The regulation of euglycemia is essential for human health with both chronic hypoglycemia and hyperglycemia having detrimental effects. Diabetes risk increases with age and exhibits racial disparity. Interestingly, mitochondrial DNA (mtDNA) damage accumulates with age and its sequence varies with geographic maternal origins (maternal race). From these two observations, we hypothesized that mtDNA background may contribute to glucose metabolism and insulin sensitivity. Pronuclear transfer was used to generate Mitochondrial-Nuclear eXchange (MNX) mice to directly test this hypothesis, by assessing physiologic parameters of glucose metabolism in nuclear isogenic C57BL/6J mice harboring either a C57BL/6J (C57ⁿ:C57^mt wild-type - control) or C3H/HeN mtDNA (C57ⁿ:C3H^mt - MNX). All mice were fed normal chow diets. MNX mice were significantly leaner, had lower leptin levels and were more insulin sensitive, with lower modified Homeostatic Model Assessment of Insulin Resistance (mHOMA-IR) values and enhanced insulin action when compared to their control counterparts. Further interrogation of muscle insulin signaling revealed higher phosphorylated Akt/total Akt ratios in MNX animals relative to control, consistent with greater insulin sensitivity. Overall, these results are consistent with the hypothesis that different mtDNA combinations on the same nuclear DNA (nDNA) background can significantly impact glucose metabolism and insulin sensitivity in healthy mice.

中文翻译：

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Mito-Mendelian 相互作用改变健康小鼠体内葡萄糖代谢和胰岛素敏感性

正常血糖的调节对于人类健康至关重要，慢性低血糖和高血糖都会产生不利影响。糖尿病风险随着年龄的增长而增加，并表现出种族差异。有趣的是，线粒体 DNA (mtDNA) 损伤随着年龄的增长而累积，其序列因地理母系起源（母系种族）而异。根据这两个观察，我们假设 mtDNA 背景可能有助于葡萄糖代谢和胰岛素敏感性。原核转移用于产生线粒体核交换 (MNX) 小鼠以直接检验这一假设，方法是评估携带 C57BL/6J（C57 ⁿ :C57 ^mt野生型 -对照）或 C3H/HeN mtDNA（C57 ⁿ :C3H^mt - MNX）。所有小鼠都喂食正常的食物。与对照小鼠相比，MNX 小鼠明显更瘦，瘦素水平更低，胰岛素敏感性更高，胰岛素抵抗的改良稳态模型评估 (mHOMA-IR) 值更低，胰岛素作用增强。对肌肉胰岛素信号的进一步询问显示，与对照相比，MNX 动物的磷酸化 Akt/总 Akt 比率更高，这与更高的胰岛素敏感性一致。总体而言，这些结果与相同核 DNA (nDNA) 背景下的不同 mtDNA 组合可以显着影响健康小鼠的葡萄糖代谢和胰岛素敏感性的假设一致。