Is Type 2 Diabetes a Primary Mitochondrial Disorder?
Is Type 2 Diabetes a Primary Mitochondrial Disorder?
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糖尿病是遗传性线粒体疾病中最常见的内分泌紊乱。必须提高对这些患者糖尿病正确诊断和治疗的认识，并在家庭成员中筛查糖尿病，因为糖尿病可能会出现不同的临床特征，并发症和不同的发病年龄。糖尿病的严重程度可能表现为大规模的表型，这取决于突变的位置以及受影响的线粒体拷贝数（异质性）是否达到临界阈值。关于糖尿病治疗，由于存在乳酸酸中毒的风险，不建议将二甲双胍作为2型糖尿病（T2 D）的首选治疗。线粒体疾病患者的糖尿病首选治疗是SGLT-2 i和线粒体GLP-1相关物质。线粒体功能障碍、葡萄糖刺激的胰岛素分泌（GSIS）减少和人类患者的糖尿病发展之间的紧密关系是公认的。然而，尽管线粒体在GSIS中的作用得到了很好的表征，但在人类中相对缺乏涉及线粒体功能障碍作为T2 D中的主要缺陷的数据。我们最近的研究提供的数据支持的重要作用，线粒体代谢链酶，细胞色素c氧化酶（考克斯），在调节GSIS在啮齿类动物模型的T2 D，科恩糖尿病敏感（CD）大鼠。营养诱导的糖尿病CD大鼠表现出线粒体疾病的几个特征：几种组织中考克斯活性显著降低，活性氧产生增加，ATP产生减少，胰岛中乳酸脱氢酶表达增加。此外，我们的数据表明，降低胰岛COX活性之前的糖尿病发病，这表明胰岛COX缺乏症是主要缺陷，导致糖尿病在这个模型。本综述探讨了将T2 D纳入原发性肾脏相关疾病的可能性。了解糖尿病和线粒体功能障碍之间的关键相互依赖关系，以考克斯的作用为中心，可能会开辟新的途径来诊断和治疗糖尿病患者的线粒体疾病和线粒体功能障碍的糖尿病患者。
Diabetes mellitus is the most common endocrine disturbance in inherited mitochondrial diseases. It is essential to increase awareness of the correct diagnosis and treatment of diabetes in these patients and screen for the condition in family members, as diabetes might appear with distinctive clinical features, complications and at different ages of onset. The severity of mitochondrial-related diabetes is likely to manifest on a large scale of phenotypes depending on the location of the mutation and whether the number of affected mitochondria copies (heteroplasmy) reaches a critical threshold. Regarding diabetes treatment, the first-choice treatment for type 2 diabetes (T2D), metformin, is not recommended because of the risk of lactic acidosis. The preferred treatment for diabetes in patients with mitochondrial disorders is SGLT-2i and mitochondrial GLP-1-related substances. The tight relationship between mitochondrial dysfunction, reduced glucose-stimulated insulin secretion (GSIS), and diabetes development in human patients is acknowledged. However, despite the well-characterized role of mitochondria in GSIS, there is a relative lack of data in humans implicating mitochondrial dysfunction as a primary defect in T2D. Our recent studies have provided data supporting the significant role of the mitochondrial respiratory-chain enzyme, cytochrome c oxidase (COX), in regulating GSIS in a rodent model of T2D, the Cohen diabetic sensitive (CDs) rat. The nutritionally induced diabetic CDs rat demonstrates several features of mitochondrial diseases: markedly reduced COX activity in several tissues, increased reactive oxygen production, decreased ATP generation, and increased lactate dehydrogenase expression in islets. Moreover, our data demonstrate that reduced islet-COX activity precedes the onset of diabetes, suggesting that islet-COX deficiency is the primary defect causing diabetes in this model. This review examines the possibility of including T2D as a primary mitochondrial-related disease. Understanding the critical interdependence between diabetes and mitochondrial dysfunction, centering on the role of COX, may open novel avenues to diagnose and treat diabetes in patients with mitochondrial diseases and mitochondrial dysfunction in diabetic patients.
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影响因子：
5.6
作者：
Dabravolski SA;Orekhova VA;Baig MS;Bezsonov EE;Starodubova AV;Popkova TV;Orekhov AN
通讯作者：
Orekhov AN
影响因子：
29
作者：
Balsa, Eduardo;Marco, Ricardo;Antonio Enriquez, Jose
通讯作者：
Antonio Enriquez, Jose
影响因子：
6
作者：
Aharon-Hananel G;Romero-Afrima L;Saada A;Mantzur C;Raz I;Weksler-Zangen S
通讯作者：
Weksler-Zangen S
影响因子：
7.7
作者：
Deng, SP;Vatamaniuk, M;Markmann, JF
通讯作者：
Markmann, JF
影响因子：
8.2
作者：
Anello, M;Lupi, R;Marchetti, P
通讯作者：
Marchetti, P