Many faces of monogenic diabetes

Abstract

Monogenic diabetes represents a heterogeneous group of disorders resulting from defects in single genes. Defects are categorized primarily into two groups: disruption of β-cell function or a reduction in the number of β-cells. A complex network of transcription factors control pancreas formation, and a dysfunction of regulators high in the hierarchy leads to pancreatic agenesis. Dysfunction among factors further downstream might cause organ hypoplasia, absence of islets of Langerhans or a reduction in the number of β-cells. Many transcription factors have pleiotropic effects, explaining the association of diabetes with other congenital malformations, including cerebellar agenesis and pituitary agenesis. Monogenic diabetes variants are classified conventionally according to age of onset, with neonatal diabetes occurring before the age of 6 months and maturity onset diabetes of the young (MODY) manifesting before the age of 25 years. Recently, certain familial genetic defects were shown to manifest as neonatal diabetes, MODY or even adult onset diabetes. Patients with neonatal diabetes require a thorough genetic work-up in any case, and because extensive phenotypic overlap exists between monogenic, type 2, and type 1 diabetes, genetic analysis will also help improve diagnosis in these cases. Next generation sequencing will facilitate rapid screening, leading to the discovery of digenic and oligogenic diabetes variants, and helping to improve our understanding of the genetics underlying other types of diabetes. An accurate diagnosis remains important, because it might lead to a change in the treatment of affected subjects and influence long-term complications.

Keywords: Monogenic diabetes; Next generation sequencing.

Figure 1

Schematic β‐cell. Subcellular localization of defects within the β‐cell leading to monogenic diabetes. Starting at glucose uptake at the GLUT2 transporter, during phosphorylation by the enzyme glucokinase or during glycolysis. Dysfunction of the adenosine triphosphate‐sensitive potassium (K_ATP) channel with the KIR6.2 subunits (brown) and SUR1 subunits (red) will interfere with insulin secretion. Malfunction of the transcription factors located in the nucleus will lead to the nucleopathies and finally endoplasmic reticulum (ER) stress and lysosomal defects can also cause diabetes. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT2, glucose transporter 2.