Kimber M. Simmons

Type 1 diabetes： A predictable disease

Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin producing beta cells and reliance on exogenous insulin for survival. T1D is one of the most common chronic diseases in childhood and the incidence is increasing, especially in children less than 5 years of age. In individuals with a genetic predisposition, an unidentified trigger initiates an abnormal immune response and the development of islet autoantibodies directed against proteins in insulin producing beta cells. There are currently four biochemical islet autoantibodies measured in the serum directed against insulin, glutamic decarboxylase, islet antigen 2, and zinc transporter 8. Development of islet autoantibodies occurs before clinical diagnosis of T1D, making T1D a predictable disease in an individual with 2 or more autoantibodies. Screening for islet autoantibodies is still predominantly done through research studies, but efforts are underway to screen the general population. The benefits of screening for islet autoantibodies include decreasing the incidence of diabetic ketoacidosis that can be life threatening, initiating insulin therapy sooner in the disease process, and evaluating safe and specific therapies in large randomized clinical intervention trials to delay or prevent progression to diabetes onset.

Immune Intervention and Preservation of Pancreatic Beta Cell Function in Type 1 Diabetes

Type 1 diabetes (T1D) results from the immune-mediated destruction of insulin-producing β cells located within the pancreatic islets of Langerhans. The autoimmune process leads to a deficiency in insulin production and resultant hyperglycemia requiring lifelong treatment with insulin administration. T1D continues to dramatically increase in incidence, especially in young children. Substantial knowledge surrounding human disease pathogenesis exists, such that T1D is now predictable with the measurement of antibodies in the peripheral blood directed against insulin and other β cell proteins. With the ability to predict, it naturally follows that T1D should be preventable. As such, over the last two decades, numerous well-controlled clinical trials have been completed attempting to prevent diabetes onset or maintain residual β cell function after clinical onset, all providing relatively disappointing results. Here, we review the T1D prevention efforts, the current landscape of clinical therapies, and end with a discussion regarding the future outlook for preventing T1D.

Reduced Bone Mineral Density Is Associated with Celiac Disease Autoimmunity in Children with Type 1 Diabetes.

OBJECTIVEnTo evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population.nnnSTUDY DESIGNnBMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative).nnnRESULTSnChildren with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (β = -1.25 ± 0.85, P = .0016) and tTGA (β = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA.nnnCONCLUSIONSnThe results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.

Lessons from Type 1 Diabetes for Understanding Natural History and Prevention of Autoimmune Disease

Type 1 diabetes (T1D) is a chronic autoimmune disorder resulting from immune-mediated destruction of insulin-producing beta cells within the pancreatic islets. Prediction of T1D is now possible, as having 2 or more islet autoantibodies confers a 100% risk of diabetes development. With the ability to predict disease development, clinical trials to prevent diabetes onset have been completed and are currently under way. This review focuses on the natural history, prediction, and prevention trials in T1D. We review the lessons learned from these attempts at preventing a chronic autoimmune disease and apply the paradigm from T1D prevention to other autoimmune disorders.

Islet Autoantibody Measurements from Dried Blood Spots on Filter Paper Strongly Correlate to Serum Levels

Type 1 diabetes (T1D) is increasing in incidence and predictable with measurement of serum islet autoantibodies (iAb) years prior to clinical disease onset. Identifying iAb positive individuals reduces diabetic ketoacidosis and identifies individuals for T1D prevention trials. However, large scale screening for iAb remains challenging as assays have varying sensitivities and specificities, insulin autoantibodies remain difficult to measure and venipuncture is generally required to obtain serum. We developed an approach to reliably measure all four major iAb, including insulin autoantibodies, from dried blood spots (DBS) on filter-paper. By spiking iAb positive serum into iAb negative whole blood in a dose titration, we optimized the conditions for autoantibody elution from filter paper as measured by fluid phase radioimmunoassays. After assessing stability of measuring iAb from DBS over time, we then screened iAb from DBS and the corresponding serum in new-onset T1D (n = 52), and controls (n = 72) which included first-degree relatives of T1D patients. iAb measured from eluted DBS in new-onset T1D strongly correlated with serum measurements (R2 = 0.96 for mIAA, GADA = 0.94, IA-2A = 0.85, ZnT8A = 0.82, p<0.01 for each autoantibody). There were no false positives in control subjects, and 5/6 with previously unknown iAb positivity in sera were detected using DBS. With further validation, measuring iAb from DBS can be a reliable method to screen for T1D risk.

ISPAD Clinical Practice Consensus Guidelines 2018: Other complications and associated conditions in children and adolescents with type 1 diabetes

Monitoring of anthropometric measurements and physical development, using age- appropriate standards and taking mid-parental height into account, is a crucial element in the care of children and adolescents with diabetes. This article is protected by copyright. All rights reserved.

Alternate Ways to Quantify Antibodies

Type 1 diabetes (T1D) is now a predictable disease with the measurement of antibodies in the peripheral blood directed against proteins within insulin-producing β-cells.1 There are currently four main biochemical islet autoantibodies measured that are directed against insulin, glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8. The presence of two or more islet autoantibodies in children with a first-degree relative having T1D indicates preclinical T1D as nearly 100% of these children develop diabetes, marked by abnormal glucose homeostasis, provided long-term follow-up.2