The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms

Abstract

Purpose of review:To explore the impact of age on type 1 diabetes (T1D) pathogenesis. Recent findings:Children progress more rapidly from autoantibody positivity to T1D and have lower C-peptide levels compared to adults. In histological analysis of post-mortem pancreata, younger age of diagnosis is associated with reduced numbers of insulin containing islets and a hyper-immune CD20 hi infiltrate. Compared to adults, children exhibit decreased immune regulatory function and increased engagement and trafficking of autoreactive CD8 + T-cells, and age-related differences in β-cell vulnerability may also contribute to the more aggressive immune phenotype observed in children. HLA and non-HLA genetic loci that influence multiple disease characteristics, including age of onset, are being increasingly characterized. Summary:The exception of T1D as an autoimmune disease more prevalent in children than adults results from a combination of immune, metabolic, and genetic factors. Age-related differences in T1D pathology have important implications for better tailoring of immunotherapies.

Genetics of Type 1 Diabetes Comes of Age

“…Genetics may provide a useful window into the puzzling age differences in the epidemiology, clinical characteristics, immunology, and histopathology of type 1 diabetes (12). Most of the genes that Inshaw et al (7) found preferentially associated with earlychildhood type 1 diabetes work in the immune system (13) (Fig.…”

Presumption of innocence for beta cells: why are they vulnerable autoimmune targets in type 1 diabetes?

“…A unifying picture is emerging that prompts us to consider type 1 diabetes as a disease of both the immune system and beta cells, resulting from a conflicting dialogue between these two players. Given the phenotypic heterogeneity of type 1 diabetes, different phenotypic subtypes (endotypes) of islet autoimmunity are increasingly recognised based on putative pathogenic mechanisms and, likely, different responsiveness to immunotherapy ('theratypes') [60,61]. It is conceivable that distinct endotypes may also exist according to the aggressiveness of islet autoimmunity (benign vs progressive) and to the relative contribution of immune and beta cell drivers to such aggressiveness (Fig.…”

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

“…These data suggest that the two patterns of insulitis may reflect different degrees of severity, since patients with higher proportion of CD20 + B cells lose β‐cells at a more rapid rate . Therefore, higher proportions of B cells in insulitic lesions potentially represent a marker of an early aggressiveness of the autoimmune process or of a rapid rate of β‐cell loss …”