Aims/hypothesis

This study interrogated mitochondrial respiratory function and content in skeletal muscle biopsies of healthy adults between 30 and 72 years old with and without uncomplicated type 1 diabetes.

Methods

Participants (12 women/nine men) with type 1 diabetes (48 ± 11 years of age), without overt complications, were matched for age, sex, BMI and level of physical activity to participants without diabetes (control participants) (49 ± 12 years of age). Participants underwent a Bergström biopsy of the vastus lateralis to assess mitochondrial respiratory function using high-resolution respirometry and citrate synthase activity. Electron microscopy was used to quantify mitochondrial content and cristae (pixel) density.

Results

Mean mitochondrial area density was 27% lower (p = 0.006) in participants with type 1 diabetes compared with control participants. This was largely due to smaller mitochondrial fragments in women with type 1 diabetes (−18%, p = 0.057), as opposed to a decrease in the total number of mitochondrial fragments in men with diabetes (−28%, p = 0.130). Mitochondrial respiratory measures, whether estimated per milligram of tissue (i.e. mass-specific) or normalised to area density (i.e. intrinsic mitochondrial function), differed between cohorts, and demonstrated sexual dimorphism. Mass-specific mitochondrial oxidative phosphorylation (OXPHOS) capacity with the substrates for complex I and complex II (C_I + II) was significantly lower (−24%, p = 0.033) in women with type 1 diabetes compared with control participants, whereas mass-specific OXPHOS capacities with substrates for complex I only (pyruvate [C_{I pyr}] or glutamate [C_{I glu}]) or complex II only (succinate [C_{II succ}]) were not different (p > 0.404). No statistical differences (p > 0.397) were found in mass-specific OXPHOS capacity in men with type 1 diabetes compared with control participants despite a 42% non-significant increase in C_{I glu} OXPHOS capacity (p = 0.218). In contrast, intrinsic C_I + II OXPHOS capacity was not different in women with type 1 diabetes (+5%, p = 0.378), whereas in men with type 1 diabetes it was 25% higher (p = 0.163) compared with control participants. Men with type 1 diabetes also demonstrated higher intrinsic OXPHOS capacity for C_{I pyr} (+50%, p = 0.159), C_{I glu} (+88%, p = 0.033) and C_{II succ} (+28%, p = 0.123), as well as higher intrinsic respiratory rates with low (more physiological) concentrations of either ADP, pyruvate, glutamate or succinate (p < 0.012). Women with type 1 diabetes had higher (p < 0.003) intrinsic respiratory rates with low concentrations of succinate only. Calculated aerobic fitness (Physical Working Capacity Test [PWC₁₃₀]) showed a strong relationship with mitochondrial respiratory function and content in the type 1 diabetes cohort.

Conclusions/interpretation

In middle- to older-aged adults with uncomplicated type 1 diabetes, we conclude that skeletal muscle mitochondria differentially adapt to type 1 diabetes and demonstrate sexual dimorphism. Importantly, these cellular alterations were significantly associated with our metric of aerobic fitness (PWC₁₃₀) and preceded notable impairments in skeletal mass and strength.

Graphical abstract

中文翻译：

---

患有单纯性 1 型糖尿病的中老年女性和男性骨骼肌中的内在线粒体呼吸正常至增强

目标/假设

这项研究询问了 30 至 72 岁健康成年人骨骼肌活检中的线粒体呼吸功能和含量，这些成年人患有或未患有单纯性 1 型糖尿病。

方法

患有 1 型糖尿病（48 ± 11 岁）且没有明显并发症的参与者（12 名女性/9 名男性）在年龄、性别、BMI 和体力活动水平方面与非糖尿病参与者（对照参与者）（49 ± 12岁）。参与者接受了股外侧肌的 Bergström 活检，以使用高分辨率呼​​吸测定法和柠檬酸合酶活性评估线粒体呼吸功能。电子显微镜用于量化线粒体含量和嵴（像素）密度。

结果

 与对照参与者相比，1 型糖尿病参与者的平均线粒体面积密度低 27% ( p = 0.006)。这主要是由于 1 型糖尿病女性线粒体碎片较小（-18%，p  = 0.057），而不是糖尿病男性线粒体碎片总数减少（-28%，p  = 0.130）。线粒体呼吸测量，无论是估计每毫克组织（即质量特异性）还是标准化为面积密度（即内在线粒体功能），在队列之间存在差异，并表现出性别二态性。_{复合物 I 和复合物 II (C I + II} )底物的质量特异性线粒体氧化磷酸化 (OXPHOS) 能力显着降低 (-24%,p  = 0.033) 与对照组参与者相比，1 型糖尿病女性的质量特异性 OXPHOS 能力仅对复合物 I（丙酮酸 [C _{I pyr} ] 或谷氨酸 [C _{I glu} ]）或复合物 II（琥珀酸 [C _{II succ} ]) 没有不同 ( p >  0.404)。_{尽管 C I glu} OXPHOS 容量 增加了 42% （ p  = 0.218） ，但与对照组参与者相比，1 型糖尿病男性的质量特异性 OXPHOS 容量没有发现统计学差异（p > 0.397）。相比之下，1 型糖尿病女性的内在 C _{I + II} OXPHOS 能力没有差异（+5%，p = 0.378），而在患有 1 型糖尿病的男性中，与对照组参与者相比， 这一比例高出 25%（p = 0.163）。患有 1 型糖尿病的男性对 C _{I pyr} (+50%, p  = 0.159)、C _{I glu} (+88%, p  = 0.033) 和 C _{II succ} (+28%, p  = 0.123)也表现出更高的内在 OXPHOS 能力，以及在 ADP、丙酮酸、谷氨酸或琥珀酸浓度较低（更生理）的情况下较高的内在呼吸频率 ( p  < 0.012)。 仅使用低浓度琥珀酸盐的1 型糖尿病女性的内在呼吸频率较高 ( p < 0.003)。计算的有氧适能（体力工作能力测试 [PWC₁₃₀ ]）在 1 型糖尿病队列中显示与线粒体呼吸功能和含量密切相关。

结论/解释

在患有单纯性 1 型糖尿病的中老年人中，我们得出结论，骨骼肌线粒体对 1 型糖尿病有不同的适应并表现出性别二态性。重要的是，这些细胞改变与我们的有氧适能指标（PWC ₁₃₀）显着相关，并且在骨骼质量和力量出现显着损伤之前。

图形概要