A rare homozygous INS variant causes adult-onset diabetes

Abstract

Introduction: Maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM) are the most prevalent causes of monogenic diabetes. MODY is an autosomal dominant condition with onset in childhood and young adulthood, while NDM is defined with diabetes onset within 6 months of age and can be caused by dominant, recessive, X-linked genes or by chromosomal abnormalities. Here, we describe a rare case of monogenic diabetes in a patient who is homozygous for an INS gene variant.

Research design and methods: The index patient, a male diagnosed with type 2 diabetes, was treated with low-dose insulin and metformin. Blood plasma was collected under fasting conditions for analysis. MODY screening was performed using a next-generation sequencing panel. In silico analysis of the insulin variant's three-dimensional structure and its interaction with the insulin receptor was conducted. Insulin receptor affinity and downstream signaling potency were evaluated in vitro.

Results: Auto-immune diabetes was excluded. A homozygous missense variant of the INS gene (c.130G>A, p.Gly44Arg) was identified in the patient. The combination of three different insulin assays showed that the biosynthesis of proinsulin into insulin was intact. In silico analysis of the mutant insulin 3D structure revealed that the INS variant is likely to affect insulin receptor binding and subsequent in vitro analysis suggested reduced potency in downstream signaling.

Conclusions: The homozygous c.130G>A variant in the INS gene results in reduced insulin receptor binding and signaling potency. This, combined with pancreatic β-cell apoptosis or dedifferentiation supposedly, has contributed in the late-onset of monogenic diabetes in the index patient.

Keywords: Biomarkers; Insulin.

Figure 1. (A) Three-dimensional structure of proinsulin with the insulin B-chain (blue) and insulin A-chain (green) connected to the C-peptide (gray) by the A–C and B–C junctions (brown). The position of the protein modification (p.Gly44Arg) induced by the insulin gene variant is marked in red. (B) Graphical representation of the interaction between the mutant insulin (cyan) and the insulin receptor (yellow and gray). The magenta dots indicate amino acids with unknown position. The mutation results in an amino acid substitution of glycine into arginine at position 20 (Gly^B20→Arg) (red) of the insulin’s B-chain (cyan). The close-up representation of the arginine substitution shows that it interferes with the structural organization of the insulin B-chain and the insulin receptor (gray). These images are generated with YASARA visualization software, using PDB file 2kpq (A) and 7STH (B).