The role of mitochondrial DNA damage at skeletal muscle oxidative stress on the development of type 2 diabetes

Abstract

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

Effects of Type 2 Diabetes Mellitus Induction and of Moderate Physical Exercise on the Hepatic Metabolism and Oxidative Stress in Wistar Rats

“…Thus, the number of animals in each group was: C-S, n = 10; C-PE, 11; HF-S, n = 10; HF-PE, n-11. As shown in our previous study (Santos et al, 2018), the used protocol for T2DM induction in rats was efficient in causing increase in capillary glucose level in animals belonging to the HF-S and HF-PE groups (P=0.002) as shown in Table 1. There was not a significant increase in body weight, lactate, plasma TAG and VLDL (Table 1 and Fig 2A and B, respectively) and 8-isoprostane ( Fig 3) of HF-S and HF-PE group animals when compared to the C-S and C-PE control groups.…”

“…On day 14 , after 12 hours of fasting, rats of HF group received a single intraperitoneal injection with low dosage of streptozotocin (STZ 25mg / kg body weight) (STZ> 98%, Sigma-Aldrich, St. Louis, MO, USA) diluted in citrate buffer, pH 4.5 Control group (C), af-ISSN 2176-7114 -vol. 20, n. 39, Edição Especial -Estresse Oxidativo -2020 ter 12 hours of fasting, received an injection of citrate buffer pH 4.5 (Fig 1) This methodology of T2DM induction was validated by Mansor et al (2013) and successfully tested by our group Santos et al (2018).…”

“…Urea and lactate plasma metabolites were determined by Labtest® colorimetric Kits. Oxidative stress was assessed by the concentration of 8-isoprostane in plasma as previous done by us Santos et al (2018) using ELISA kit (Detroit, R & D, Inc).…”

“…The role of oxidative stress has been an important element for the understanding of the complex mechanism by which diabetes and its complications are developed (SANTOS et al, 2011). Using a methodology to induce T2DM in rodents (a single low injection of streptozotocin combined with high fat diet), our previous study demonstrated that 8-isoprostane (a marker for oxidative stress) is increase in skeletal muscle accounting to mitochondrial dysfunction and insulin resistance (SANTOS et al, 2018). The increase of oxidative stress was suggested to also be involved on the underlying mechanism of diabetes that contributes to liver damage (MOHAMED et al, 2016).…”

Leukocyte Telomere Length Independently Predicts 3-Year Diabetes Risk in a Longitudinal Study of Chinese Population

“…In turn, oxidative stress and inflammation have also been demonstrated to damage telomere [28][29][30] and mtDNA [31,32], which results in a vicious cycle. These changes may contribute to the development of diabetes via their possible involvement in insulin resistance [31,33,34] and β-cell dysfunction [35,36]. Our finding of the positive correlation between LTL and the insulin sensitivity index, the Matsuda index, at baseline indicates an association between telomere shortening and resistance to insulin.…”