Maria J. Redondo

Heterogeneity of Type I diabetes: analysis of monozygotic twins in Great Britain and the United States

Aims. To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. Methods. Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). Results. The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01–57) at 40 years of discordance estimated a 39 % probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50 %. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4 %. Twins of probands diagnosed at 24 years of age or younger had a 38 % probability of diabetes by 30 years of discordance, compared with 6 % for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). Conclusion/interpretation. Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25 % of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age. [Diabetologia (2001) 44: 354–362]

Self-antigen–presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs

Recent reports indicate that genes with tissue-restricted expression, including those encoding the type 1 diabetes autoantigens insulin, glutamic acid decarboxylase (GAD), and the tyrosine-phosphatase-like protein IA-2 (or ICA512), are transcribed in the thymus. The reported modulation of diabetes susceptibility by genetically determined differences in thymic insulin levels and studies in transgenic mice provide correlative and functional evidence that thymic expression of peripheral proteins is crucial for immunological self-tolerance. However, there are no specific data about the existence, tissue distribution, phenotype, and function of those cells that express insulin and other self-antigens in the human thymus. We find that the human thymus harbors specialized cells synthesizing (pro)insulin, GAD, and IA-2, mainly localized in the medulla, and we demonstrate such cells also in peripheral lymphoid organs (spleen and lymph nodes). Phenotypic analysis qualifies these cells as antigen-presenting cells (APCs), including both dendritic cells and macrophages. These cells often appear surrounded by apoptotic lymphocytes, both in thymus and spleen, and may therefore be involved in the deletion of autoreactive lymphocytes. Our findings demonstrate the existence of, and define the tissue distribution and phenotype of, a novel subset of APCs expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.

Concordance for Islet Autoimmunity among Monozygotic Twins

To the Editor: The risk of type 1 diabetes among the monozygotic twins of patients with type 1 diabetes is reported to be as low as 30%; this percentage is usually based on the ascertainment of dat...

Genetic control of autoimmunity in Type I diabetes and associated disorders

Abstract Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immune-mediated diabetes is also heterogeneous with “monogenic”, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45: ▪–▪]

Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study

Abstract Objective: To test the hypothesis that non-diabetic dizygotic and monozygotic twin siblings of patients with type 1 diabeteshave a similar high prevalence of islet cell autoantibodies, thus suggesting that islet cell autoimmunity is mainly environmentally determined. Design: Prospective twin study. Setting: Two specialist centres for diabetes in the United States. Participants: Non-diabetic monozygotic twin (n=53), dizygotic twin (n=30), and non-twin (n=149) siblings of patients with type 1 diabetes; 101 controls. Main outcome measures: Analysis of progression to diabetes and expression of anti-islet autoantibodies. Results: Monozygotic twin siblings had a higher risk of progression to diabetes (12/53) than dizygotic twin siblings (0/30; P<0.005). At the last follow up 22 (41.5%) monozygotic twin siblings expressed autoantibodies compared with 6 (20%) dizygotic twin siblings (P<0.05), 16 (10.7%) non-twin siblings (P<0.0001), and 6 (5.9%) controls (P<0.0001). Monozygotic twin siblings expressed multiple (≤2) antibodies more often than dizygotic twin siblings (10/38 v 1/23; P<0.05). By life table analysis the probability of developing positive autoantibodies was higher among the monozygotic twin siblings bearing the diabetes associated HLA DQ8/DQ2 genotype than in those without this genotype (64.2% (95% confidence interval 32.5% to 96%) v 23.5% (7% to 40%) at 10 years of discordance; P<0.05). Conclusion: Monozygotic and dizygotic twins differ in progression to diabetes and expression of islet cell autoantibodies. Dizygotic twin siblings are similar to non-twin siblings. These two observations suggest that genetic factors play an important part in determination of islet cell autoimmunity, thus rejecting the hypothesis. In addition, there is a high penetrance of islet cell autoimmunity in DQ8/DQ2 monozygotic twin siblings.

Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes

Type 1 diabetes of both the NOD mouse and man is associated with autoimmunity directed against insulin which is the only beta cell specific autoantigen identified to date. One can use autoantibodies to insulin to predict diabetes, use insulin peptides to create insulin autoantibodies, insulitis and diabetes, and use insulin or its peptides in animal models to prevent diabetes. An expanding set of resources are now available for the development and testing in man of therapies to prevent type 1 diabetes, and a number of trials utilizing insulin peptides are now underway.

Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes

To examine the relationship between BMI and beta‐cell function at diagnosis of autoimmune type 1 diabetes (T1D) in a large group of ethnically diverse children.

LADA: Time for a New Definition

In this issue of Diabetes , Zhou et al. (1) report on the prevalence and characteristics of latent autoimmune diabetes in adults (LADA) in China. Findings from this study underscore the profound need for a new definition of LADA. LADA, a slowly progressive form of autoimmune diabetes that develops in adults and does not require insulin therapy for some time after diagnosis, was first described over 25 years ago (2). Subsequently, clinical, metabolic, immunological, and genetic characteristics that are unique to LADA have been identified (3–6). For example, relative to patients with type 1 diabetes (T1D), those with LADA are more likely to be obese and have other elements of the metabolic syndrome. They are also more likely to retain greater β-cell function, express a single autoantibody (particularly GAD65) and certain GAD65 epitopes (7), and carry the transcription factor 7-like 2 ( TCF7L2 ) gene polymorphism, which is strongly associated with type 2 diabetes (T2D) (8). However, the rationale for the strict criteria that are most often used to define LADA, including age >30 years at diagnosis and insulin independence for at least 6 months after diagnosis (5), have been questioned repeatedly (9–13). Furthermore, there is substantial heterogeneity in LADA, with some cases closely resembling T1D (e.g., low BMI, association with other autoimmune diseases), and others that share many features with T2D (14–16). Many authors and clinicians question …

Depressive Symptoms in Youth With Type 1 or Type 2 Diabetes: Results of the Pediatric Diabetes Consortium Screening Assessment of Depression in Diabetes Study

OBJECTIVE To evaluate the frequency of depressive symptoms and the diagnosis and management of depression in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium T1D and T2D registries. RESEARCH DESIGN AND METHODS The Children’s Depression Inventory (CDI) 2 Self-Report (Short) version was completed by 261 T1D and 339 T2D youth aged 10–17 years. RESULTS Symptoms of depression were identified in 13% of T1D and 22% of T2D (P = 0.007) participants; of these, only 4% of T1D and 9% of T2D youth were treated by a therapist within the prior 12 months. Depressive symptoms were associated with lower family income (P = 0.006) and obesity (P = 0.002) in T1D but not T2D youth. CONCLUSIONS Depressive symptoms are more frequent than diagnosed depression in youth with T1D or T2D. These results underscore the need for regular depression screening and appropriate referral for youth with diabetes.

What can we learn from patient-reported outcomes of insulin pen devices?

Although a variety of effective treatment options are available for patients with type 1 or type 2 diabetes, many patients in the United States have difficulty reaching their glycemic goals. Patient adherence to insulin therapy, which often involves self-administered subcutaneous injections of insulin using either a vial and syringe or an insulin pen device, is often poor. Various factors associated with the type of injection device have been shown to influence the rate of patient adherence to insulin therapy. This article reviews patient-reported outcome (PRO) evidence from pediatric and adult studies that compared insulin pen devices with vial and syringe use. In a majority of these cases, patients preferred the pen devices over vial and syringe, stating advantages such as ease of use, convenience, greater confidence in their ability to properly administer the drug, and a greater perceived social acceptance. The pens were considered less painful than syringes and were associated with less needle fear. In addition, PRO evidence has directed pen technology design, leading to development of more advanced insulin pen devices. By appreciating the correlation between adherence to insulin regimens and a patients device preference, clinicians can make improved treatment recommendations to facilitate achievement and maintenance of glycemic targets.