Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
PLoS One. 2013;8(2):e54351. doi: 10.1371/journal.pone.0054351. Epub 2013 Feb 7.
Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing evidence indicates that in early stages of type-2 diabetes and some types of monogenic diabetes linked with malfunctioning endoplasmic-reticulum (ER), the β-cell ER fails to process sufficient proinsulin once it becomes overloaded. These changes manifest with ER distention (ER-crowding) and deficiency of secretory granules. We hypothesize that insulin therapy may improves β-cell function by alleviating ER-crowding. To support this hypothesis, we investigated pre-diabetic β-cell changes in hProC(A7)Y-CpepGFP transgenic mice that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding. We attenuated the β-cell ER proinsulin synthesis with a treat-to-target insulin therapy while avoiding hypoglycemia and weight gain. Alleviation of ER-crowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tolerance. Our observations suggest that alleviation of pre-diabetic ER-crowding using a treat-to-target insulin therapy may improve β-cell function and may prevent further metabolic deterioration.
胰岛素治疗通过可能超过缓解糖毒性的机制改善糖尿病早期的β细胞功能。在 2 型糖尿病的早期阶段，高血糖会导致β细胞损伤，最终导致β细胞丧失。在这种晚期阶段，治疗方法往往不够充分。越来越多的证据表明，在 2 型糖尿病的早期阶段和一些与内质网（ER）功能障碍相关的单基因糖尿病中，β细胞 ER 一旦超载，就无法处理足够的胰岛素原。这些变化表现为 ER 扩张（拥挤）和分泌颗粒缺乏。我们假设胰岛素治疗可以通过缓解 ER 拥挤来改善β细胞功能。为了支持这一假设，我们研究了 hProC(A7)Y-CpepGFP 转基因小鼠的前糖尿病β细胞变化，这些小鼠由于胰岛素原发育不良和 ER 拥挤而发展为长期前糖尿病。我们使用针对目标的胰岛素治疗来减轻β细胞 ER 中胰岛素原的合成，同时避免低血糖和体重增加。缓解 ER 拥挤导致胰岛素原成熟、胰岛素分泌和葡萄糖耐量的暂时性改善。我们的观察结果表明，使用针对目标的胰岛素治疗来缓解前糖尿病 ER 拥挤可能会改善β细胞功能，并可能防止进一步的代谢恶化。
