Heterogeneity of Type 1 Diabetes at Diagnosis Supports Existence of Age-Related Endotypes

Abstract

OBJECTIVE Previous findings suggest that there are age-related endotypes of type 1 diabetes with different underlying etiopathological mechanisms in those diagnosed at age <7 years compared with those diagnosed at age ≥13 years. We set out to explore whether variation in demographic, clinical, autoimmune, and genetic characteristics of children and adolescents with newly diagnosed type 1 diabetes support the existence of these proposed endotypes. RESEARCH DESIGN AND METHODS We used data from the Finnish Pediatric Diabetes Register to analyze characteristics of 6,015 children and adolescents diagnosed with type 1 diabetes between 2003 and 2019. We described and compared demographic data, clinical characteristics at diagnosis, autoantibody profiles, and HLA class II–associated disease risk between three groups formed based on age at diagnosis: <7, 7–12, and ≥13 years. RESULTS We found significant age-related differences in most of the characteristics analyzed. Children diagnosed at age <7 years were characterized by a higher prevalence of affected first-degree relatives, stronger HLA-conferred disease susceptibility, and higher number of autoantibodies at diagnosis, in particular a higher frequency of insulin autoantibodies, when compared with older children. Those diagnosed at age ≥13 years had a considerably higher male preponderance, higher frequency of glutamic acid decarboxylase autoantibodies, longer duration of symptoms before diagnosis, and more severe metabolic decompensation, reflected, for example, by a higher frequency of diabetic ketoacidosis. CONCLUSIONS Our findings suggest that the heterogeneity of type 1 diabetes is associated with the underlying disease process and support the existence of distinct endotypes of type 1 diabetes related to age at diagnosis.

Maternal depression or anxiety during pregnancy and offspring type 1 diabetes: a population-based family-design cohort study

“…This is in line with the growing body of current research on disease heterogeneity in type 1 diabetes and the concept of endotypes with different underlying disease pathways 29. Age-varying differences in risk factors for the progression from autoantibody positivity to clinical disease as well as in characteristics at diagnosis of type 1 diabetes have been shown 30–32…”

Comparison of diabetes distress and depression screening results of emerging adults with type 1 diabetes onset at different ages: findings from the German early-onset T1D study and the German Diabetes Study (GDS)

“…Age at disease onset is a rarely studied risk factor for T1D complications. Findings suggest that early disease onset is a nonmodifiable risk factor for survival [ 13 ], cardiovascular outcomes [ 13 ], nephropathy [ 14 ] and cognitive impairment [ 15 ] and that distinct endotypes of T1D related to age at diagnosis exist [ 16 ]. To date, the possible relationship between age at onset and psychosocial issues is largely unexplored.…”

Imprecise Diagnosis of Diabetes Type in Youth: Prevalence, Characteristics, and Implications

“…Although distinct categorization of diabetes types seems clinically more practical in real-word settings, evidences supporting the complexity of diabetes and the existence of a spectrum of diabetes phenotypes with differential contributions of multiple pathophysiologic processes in concert with each other as suggested by Palette Model are accumulating [3,40]. This led to multiple efforts by us and other investigators looking into improved classi cation of diabetes types and subtypes to allow for personalized treatment approaches [5,10,16,41,42].…”