Diabetes increases the risk of heart failure and kidney disease. Until now, it was primarily assumed that high blood sugar levels put strain on blood vessels and tissue in the long term. A new study now shows that diabetes also triggers an immune mechanism that directly leads to inflammation, tissue damage and organ failure.
What is new is the clear evidence that high sugar levels immediately activate neutrophils. In heart biopsies from patients with heart failure and diabetes, the researchers found significantly more neutrophil extracellular traps (NETs). These networks of DNA and proteins are formed when neutrophils respond to stress. The more NETs that had accumulated in the heart muscle, the more severely the pumping function was impaired.
Enzyme PAD4 is the link between diabetes and organ damage
The study shows for the first time that this process is controlled by the enzyme PAD4 and that PAD4 is a key link between diabetes and organ damage. The researchers found significantly more NETs in heart tissue from patients with heart failure and diabetes than in samples from people without diabetes. The more pronounced these NET deposits were, the poorer the heart's pumping function. This direct link between diabetes, NETs in the heart muscle and impaired heart function had not been demonstrated previously.
The mechanism was confirmed in a mouse model. Although all animals were equally diabetic, only mice with functioning PAD4 developed heart failure, fibrosis in the heart muscle and kidney damage. Mice without PAD4 remained largely protected. This shows that the damage is not caused solely by high sugar levels, but by the immune response enabled by PAD4.
‘We see here a mechanism that explains the transition from diabetes to heart and kidney disease,’ says the group. ‘PAD4 acts like a switch that programmes neutrophils for inflammation. Without this switch, the typical consequential damage does not occur.’
The results open up a new therapeutic approach: targeted inhibition of PAD4 could prevent diabetes from leading to heart and kidney failure.
Original publication:
Schommer N, Gendron N, Krauel K, et al. Neutrophil extracellular traps and peptidylarginine deiminase 4-mediated inflammasome activation link diabetes to cardiorenal injury and heart failure. Eur Heart J. Published online November 27, 2025. doi:10.1093/eurheartj/ehaf963
