Incretin effect is sufficient for glucose control in developing rats

Hyperglycemia is common in extremely preterm infants, and the treatment of neonatal hyperglycemia should be associated with a low risk of hypoglycemia. Incretin-based therapies are characterized by a low risk of hypoglycemia and are efficacious and safe in adults. We aimed to investigate the extent to which the glucose-lowering effect of incretin hormone-enhanced insulin secretion contributes to glucose regulation in healthy, developing rat pups and to evaluate the associated risk of hypoglycemia. We performed oral glucose tolerance (OGTT) and intraperitoneal glucose tolerance test (IPGTT) in 2-week-old Wistar rats and compared the serum concentrations of glucose, insulin, and incretin hormones. OGTT was associated with significantly higher serum incretin hormone concentrations than IPGTT in the pups, and the serum insulin concentrations were higher during OGTT than during IPGTT (the incretin effect was 63%). Thus, the incretin effects were present and substantial in the rat pups. We next administered two drugs (a dipeptidyl peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist) with incretin effects and evaluated the risk of adverse hypoglycemic events in normal developing rats. Standard therapeutic doses of linagliptin and liraglutide did not influence the blood glucose concentrations of 2-week-old pups, and no hypoglycemia developed. In conclusion, we have shown that endogenous incretin hormones stimulate insulin secretion in normal 2-week-old rats, as in adults. Furthermore, neither a DPP-4 inhibitor nor a GLP-1 receptor agonist induced hypoglycemia as an adverse effect. Therefore, incretin hormones may be safe therapeutic targets for hyperglycemia in preterm infants.