Department of Endocrinology and Metabolism, the First Hospital of Jilin University, Changchun, China.
Front Endocrinol (Lausanne). 2020 Nov 23;11:592129. doi: 10.3389/fendo.2020.592129. eCollection 2020.
Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.
线粒体和内质网（ER）在多个位点相连，这些位点被称为线粒体相关内质网膜（MAMs）。这些关联被认为在维持细胞内稳态中起着重要作用。MAM 信号转导受损在许多疾病中产生广泛影响，如肥胖症、糖尿病和神经退行性疾病。越来越多的证据表明，MAMs 通过不同的途径影响胰岛素信号转导，包括与 Ca 信号转导、脂质代谢、线粒体功能、ER 应激反应和炎症相关的途径。MAM 信号转导的改变是不同组织（包括肝脏、肌肉，甚至大脑）中胰岛素抵抗的共同特征。在肝脏中，MAMs 是关键的葡萄糖感应调节剂，被认为是胰岛素信号转导的枢纽。据报道，MAM 完整性受损会破坏肝脏在营养转变过程中对葡萄糖供应变化的反应，并诱导肝脏胰岛素抵抗。同时，这些效应可以通过加强 MAM 相互作用来挽救。相比之下，有几项研究提出增强 ER-线粒体连接对肝脏胰岛素信号转导有害，并可能导致线粒体功能障碍。因此，鉴于这些相互矛盾的结果，MAM 在调节肝脏胰岛素信号转导中的作用仍然难以捉摸。同样，在骨骼肌中，早期增强 MAM 形成可能是有益的，而持续增强 MAM 则会加剧胰岛素抵抗。此外，最近的研究表明，内质网应激可能是 MAMs 诱导大脑胰岛素抵抗的主要途径，特别是在下丘脑中。本综述将讨论与 MAM 相关的胰岛素抵抗的潜在机制，以及靶向 MAM 在治疗 2 型糖尿病中的治疗潜力。
