Maternally inherited diabetes and deafness (MIDD) is a monogenic mitochondrial disorder caused by a pathogenic variant in the MT-TL1 gene encoding for a leucine transfer RNA. We propose a new hypothesis that explains how the MT-TL1 variant causes impaired glucose tolerance and diabetes in MIDD. We suggest that diabetes in MIDD primarily depends on a variable combination of insulin resistance and impaired beta cell function that seems more likely to occur in the presence of high skeletal muscle heteroplasmy and moderate beta cell heteroplasmy for m.3243A>G. The underlying genetic defect generates oxidative stress and disrupts the tricarboxylic acid cycle, leading to mTORC1 hyperactivity and modifying mitochondrial retrograde signalling. mTORC1 hyperactivity contributes to insulin resistance and beta cell dysfunction and to an increased load of the m.3243A>G phenotypic variant. Abnormal mitochondrial signalling affects the nuclear epigenome and influences MIDD phenotype. Despite being an apparent pathogenic factor, we highlight evidence showing that heteroplasmy in the blood and in tissues, does not fully explain the phenotypic variability of this condition, and that other factors, including mtDNA copy number, additional nuclear or mitochondrial variants, environmental factors and metabolic characteristics of the patient may be contributing factors. A better understanding of the mechanisms leading to MIDD diabetes will help inform novel management strategies for this form of diabetes.

中文翻译：

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与母系遗传性糖尿病和耳聋 （MIDD） 相关的糖尿病：从致病性变异到表型


母系遗传性糖尿病和耳聋 （MIDD） 是一种单基因线粒体疾病，由编码亮氨酸转移 RNA 的 MT-TL1 基因的致病性变异引起。我们提出了一个新的假设，解释了 MT-TL1 变体如何导致 MIDD 中的葡萄糖耐量受损和糖尿病。我们认为 MIDD 中的糖尿病主要取决于胰岛素抵抗和 β 细胞功能受损的可变组合，这似乎更有可能发生在 m.3243A>G 存在高度骨骼肌异质性和中度 β 细胞异质性的情况下。潜在的遗传缺陷产生氧化应激并破坏三羧酸循环，导致 mTORC1 过度活跃并改变线粒体逆行信号。mTORC1 多动导致胰岛素抵抗和 β 细胞功能障碍，并导致 m.3243A>G 表型变异负荷增加。异常的线粒体信号传导会影响核表观基因组并影响 MIDD 表型。尽管是一个明显的致病因素，但我们强调的证据表明，血液和组织中的异质性并不能完全解释这种情况的表型变异性，其他因素，包括 mtDNA 拷贝数、额外的核或线粒体变异、环境因素和患者的代谢特征可能是促成因素。更好地了解导致 MIDD 糖尿病的机制将有助于为这种类型糖尿病的新管理策略提供信息。