevated intracellular free Ca is needed for α-cell exocytosis, but interpreting Ca data is tricky since it is heterogeneous among α-cells at all physiological glucose levels. Total Ca activity in α-cells increases slightly with glucose, so Ca may serve a permissive, rather than regulatory, role in glucagon secretion. On the other hand, cAMP is a more promising candidate for controlling glucagon secretion and is itself driven by paracrine signalling from β- and δ-cells. Another pathway, juxtacrine signalling through the α-cell EphA receptors, stimulated by β-cell ephrin ligands, leads to a tonic inhibition of glucagon secretion. We discuss potential combinations of Ca , cAMP, paracrine and juxtacrine factors in the regulation of glucagon secretion, focusing on recent data in the literature that might unify the field towards a quantitative understanding of α-cell function.
胰岛中的 Langerhans 岛在葡萄糖稳态中起着关键作用，通过调节胰岛素和胰高血糖素等激素的分泌。胰岛研究主要集中在胰岛素分泌的β细胞上，尽管α细胞中异常的胰高血糖素分泌也与糖尿病的病因有关。尽管其重要性，控制胰高血糖素分泌的机制仍存在争议。适当的α细胞功能需要胰岛微环境，其中β和δ细胞驱动并限制α细胞的动态。在离体胰岛和体内测量的情况下，胰高血糖素对葡萄糖的反应是相似的，因此似乎葡萄糖的依赖性只需要胰岛内在因素，而不需要来自血流或神经系统的输入。细胞内游离 Ca 对于α细胞胞吐作用是必需的，但解释 Ca 数据是棘手的，因为在所有生理葡萄糖水平下，α细胞之间的 Ca 数据是不均匀的。α细胞中的总 Ca 活性随着葡萄糖的增加而略有增加，因此 Ca 可能在胰高血糖素分泌中起许可作用，而不是调节作用。另一方面，cAMP 是控制胰高血糖素分泌的更有希望的候选者，它本身是由β和δ细胞的旁分泌信号驱动的。另一种途径是通过α细胞 EphA 受体的旁分泌信号，通过β细胞的 ephrin 配体刺激，导致胰高血糖素分泌的持续抑制。我们讨论了 Ca 、 cAMP 、旁分泌和旁分泌因素在调节胰高血糖素分泌中的潜在组合，重点介绍了文献中的最新数据，这些数据可能会将该领域统一到对α细胞功能的定量理解上。
