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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #363757
Title: Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: The TODAY clinical trial

Author
item KLEINBERGER, JEFFREY - University Of Maryland School Of Medicine
item COPELAND, KENNETH - University Of Oklahoma
item GANDICA, RACHELLE - Columbia University - New York
item HAYMOND, MOREY - Baylor College Of Medicine
item LEVITSKY, LYNNE - Massachusetts General Hospital
item LINDER, BARBARA - National Institutes Of Health (NIH)
item SHULDINER, ALAN - University Of Maryland School Of Medicine
item TOLLEFSEN, SHERIDA - St Louis University
item WHITE, NEIL - Washington University School Of Medicine
item POLLIN, TONI - University Of Maryland School Of Medicine

Submitted to: Genetics in Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2017
Publication Date: 6/1/2018
Citation: Kleinberger, J.W., Copeland, K.C., Gandica, R.G., Haymond, M.W., Levitsky, L.L., Linder, B., Shuldiner, A.R., Tollefsen, S., White, N.H., Pollin, T.I. 2018. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: The TODAY clinical trial. Genetics in Medicine. 20(6):583-590. https://doi.org/10.1038/gim.2017.150.
DOI: https://doi.org/10.1038/gim.2017.150

Interpretive Summary: Some patients develop diabetes early in their lives as a result of the inheritance of a single gene that can result in various forms of diabetes. It is estimated that some 2% of cases of diabetes could be the result of one of these gene defects. In a cross sectional study of 488 adolescents with established adult onset type diabetes participating the study called the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, we identified 22 individuals of the 488 had one of 5 known causes for monogenic diabetes. These subjects were slightly lighter (less fat) than the others in the study without monogenic diabetes. Depending on their particular gene defect, some failed therapy early and some never failed therapy. We reported that adolescents and children presenting without the typical positive plasma antibodies associated with type 1 diabetes, the diagnosis of monogenic diabetes should be considered. Findings from this study aid in managing diabetes in youth.

Technical Abstract: 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). 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. Over four percent (22/488) had genetic variants causing monogenic diabetes (7 GCK, 7 HNF4A, 5 HNF1A, 2 INS, and 1 KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower BMI Z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (HR=5.03, p=0.0002), while none with GCK variants failed treatment. Discovery of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests 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.