Subphenotypes of youth-onset type 2 diabetes mellitus and their association with distal symmetrical polyneuropathy

ContextIndividuals with youth-onset type 2 diabetes mellitus (T2DM) display substantial, but unexplained, heterogeneity in their clinical presentations and risk of complications such as diabetic neuropathy. Data-driven clustering may be useful in characterizing this heterogeneity. ObjectiveTo identify data-driven subphenotypes of newly diagnosed youth-onset T2DM and study their association with distal symmetric polyneuropathy (DSPN) at time of diagnosis. DesignCross-sectional SettingUSA Participants641 individuals with newly diagnosed T2DM aged 10-19 years from the SEARCH for Diabetes in Youth Study and the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Exposure(s)Body mass index, HbA1c, fasting C-peptide, systolic blood pressure, diastolic blood pressure, LDL cholesterol and HDL cholesterol Main Outcome MeasuresData-driven subphenotypes were identified from k-means clustering. The cross-sectional association of subphenotypes with DSPN, based on expert examination scores ([≥]2.5) from the Michigan Neuropathy Screening Instrument, were assessed using Poisson regressions with robust standard errors. ResultsAmong 641 youth-onset T2DM, 58.2% were female, with 38.2% of participants [≤]13 years having average BMI of 34.5 kg/m2 (SD: 6.5 kg/m2), and average HbA1c of 6.1% (IQR: 5.6-7.0). Three youth-onset subphenotypes were identified: mild obesity related diabetes (yMOD, 48.5%), severe insulin deficient diabetes (ySIDD, 18.7%) and severe insulin resistant diabetes (ySIRD, 32.7%). After adjusting for covariates, the prevalence of abnormal DSPN were 2.58 (95%CI: 1.74, 3.81) and 2.02 (95%CI: 1.40, 2.93) times among those classified as the ySIDD and ySIRD subphenotypes, relative to the yMOD subphenotype. ConclusionsYouth-onset T2DM consisted of heterogeneous clinical subphenotypes with differences prevalence of DSPN. Management of youth-onset T2DM may need to consider strategies tailored to each subphenotype.