Kumar et al. (2020) recently published a novel manuscript that combined work on cellular and mouse models shows that hyperglycemic conditions and the resultant metabolic alterations cause DNA double‐strand break (DSB)‐dependent inflammation and fibrosis, suggesting a new paradigm for therapeutic interventions.
Metabolic changes that occur in cases of diabetes are associated with an inability to repair damaged organs. In individuals affected with diabetes, incidences of fibrosis are commonly seen in organs such as the kidneys, lungs, and liver. It has been described that increased DNA damage and an inability for DNA repair mechanisms occur in both Type 1 and Type 2, which can lead to cellular senescence, increased inflammatory profiles, and ultimately organ fibrosis. The goal of this paper was to provide evidence that maladaptive metabolic stress is a result of impaired DNA repair and DSB dependent inflammation and fibrosis by using mechanisms involved in DNA repair to overcome diabetes-induced damage.
The researchers looked at different aspects of DNA repair and DNA damage, some of which included:
- Cellular impact of decreased pre-natal O2 exposure on survival and DNA repair
- Prolonged exposure of high concentration of reducing sugars on DNA damage and repair
- DNA repair mechanisms present in murine diabetic models compared to WT
- DNA signalling and repair mechanisms and the incidence of organ fibrosis
- Lung function analysis of fibrotic incidence:
- The flexiVent was used to measure pressure-volume loops to assess the distensibility of the respiratory system over the entire inspiratory capacity (i.e. from the end of expiration to total lung capacity)
Mechanism of DNA Damage: Firstly, the researchers sought to identify which mechanisms of DNA damage were involved with maladaptive metabolic processes by assessing increased ROS and the effect of prolonged exposure to a high concentration of reducing sugars. They concluded that high carbohydrate exposure results in cellular NAD+ pool depletion and defective DSB DNA‐repair. Additionally, high blood glucose is associated with cellular senescence and persistent DNA damage in vivo.
Incidence of fibrosis: Secondly, they looked at the level of fibrosis in their SKT murine diabetic models compared to the WT and concluded diabetes‐induced, persistent DNA damage signalling is associated with pulmonary and renal fibrosis. They characterized the functional impact of pulmonary fibrosis in vivo and concluded that diabetes results in a significant decrease in lung function, mimicking the condition of restrictive lung disease. Please see the graphical summary below:
Therapeutic intervention: Finally, the researchers sought to investigate novel DNA repair mechanisms to overcome the DSB dependant inflammatory and fibrotic response seen in the diabetic models. They utilized non phosphorylated nuclear RAGE given its DNA repair potential. When the phosphomimetic mutant (RAGES376E–S389E) was transduced in STZ mice, diabetic for 6 months, a drastic reduction of the DNA-DSBs-associated damage was seen on a cellar and in-vivo function level.
Metabolite-induced DNA damage, DDR, and persistent DNA damage signaling are seen for several complications of diabetes. Identifying these similarities may lead the way to novel therapies, including phosphomimetic RAGE, aiming not only to prevent but rather to reduce diabetes-induced organ fibrosis and dysfunction.
For a very effective visual summary, the researchers created a 4-minute-long YouTube video reviewing the mechanism in which maladaptive metabolic processes and DNA damage can lead to fibrosis:
The full publication is freely accessible with the link below:
- Kumar, V., et al. (2020). Compromised DNA repair is responsible for diabetes associated fibrosis. The EMBO Journal
Additional publications featuring the flexiVent and diabetic research
There is a significant amount of research indicating obesity and diabetes may lead to pulmonary hypertension and higher rates of respiratory disease such as ARDS and asthma. Additionally, there are consistent epidemiological reports of reduced force vital capacity measurements in diabetic subjects vs. healthy subjects (Klien et al. 2010). The flexiVent can be used in preclinical subjects to study:
- Measurements of central vs. peripheral airways resistance, combined with delivered dose estimators and automated dose-response features
- Forced Expired Volume (FEV) measurements for clinically translatable outcomes
- Comprehensive analysis of the mechanical properties of the lung with inflammation and during the evolution of lung injury, including Pressure-Volume loops and static compliance (Cst)
For further reading, below are a collection of publications featuring the flexiVent and in-vivo pulmonary function assessment of diabetic models:
- Baack et al. (2016) Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung. Respiratory Physiology and Neurobiology. 247:96-102
- Diabetes only-exposed offspring demonstrated the most compliant lungs with a significantly higher pressure-volume loop area (Fig 6A and 6B). However, combination-exposed offspring had the least compliant lungs with a significantly lower pressure-volume loop area and reduced static compliance (Fig 6A–6C)
- Dias et al. (2018). Metformin influences on respiratory system in obese mice induced by postnatal overnutrition
- Using the flexiVent for dose-response assessment, there was evidence of increased pulmonary hypersensitivity in the control group vs. obese group but no change in the obese group vs. metformin-treated group (Figure 2). In addition, metformin did not improve other pulmonary function such as VEGF-a.
- Pascoe, C. et al. (2019). Investigating the link between gestational diabetes and risk of asthma in offspring using a mouse model. American Journal of respiratory and Critical Care Medicine
- Offspring from the high-fat diet mice had an increase in lung hysteresivity and resistance compared to low-fat diet offspring in male subjects but not female subjects.