In people with diabetes, high levels of blood sugar disrupts the function of key cell subsets in the lungs that regulate the immune response, increasing the risk of developing severe lung disease if infected with viruses such as influenza, as well as with bacteria and fungi.
To understand the mechanism behind, researchers from the Weizmann Institute of Science in Israel subjected multiple mouse models of types 1 and 2 diabetes to a variety of viral lung infections.
Just as in diabetic humans, in all these models the diabetic mice developed a severe, fatal lung infection following exposure to lung pathogens such as influenza.
The immune reaction, which in nondiabetics eliminates the infection and drives tissue healing, was severely impaired in the diabetic mice, leading to uncontrolled infection, lung damage and eventual death, revealed the study published in Nature.
Further, to decode the basis of this heightened risk, the team performed an evaluation of gene expression on the level of individual cells, in more than 150,000 single lung cells of infected diabetic and nondiabetic mice.
In the diabetic mice they identified a dysfunction of certain lung dendritic cells, the immune cells that orchestrate a targeted immune response against pathogenic infection.
“High blood sugar levels severely disrupt certain subsets of dendritic cells in the lung, preventing these gatekeepers from sending the molecular messages that activate the critically important immune response,” said Samuel Nobs, a postdoctoral researcher at the Institute. “As a result, the infection rages on, uncontrolled.”
Importantly, the scientists discovered how high sugar levels in diabetic mice disrupt the normal function of lung dendritic cells during infection. Altered sugar metabolism in these cells led to the accumulation of metabolic byproducts that markedly disrupted the normal regulation of gene expression, leading to aberrant immune protein production.
“This could explain why the functioning of these cells is disturbed in diabetes, and why the immune system is unable to generate an effective anti-infection defence,” said Aleksandra Kolodziejczyk, another postdoctoral student at the Institute.
The scientists next found that tight control of blood sugar levels by insulin supplementation prompted the dendritic cells to regain their capacity to generate a protective immune response that could prevent the cascade of events leading to a severe, life-threatening viral lung infection.
Alternatively, administration of small molecules reversing the sugar-induced regulatory impairment corrected the dendritic cells’ dysfunction and enabled them to generate a protective immune response despite the presence of high sugar levels.