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

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

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


PurposeMonogenic 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).MethodsSequencing 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.ResultsMore 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.ConclusionThe 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.

Original languageEnglish
Pages (from-to)583-590
Number of pages8
JournalGenetics in Medicine
Issue number6
StatePublished - Jun 1 2018


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