Anti-inflammatory cytokine linked to capillary obstruction and cognitive decline in diabetes

Researchers find that capillary obstruction in diabetes, caused by increased interleukin-10 signaling, may contribute to cognitive deficits independent of blood sugar levels.

From a recent study published in Nature metabolismresearchers examined the impact of type 1 diabetes on capillary blood flow in the brain, investigating the mechanisms behind capillary flow blockages and their association with cognitive impairment.

The study focused on the role of interleukin (IL)-10 signaling in capillary obstruction and used mouse models to investigate potential therapeutic options.

Background

The brain depends on a constant supply of nutrients and oxygen to maintain its high metabolic activity. It obtains this through the blood supplied by a network of small blood vessels. Capillaries make up most of the brain’s vascular structure, and because they are narrow and have low pressure, they support effective oxygen and nutrient exchange.

However, the same properties of capillaries also make them vulnerable to blockages that can temporarily or permanently interrupt circulation. Although the risk of such blockages in healthy individuals is relatively low, inflammatory responses and diseases such as Alzheimer’s disease and stroke significantly increase the risk.

Vascular complications are also quite common with type 1 diabetes, especially in organs such as the eyes, kidneys and brain. Despite the higher risk of stroke and cognitive impairment in type 1 diabetes patients, there is a lack of research on the impact of type 1 diabetes on capillary function in the brain.

About the study

In the current study, the researchers used different genetic mouse models to study IL-10 signaling, which involved knocking out the IL-10 receptor in endothelial cells. In addition, type 1 diabetes was induced in the mice using low doses of streptozotocin injections, after which blood glucose levels were regularly monitored and controlled using insulin pellets during the study.

The researchers carried out in vivo photon imaging using skull window surgery to visualize blood flow in the brain. To do this, the mice were anesthetized, a small part of their skull thinned, and a coverslip placed to allow imaging.

Labeled antibodies and fluorescent dyes were used during two-photon imaging to monitor the leukocytes, neutrophils, and capillary obstructions. The blockages in the capillaries were also measured using a microsphere test in which fluorescent microspheres were injected into the mice and used to analyze obstructions in brain tissue.

The researchers also conducted several behavioral tests at four- and eight-week time points to assess the impact of type 1 diabetes on behavior and to determine whether treatment with IL-10 receptor blocking antibodies was effective in reversing the behavioral disturbances caused. due to diabetes.

The behavioral tests included the novel object recognition test, in which the mice were initially familiarized with a series of objects and then tested with a novel object to determine whether they preferred novelty.

In addition, the Morris water maze test, in which the mice learned to detect the hidden platform in a swimming pool, was used to assess escape latency, swimming speed and memory by changing the location of the platform. The mice were also trained to find a visible platform. Other tests included measurements of the time it took to remove the tape from the paws and assessments of the total distance traveled in an arena.

In addition, the researchers used laser Doppler to assess cerebral blood flow responses to various stimuli, such as inhaling carbon dioxide and sensory stimuli. Blood cytokine levels were also measured and endothelial cells were isolated to perform ribonucleic acid (RNA) analysis and sequencing.

Results

The scientists found that type 1 diabetes mellitus significantly increased the risk of capillary blockages in the brain, which may contribute to cognitive impairment. The diabetic mice had a two to four times higher incidence of blocked capillaries than the healthy controls despite insulin treatment.

The capillary blockages mainly involved red blood cells and not immune cells, suggesting that the microvascular complications in type 1 diabetes may be due to endothelial dysfunction rather than white blood cell clumping. Furthermore, the obstructions occurred more frequently in capillaries branching from arteriovenous vessels, similar to what was observed in Alzheimer’s disease models, but to a more pronounced extent.

The study also identified increased levels of IL-10, an inflammatory cytokine that has shown both harmful and protective effects in several diseases. In this case, the increased levels of IL-10 were found to worsen capillary blockages and cognitive impairment.

However, experimental treatment blocking IL-10 receptors in endothelial cells was found to increase capillary diameter by 25%, improve blood flow, and reduce capillary obstructions by 63%. These improvements were also accompanied by better cognitive outcomes in the areas of memory, cognitive flexibility and learning.

The researchers reported that IL-10 could increase the incidence of blockages in diabetic mice by lowering nitric oxide levels, which in turn increased the expression of adhesion molecules in the capillaries, causing red blood cell aggregation.

Conclusions

Overall, the study suggested that blocking IL-10 signaling in endothelial cells in type 1 diabetes patients could lower the risk of capillary blockages in the brain and possibly improve cognitive function. However, the researchers believe that further research is essential to understand how inhibition of IL-10 would affect other diabetes symptoms.