INRA, Institut National de la Recherche Agronomique, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université Montpellier 1, Montpellier, France; Université Montpellier 2, Montpellier, France.
PLoS One. 2013 Sep 30;8(9):e75111. doi: 10.1371/journal.pone.0075111. eCollection 2013.
Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43-/- mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43-/- mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43-/- mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.
甲状腺激素 (TH) 在能量消耗调节中发挥着重要的调节作用，是线粒体活性的关键调节剂。我们之前已经鉴定出一种线粒体三碘甲状腺原氨酸 (T3) 受体 (p43)，它作为细胞器基因组的线粒体转录因子起作用，导致体外和体内线粒体生物发生的刺激。最近，我们生成了携带特定 p43 无效突变的小鼠。在 2 个月大时，我们报告称 p43 耗竭在小鼠中诱导了体内和分离的胰岛中胰岛素分泌的主要缺陷，以及葡萄糖刺激的胰岛素分泌丧失。本研究旨在确定 p43 无效突变是否影响预期寿命，并在衰老过程中调节血糖和胰岛素水平以及葡萄糖耐量或胰岛素敏感性。我们报告称，从 4 个月大开始，缺乏 p43 的小鼠比野生型小鼠更瘦。与野生型相比，p43-/- 小鼠的预期寿命也适度缩短。我们发现血糖水平没有差异，除了在 24 个月大时，p43-/- 小鼠在禁食条件下表现出强烈的高血糖，与对照动物相比。然而，无论缺乏 p43 的小鼠的年龄如何，葡萄糖刺激的胰岛素分泌丧失都得以维持。如果直到 12 个月大，葡萄糖耐量保持不变，超过这个年龄，p43-/- 小鼠对葡萄糖的耐受性逐渐降低。此外，如果直到 12 个月大，p43 缺乏的动物对胰岛素更敏感，超过这个年龄，我们观察到这种能力丧失，最终导致 24 个月大的小鼠对激素的敏感性降低。总之，我们证明在衰老过程中，小鼠中线粒体 T3 受体 p43 的耗竭逐渐导致空腹状态下血糖升高、葡萄糖耐量降低和胰岛素抵抗，这些都是 2 型糖尿病的特征。
