Neonatal diabetes mellitus around the world: Update 2024

Abstract

Neonatal diabetes mellitus (NDM), defined as diabetes with an onset during the first 6 months of life, is a rare form of monogenic diabetes. The initial publications on this condition began appearing in the second half of the 1990s and quite surprisingly, the search for new NDM genes is still ongoing with great vigor. Between 2018 and early 2024, six brand new NDM-genes have been discovered (CNOT1, FICD, ONECUT1, PDIA6, YIPF5, ZNF808) and three genes known to cause different diseases were identified as NDM-genes (EIF2B1, NARS2, KCNMA1). In addition, NDM cases carrying mutations in three other genes known to give rise to diabetes during childhood have been also identified (AGPAT2, BSCL2, PIK3R1). As a consequence, the list of NDM genes now exceeds 40. This genetic heterogeneity translates into many different mechanism(s) of disease that are being investigated with state-of-the-art methodologies, such as induced pluripotent stem cells (iPSC) and human embryonic stem cells (hESC) manipulated with the CRISPR technique of genome editing. This diversity in genetic causes and the pathophysiology of diabetes dictate the need for a variety of therapeutic approaches. The aim of this paper is to provide an overview on recent achievements in all aspects of this area of research.

Keywords: Diabetes; Mellitus; Neonatal.

Figure 1

Neonatal diabetes genes. Most gene products are located in the nucleus (transcription factors) or in the endoplasmic reticulum (ER). Gene in black font in the nucleus and in red font in the ER are recently identified genes. Genes responsible of glucose‐induced insulin secretion are on the beta cell membrane (e.g. KCNJ11, ABCC8) or in the cytoplasm (GCK). Large deletions of mitochondrial DNA (m.DNA) have been recently reported to give rise to neonatal diabetes; NARS2 is also expressed in mitochondria. INSR causes severe insulin resistance and neonatal diabetes by impairing insulin action in all major insulin‐sensitive tissues (skeletal muscle, liver and adipose tissue). Genes responsible for congenital generalized lipodystrophies AGPAT2, BSCL2) or partial loss of subcutaneous fat (SHORT syndrome, PIK3R1) are depicted in adipose tissue, though all 3 genes are expressed in many organs/tissues. Please note that chromosomal abnormalities of 6q24 leading to transient neonatal diabetes mellitus and trisomy 21 leading to autoimmune permanent neonatal diabetes not linked to HLA are not included in the figure. KCNMA1 is not shown because only one patients has been reported so far.