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

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 Sequ...

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Bibliographic Details
Published in:Genetics in medicine Vol. 20; no. 6; pp. 583 - 590
Main Authors: Kleinberger, Jeffrey W, Copeland, Kenneth C, Gandica, Rachelle G, Haymond, Morey W, Levitsky, Lynne L, Linder, Barbara, Shuldiner, Alan R, Tollefsen, Sherida, White, Neil H, Pollin, Toni I
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.06.2018
Elsevier Limited
Subjects:
692/308/2779/109
692/699/2743/137/773
692/699/2743/393
692/700/139
Adolescent
Biomedical and Life Sciences
Biomedicine
Body Mass Index
Child
Clinical trials
Cohort Studies
Diabetes
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Female
Germinal Center Kinases
Hepatocyte Nuclear Factor 1-alpha - genetics
Hepatocyte Nuclear Factor 1-alpha - metabolism
Hepatocyte Nuclear Factor 4 - genetics
Hepatocyte Nuclear Factor 4 - metabolism
Human Genetics
Humans
Laboratory Medicine
Male
Obesity
Obesity - complications
Obesity - genetics
original-research-article
Overweight - complications
Overweight - genetics
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Teenagers
clinical trial
type 2 diabetes
monogenic diabetes
obesity
youth
ISSN:1098-3600, 1530-0366, 1530-0366
Online Access:Get full text
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Summary: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.
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A listing of the TODAY Study Group can be found in the online appendix
ISSN:1098-3600
1530-0366
1530-0366
DOI:10.1038/gim.2017.150