Johns Hopkins University has received a USD 2.5 million NIH R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to investigate whether Toll-like receptor 4 (TLR4)-driven pancreatic islet loss and hyperglycemia are causative drivers of necrotizing enterocolitis (NEC), a gastrointestinal condition that carries high mortality in premature infants, and to develop dual-action therapeutic agents targeting this axis.
NEC remains among the most lethal gastrointestinal emergencies in neonatal medicine, with no approved disease-modifying therapies. Most research has focused on intestinal barrier dysfunction and bacterial translocation as primary mechanisms. The Hopkins work, led by principal investigator David J. Hackam in the Department of Surgery, repositions pancreatic endocrine failure — specifically TLR4-mediated islet loss and the resulting hyperglycemia — as an upstream driver rather than a bystander finding.
Preclinical and translational evidence supporting this hypothesis includes reduced islet mass in autopsy specimens from infants who died with NEC, elevated blood glucose preceding NEC onset in mouse and piglet models, and, in a multicenter cohort of 854 patients, hyperglycemia documented several weeks before clinical NEC diagnosis. In mice, insulin administration reversed hyperglycemia and prevented NEC development. The team also reported that enhancing islet regeneration through an intra-pancreatic adenoviral gene transfer approach, or through peroxisome proliferator-activated receptor gamma (PPARγ) activation, reduced NEC severity. Genetic deletion of TLR4 specifically in insulin-producing cells, and pancreatic injection of the TLR4 inhibitor C34, each protected animals from islet loss.