Person:

Levitsky, Lynne

OBJECTIVE To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy. RESEARCH DESIGN AND METHODS TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: 1) those who remained in glycemic control for at least 48 months of follow-up and 2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points. RESULTS In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1). CONCLUSIONS Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non–diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.

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 TODAY clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed. Results: 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. Conclusions: 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.