Ullsten Sara, Bohman Sara, Oskarsson Marie E, Nilsson K Peter R, Westermark Gunilla T, Carlsson Per-Ola
Department of Medical Cell BiologyUppsala University, Uppsala, Sweden
Department of Medical Cell BiologyUppsala University, Uppsala, Sweden.
Endocr Connect. 2017 Oct;6(7):458-468. doi: 10.1530/EC-17-0148. Epub 2017 Aug 8.
Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.
2型糖尿病中的胰岛淀粉样变和β细胞死亡是异质性事件，其中一些胰岛在疾病过程早期就受到影响，而另一些则明显未受影响。本研究调查了胰岛间功能和血管差异可能解释某些胰岛中淀粉样蛋白积累倾向的可能性。通过微球在喂食高脂饮食3个月或10个月的人胰岛淀粉样多肽表达小鼠中鉴定出高血液灌注的胰岛。这些高血液灌注的胰岛比其他胰岛具有更好的葡萄糖刺激胰岛素分泌能力，并且在高脂饮食10个月后形成了更多的淀粉样沉积物。同样，在高糖培养中，释放能力较强的人胰岛比释放能力较弱的胰岛形成更多的淀粉样蛋白。与淀粉样蛋白较少的胰岛相比，小鼠胰岛中的淀粉样蛋白形成与更高水平的激素原转化酶1/3以及其抑制剂proSAAS的表达降低有关。相比之下，激素原转化酶2的水平及其抑制剂神经内分泌蛋白7B2的表达未发生改变。激素原转化酶水平的失衡可能会中断胰岛淀粉样多肽的正常加工并诱导淀粉样蛋白形成。血液灌注最丰富且功能最强的胰岛中优先积累淀粉样蛋白可能会加速2型糖尿病的进展。
