Boland Brandon B, Brown Charles, Alarcon Cristina, Demozay Damien, Grimsby Joseph S, Rhodes Christopher J
Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, Illinois.
Division of Cardiovascular and Metabolic Disease, MedImmune LLC, Gaithersburg, Maryland.
Endocrinology. 2018 Feb 1;159(2):895-906. doi: 10.1210/en.2017-03120.
Mammalian metabolism has evolved to adapt to changes in nutrient status. Insulin, the key anabolic hormone, facilitates intracellular storage of nutrient fuels and plays a pivotal role in the transition away from catabolism upon refeeding. Although circulating insulin relative to nutrient levels has been well characterized during fasting and refeeding, how pancreatic β-cell biology caters to acute changes in insulin demand has not been sufficiently addressed. Here, we examined the dynamics of (pro)insulin production and associated changes in β-cell ultrastructure during refeeding after a 72-hour fast in male rats. We found that fasted β-cells had marked degranulation, which inversely coordinated with the upregulation of autophagolysomal and lysosomal organelles. There was also expanded Golgi that correlated with enhanced (pro)insulin biosynthetic capacity but, conversely, blunted in vivo insulin secretion. Within 4 to 6 hours of refeeding, proinsulin biosynthesis, cellular ultrastructure, in vivo insulin secretion, and glucose tolerance normalized to levels near those of fed control animals, indicating a rapid replenishment of normal insulin secretory capacity. Thus, during a prolonged fast, the β-cell protects against hypoglycemia by markedly reducing insulin secretory capacity in vivo but is simultaneously poised to efficiently increase (pro)insulin production upon refeeding to effectively return normal insulin secretory capacity within hours.
哺乳动物的新陈代谢已经进化到能够适应营养状态的变化。胰岛素是关键的合成代谢激素，它促进营养物质燃料在细胞内的储存，并在再进食后从分解代谢向合成代谢的转变中发挥关键作用。尽管在禁食和再进食期间，循环胰岛素相对于营养水平的情况已得到充分表征，但胰腺β细胞生物学如何满足胰岛素需求的急性变化尚未得到充分研究。在此，我们研究了雄性大鼠禁食72小时后再进食期间（前）胰岛素产生的动态变化以及β细胞超微结构的相关变化。我们发现，禁食的β细胞有明显的脱颗粒现象，这与自噬溶酶体和溶酶体细胞器的上调呈负相关。高尔基体也有扩张，这与增强的（前）胰岛素生物合成能力相关，但相反，体内胰岛素分泌减弱。再进食4至6小时内，胰岛素原生物合成、细胞超微结构、体内胰岛素分泌和葡萄糖耐量恢复到接近喂食对照动物的水平，表明正常胰岛素分泌能力迅速恢复。因此，在长时间禁食期间，β细胞通过显著降低体内胰岛素分泌能力来预防低血糖，但同时准备好在再进食时有效增加（前）胰岛素的产生，以便在数小时内有效恢复正常胰岛素分泌能力。
