Type 2 diabetes family history as a significant index on the clinical heterogeneity differentiation in type 1 diabetes

<strong>Aims: </strong>Family history of type 2 diabetes (T2D) is a significant but neglected parameter; however, its role in identifying the heterogeneity, subtypes, or endotypes of type 1 diabetes (T1D) remains unclear. Herein, we investigated the impact of family history of T2D on the clinical phenotype of type 1 diabetes patients and evaluated its value in T1D classification. <strong>Methods: </strong>A total of 1410 T1D patients were enrolled in this prospective study. Information on family history of T2D in first-degree relatives was collected by research nurses using a semi-structured questionnaire. The impact of family history of T2D on clinical characteristics was evaluated in overall and subgroups of T1D patients stratified by islet autoantibodies, onset age, and human leukocyte antigen (HLA) genotype. Cluster analysis was performed to identify family history of T2D -related subgroups. <strong>Results: </strong>Ten percent (141/1410) patients had at least one first-degree relatives diagnosed with T2D. A milder phenotype associated with family history of T2D was presented in overall type 1 diabetes patients, including older onset age (<em>p</em>&lt;0.001), higher body mass index (<em>p</em>&lt;0.001), higher fasting and postprandial C-peptide levels (all <em>p</em>&lt;0.01), lower positive rates of all islet autoantibodies and susceptible HLA genotypes (all <em>p</em>&lt;0.05). Clinical heterogeneity associated with family history of T2D in the T1D subgroup stratified by autoimmunity, age of onset, and HLA genotypes was consistent. Using family history of T2D as a cluster variable, T1D patients were divided into five clusters, and patients in the T2D family history cluster displayed a milder phenotype than others. <strong>Conclusions:</strong> Family history of T2D should be considered as an important indicator for precise sub-classification of T1D patients based on clinical heterogeneity.