Endocrine Abstracts

Background and aims: INSmutations can cause INS-MODy and have been described more frequently in cases of neonatal diabetes mellitus. The reported phenotypic expression of INS-MODy is quite variable.

Objective: To clinically, biochemically and molecularly characterize INS-MODy patients in two Spanish tertiary level hospitals during the period 2009-2023.

Methods: Cross-sectional study that included 121 pediatric patients with suspected monogenic diabetes analyzed by targeted NGS with a custom panel (MonDIABV1-4) including up to 482 genes involved in or associated with different types of dysglycemia. Variants were classified according to ACMG and prioritized using confidence and quality criteria, coverage (20x/pb >95%), allele frequency (<1% gnomAD controls), impact and in silico prediction of pathogenicity (CADD V1.6, score >15).

Results: 3/121 patients (2.5%), 2 males and 1 female, aged 15±4.58 years and with BMI 21.8±3.5 Kg/m2, presented with heterozygous INS deleterious variants. Segregation analysis revealed that the previously described (HGMD) pathogenic INS variants NM_000207.3:c.140G>A, p.(Gly47Asp) and NM_000207.3:c.163C>T, p.(Arg55Cys) were de novo. No allelic segregation study could be performed for the NM_000207.3:c.62 C>T; p.(Pro21Leu) (VUS), located in the preproinsulin signal peptide. All patients had a family history of DM, with diabetic debut at 12±2.6 years as simple hyperglycemia without cardinal clinic, negative pancreatic autoimmunity, preserved C-peptide at diagnosis and 2/3 after 4 years from diagnosis. Initial HbA1c was 6.4±0.5% (currently 6.7±2.1%) and their lipoproteic profile was normal. None developed acute or chronic complications after 4±2 years of follow-up. The patient with the INS p.(Pro21Leu) variant was overweight and his HOMA-IR (7.2) indicated insulin resistance, treated with metformin. The patient with the INS p.(Gly47Asp) variant presented poor metabolic control due to poor adherence to low-dose insulin therapy (0.32UI/Kg/day), his DM was initially classified as type 1b, delaying the molecular diagnosis for about 3 years. The patient with the INS p.(Arg55Cys) variant presented good metabolic control with hygienic-dietary measures.

Conclusion: The prevalence of INS-MODy is higher than reported in the literature. In our experience, phenotypic expression occurred in early childhood, varying from mild to severe hyperglycemia with insulinopenia up to insulin resistance in association with other predicted deleterious variants in candidate genes (MODy-X). Suspicion of INS-MODy should be raised in patients with early diabetic debut without pancreatic autoimmunity, even in the absence of a family history of DM. Therefore, the analysis of INS should be included in the molecular diagnostic routine of suspected monogenic diabetes.