Molecular Basis of Neonatal Diabetes Mellitus and Transient Hyperglycemia in the Neonate

Neonatal diabetes mellitus (NDM) is a rare monogenic disorder characterized by persistent hyperglycemia requiring insulin therapy, typically diagnosed within the first six months of life and less commonly between six and 12 months. NDM may be transient, with frequent relapses during puberty, or permanent and can be associated with extra-pancreatic manifestations or be part of a syndrome. This monogenic form of diabetes is caused by pathogenic variants in genes or chromosomal loci involved in the development and function of pancreatic beta-cells and in insulin synthesis and secretion. Mutations in more than 40 genes have been identified to be implicated in the pathogenesis of NDM. Abnormalities of the 6q24 locus have been recognized as the most common cause of transient NDM, whereas mutations in genes encoding ATP-sensitive potassium (KATP) channels, particularly KCNJ11, are more commonly identified in permanent NDΜ cases. In NDM cases, the clinical course, the presence of extra-pancreatic manifestations, and the optimal treatment depend on the causative gene. Therefore, genetic diagnosis is imperative, as it can facilitate the individualization of management strategies and long-term follow-up, as well as genetic counselling. However, hyperglycemia in the neonatal population, particularly in preterm and/or critically ill neonates, may be observed outside the NDM range due to immaturity and transient beta-cell dysregulation, insulin resistance, epigenetic modifications, or drug administration. The aim of this narrative review is to provide an overview of the genetic basis of NDM and the mechanisms underlying transient hyperglycemic states in neonates.