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10-12-2017 | MODY | Article

Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial

Authors: Jeffrey W Kleinberger, Kenneth C Copeland, Rachelle G Gandica, Morey W Haymond, Lynne L Levitsky, Barbara Linder, Alan R Shuldiner, Sherida Tollefsen, Neil H White, Toni I Pollin

Abstract

Purpose

Monogenic diabetes accounts for 1–2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).

Methods

Sequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.

Results

More than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.

Conclusion

The finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.

Genet Med 2017. doi: 10.1038/gim.2017.150

 

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