Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #163: Immunopathogenesis of Type 1 Diabetes in Western Society Part 6

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #163: Immunopathogenesis of Type 1 Diabetes in Western Society Part 6

Feb 5, 2019

The relationship between pathogenic factors and 𝛃-cell destruction remains poorly understood

Longitudinal studies of newborns and children at genetic risk [5,103,104] and follow-up of at-risk first-degree relatives in natural history studies link the triggering of autoimmunity with the appearance of autoantibodies to one or more islet autoantigens; individuals with multiple autoantibodies have higher risk of diabetes progression [3]. Data from the Diabetes Prevention Trial-Type 1 document a progressive impairment of insulin secretion and glucose metabolism as subjects progressed towards diagnosis [105]. Recent clinical studies have led to increased awareness that stimulated C-peptide responses are only partially reduced in many newly diagnosed patients, to an extent as a function of age [106,107]. A two-year follow-up of new onset patients shows greater C-peptide loss during the first year post diagnosis; importantly, not every patient experienced further loss during this period [108]. At least low levels of C-peptide production may persist for several years in a significant proportion of patients, even decades after diagnosis [79,80]. In parallel, it has been proposed that physical β-cell loss at diagnosis may be also age dependent and, importantly, less severe than previously estimated; a recent meta-analysis estimates the average β-cell loss by age 20 at approximately 40% [109]. The effect of age of onset on residual β-cell mass may reflect age-related differences in the number of β cells, but also the influences on β-cell mass and diabetes progression of body mass index and insulin resistance, which increase as children go through adolescence and puberty. Related to the above, the severity of insulitis from pathology specimens also appears to be a function of age, besides disease duration [110]. Insulitis in the human pancreas is generally not as severe and extensive as observed in NOD mice; even among younger patients with short disease duration, who typically have the most severe insulitis and β-cell loss, only about 30% of insulin-positive islets had a lymphocytic infiltrate [110]. Moreover, recent studies described heterogeneous β-cell loss patterns in pancreas pathology specimens from patients diagnosed in childhood with variable disease duration [111]. While it is not possible to correlate insulin secretion with an assessment of β-cell mass in patients with new onset diabetes, studies in pancreas transplant patients with recurrent diabetes, in whom a pancreas transplant biopsy was obtained, often showed moderate β-cell loss and insulitis despite a frank diabetic state [76]. Collectively, these observations raise the provocative question of whether additional co-factors may be impairing β-cell function at the time of diagnosis.


Both genetic and immunologic studies show that autoimmunity plays a major role in T1DM pathogenesis. The molecular characterization of several autoantigens and disease-associated gene variants has led to the identification of several disease pathways and functional abnormalities that contribute to the immune-mediated component of T1DM pathogenesis, many of which are being targeted in clinical trials. Islet autoimmunity appears to be the dominant effector mechanism. Over time, chronic autoimmunity will lead to the virtually complete loss of pancreatic β cells in many but not all patients, given that C-peptide production is detected in a significant proportion of patients, even decades after diabetes onset. There is growing evidence that additional factors contribute to disease pathogenesis and progression; moreover, re-examination of both literature data and emerging findings suggest the hypothesis that a degree of functional impairment may contribute to diabetes symptoms at diagnosis, at least in some patients. If so, additional pathogenic mechanisms and in turn therapeutic targets may exist at diagnosis. Ultimately, a critical gap in our understanding of the disease pathogenesis stems from our inability to assess pathology in the pancreas in relation to secretory function.This prevents us from fully understanding the relationships among insulin secretion, β-cellmass, disease activity, and relative contributions of various factors to disease pathogenesis and clinical symptoms. Longitudinal assessments of T-cell responses during the prediabetic phase are still quite limited; with recent technical improvements future studies should illustrate the dynamics of T-cell responses, antigen specificity, and functional properties of autoreactive T cells in relation to disease progression. Correlations with biomarkers of β-cell destruction have not yet been possible, as another unmet need is a validated biomarker; the levels of circulating, demethylated insulin gene DNA levels could represent such a biomarker if validated in larger studies [112]. There is also hope that further progress will lead to advanced imaging modalities to noninvasively assess β-cell mass and insulitis [113]. This need is even more critical now that improved knowledge of the disease natural history shows relative preservation of C-peptide secretion at diagnosis and later follow-up in many patients, suggesting that the therapeutic window for intervention may extend beyond the first few months from clinical diagnosis.

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