Clinical Characterization of Atypical Diabetes: Insights from the GENEPEDIAB Study into the Spectrum Between Type 1 and Monogenic Diabetes

TL;DR

This study shows that diabetes has overlapping features between type 1 and monogenic forms, with atypical diabetes acting as an intermediate stage.

Contribution

The study identifies a phenotypic gradient between type 1 diabetes and monogenic diabetes, emphasizing the need for better screening for accurate diagnosis.

Findings

Atypical diabetes represents an intermediate stage between type 1 and monogenic diabetes.

Glycemic control improves from type 1 diabetes to atypical diabetes and then to MODY.

Rare genetic variants were found in the atypical diabetes cohort, but no uniform causative variant was identified.

Abstract

What are the main findings?
Our results suggest that diabetes encompasses heterogeneous clinical presentations, with features that may overlap between type 1 and monogenic forms. In this study, atypical diabetes represents the intermediate stage, thus bridging the gap between the two other forms.This gradient, although less statistically robust, was also observed when the atypical diabetes cohort was divided based on the number of positive DIAMODIA criteria met.

Our results suggest that diabetes encompasses heterogeneous clinical presentations, with features that may overlap between type 1 and monogenic forms. In this study, atypical diabetes represents the intermediate stage, thus bridging the gap between the two other forms.

This gradient, although less statistically robust, was also observed when the atypical diabetes cohort was divided based on the number of positive DIAMODIA criteria met.

What are the implications of the main findings?
These findings emphasize the clinical heterogeneity of diabetes, complicating the precise etiological diagnosis and highlighting overlap between the different forms of diabetes.Screening for different forms of diabetes is essential to optimizing treatment and care for patients with diabetes.

These findings emphasize the clinical heterogeneity of diabetes, complicating the precise etiological diagnosis and highlighting overlap between the different forms of diabetes.

Screening for different forms of diabetes is essential to optimizing treatment and care for patients with diabetes.

Background: Type 1 diabetes (T1D) shares clinical characteristics with other forms of diabetes, particularly monogenic diabetes such as maturity-onset diabetes of the young (MODY). Differential diagnosis is complicated by the existence of intermediate phenotypes. We aimed to delineate the phenotypic continuum between T1D and monogenic diabetes. Methods: The multicentric GENEPEDIAB study included patients aged 6 months to 18 years diagnosed with diabetes and treated for either T1D or monogenic diabetes. Analyses comprised glycemic variability, continuous glucose monitoring metrics, application of the DIAMODIA criteria, and genetic investigations. Results: A gradient was observed across T1D, atypical diabetes (Adia), and MODY cohorts for several glycemic parameters. T1D patients exhibited values furthest from treatment targets, whereas MODY patients showed better glycemic control. Stratification of the Adia cohort according to the number of positive DIAMODIA criteria further supported this trend, as demonstrated by glycemic measures and multiple correspondence analysis. Genetic analyses did not identify a uniform causative variant in the Adia cohort; however, several rare variants, including variants of uncertain significance and likely pathogenic variants in diabetes-related genes, were detected. Conclusions: These findings showed, in our specific cohort of pediatric patients, the existence of a phenotypic gradient between T1D and monogenic diabetes, with atypical diabetes occupying an intermediate position, including when stratified by DIAMODIA criteria.

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