Prevalence of Type 1 Diabetes Autoantibodies (GADA, IA2, and IAA) in Overweight and Obese Children

OBJECTIVE

Little is known about the prevalence of β-cell autoantibodies in children with excess body weight. The prevalence of type 1 diabetes autoantibodies and its relation with hyperglycemia was analyzed in 686 overweight/obese children and adolescents.

RESEARCH DESIGN AND METHODS

All children underwent an oral glucose tolerance test, and anti-GAD, anti-IA2, and anti-IAA autoantibodies were measured. Autoantibody prevalence was evaluated in 107 normal-weight children for comparison.

RESULTS

A single autoantibody was present in 2.18% of overweight/obese subjects and 1.86% normal-weight subjects (P = NS). Postload glycemia was significantly higher in antibody-positive children (133 ± 69.9 vs. 105.4 ± 17.7 mg/dl, P < 0.0001) compared with autoantibody-negative subjects. No difference in autoantibody distribution was seen when our cohort was stratified by age, sex, SDS-BMI, pubertal stage, and homeostasis model assessment–insulin resistance (HOMA-IR).

CONCLUSIONS

The 2.18% prevalence of type 1 diabetes autoantibodies is similar to that reported in nonobese children. This study provided evidence that excess body weight and insulin resistance do not influence autoantibody frequency.Over the last 60 years, a striking increase in the incidence of childhood type 1 diabetes has been observed consistently in almost all populations. EURODIAB (1) reported an overall increase of 3.2% per annum in Europe between 1989 and 1998. There have also been considerable changes in childhood nutrition, which have resulted in changes in growth. Increased weight, height, and BMI in children have all been associated with a higher risk of type 1 diabetes (2). The so-called “accelerator hypothesis” argues that obesity causing overworked β-cells underlies both type 1 and type 2 diabetes and that these “types” are only distinguished by how the body responds to this growth-induced β-cell stress. This hypothesis therefore attributes the rise in type 1 diabetes to an increase in child obesity (3). A variation of the hypothesis suggests that, once initiated, islet autoimmunity progresses more rapidly in the context of “overload” of the β-cells due to increased insulin resistance (4).Sardinia has one of the highest incidences of type 1 diabetes worldwide, second only to Finland (5). Moreover, Sardinian children and adolescents are experiencing the same increase in obesity as other European populations (6). To date, little is known on the prevalence of autoantibodies against β-cells in children with excess body weight.The aim of our study was to analyze the prevalence of type 1 diabetes autoantibodies in a cohort of Sardinian overweight/obese children and adolescents and to evaluate their distribution in relation to the presence of glucose abnormalities.     

Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties

A wild-type (wt) p53 gene characterizes thyroid tumors, except for the rare anaplastic histotype. Because p53 inactivation is a prerequisite for tumor development, alterations of p53 regulators represent an alternative way to impair p53 function. Indeed, murine double minute 2 (MDM2), the main p53 negative regulator, is overexpressed in many tumor histotypes including those of the thyroid. A new p53 regulator, MDM4 (a.k.a. MDMX or HDMX) an analog of MDM2, represents a new oncogene although its impact on tumor properties remains largely unexplored. We estimated levels of MDM2, MDM4, and its variants, MDM4-S (originally HDMX-S) and MDM4-211 (originally HDMX211), in a group of 57 papillary thyroid carcinomas (PTC), characterized by wt tumor protein 53, in comparison to matched contra-lateral lobe normal tissue. Further, we evaluated the association between expression levels of these genes and the histopathological features of tumors. Quantitative real-time polymerase chain reaction revealed a highly significant downregulation of MDM4 mRNA in tumor tissue compared to control tissue (P<0.0001), a finding confirmed by western blot on a subset of 20 tissue pairs. Moreover, the tumor-to-normal ratio of MDM4 levels for each individual was significantly lower in late tumor stages, suggesting a specific downregulation of MDM4 expression with tumor progression. In comparison, MDM2 messenger RNA (mRNA) and protein levels were frequently upregulated with no correlation with MDM4 levels. Lastly, we frequently detected overexpression of MDM4-S mRNA and presence of the aberrant form, MDM4-211 in this tumor group. These findings indicate that MDM4 alterations are a frequent event in PTC. It is worthy to note that the significant downregulation of full-length MDM4 in PTC reveals a novel status of this factor in human cancer that counsels careful evaluation of its role in human tumorigenesis and of its potential as therapeutic target.     

Airway eosinophil accumulation and eotaxin-2/CCL24 expression following allergen challenge in BALB/c mice

Eotaxin-1/CCL11 is important for early eosinophil recruitment to the airways of asthmatics. In order to clarify whether eotaxin-2/CCL24 accounts for prolonged airway eosinophilia, the authors determined the expression of CCL11 and CCL24 in lung tissue and bronchoalveolar lavage (BAL) as well as eosinophil infiltration over 14 days in BALB/c mice sensitised (intraperitonealy) and challenged (inhalations) with ovalbumin (OVA). Allergen exposure induced perivascular, peribronchial, and BAL eosinophilia for up to 7 days. CCL11 and CCL24 were highly expressed in lung tissue from 6 and up to 72 hours. Peak expression of CCL11 protein was 1557 +/- 109 pg/mL for OVA (mean +/- SEM) versus 404 +/- 73 pg/mL in controls (SAL) (P < .001) and 1690 +/- 54 versus 455 +/- 165 pg/mL for CCL24 (P < .01). In BAL, only eotaxin-2/CCL24 was significantly increased (1623 +/- 85 pg/mL for OVA versus 157 +/- 22 pg/mL for SAL, P < .01). Peak eosinophilia and CCL24 expression occurred later in BAL than in lung tissue. These data suggest that both CCL11 and CCL24 are important for recruitment of eosinophils to perivascular and peribronchial tissue seen up to 72 hours. This finding implies redundancy between these chemokines rather than differentially regulated expression over time. In contrast, only CCL24 seems important for recruitment of eosinophils into BAL. Specific inhibition of CCL11 alone is therefore unlikely to inhibit eosinophil recruitment to the airways.     

Secretory mechanisms of human ceruminous glands: A transmission and scanning electron microscopic study

Two secretory mechanisms (eccrine and apocrine) were observed by transmission and scanning electron microscopy in the same secretory cells of the human ceruminous glands. The eccrine secretion occurs as a typical exocytosis by fusion of the limiting membrane of the secretory granule with the apical plasmalemma. The apocrine secretion is more complex and takes place by sequential steps: bulging of the cellular apex into the lumen, constriction of the projection, and detachment of it from the cell. This mechanism generally causes the removal of the entire projection all at once by decapitation at its base; some variations of this process have been found, however, and are described in the present work. A double membrane, apparently separating the apical protrusion from the rest of the cell, is noticeable in our photographs. Nevertheless, even if this membrane is very similar to a demarcation layer, we consider it as an intercellular double membrane separating two obliquely sectioned cells.     

Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases

Mast cells and eosinophils are the key cells in the early and late stages of allergic inflammation. There is increasing evidence that angiogenesis plays an important role both in the development of inflammation and in the pathophysiology of tissue remodeling during allergic disorders. In this review we provide recent data showing a link between allergy and angiogenesis and some possible mechanisms through which vascular endothelial growth factor and the immune system can interact. We discuss the multifaceted roles of mast cells and eosinophils in tissue remodeling and angiogenesis during allergic diseases and whether these cells can be both source and target cells for pro-angiogenic mediators.