The Presence of GAD and IA-2 Antibodies in Youth With a Type 2 Diabetes Phenotype: Results from the TODAY study

OBJECTIVE

To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.

RESEARCH DESIGN AND METHODS

Children (10–17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations.

RESULTS

Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects.

CONCLUSIONS

Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.Type 2 diabetes in youth was rarely reported before the 1990s, but increased in the late 1990s, associated with the burgeoning of childhood obesity (1–3). Type 2 diabetes now accounts for 15–87% of new-onset diabetes in U.S. youth aged 10–20 years, varying with race/ethnicity (4). In addition, there have been significant increases in the occurrence of type 1 diabetes in the last 25 years (5–7). Given the obesity epidemic, many youth with type 1 diabetes are either overweight or obese at diagnosis (8,9), making it difficult for clinicians to distinguish between type 1 and type 2 diabetes based on weight alone. As the classic criteria for distinguishing between these two major types of diabetes (i.e., age at onset and weight) are increasingly blurred, there has been a need to develop better methods of diabetes classification in youth.This dilemma was highlighted by the SEARCH for Diabetes in Youth study, which reported that 21.2% of children aged 10–19 years of age with physician-identified type 2 diabetes were found to be positive for GAD-65 antibodies (4). Although the significance of these antibodies in children with phenotypic type 2 diabetes is not currently understood, in adults in the UK Prospective Diabetes Study (UKPDS) who had positive GAD-65 antibodies and physician-diagnosed type 2 diabetes, oral treatment failed significantly more rapidly than in those without autoimmunity (94 vs. 14% at 6 years) (10). These and other studies suggest that there are clinically significant differences between individuals with clinical signs of type 2 diabetes and islet autoimmunity compared with those without evidence of autoimmunity.With the dramatic increase in type 2 diabetes in youth of all ethnic origins, the importance of determining the effectiveness of treatment options became a child health priority. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a National Institutes of Health (NIH)-sponsored multicenter clinical trial designed to compare treatment with metformin alone, metformin with rosiglitazone, and metformin with an intensive lifestyle intervention program in children 10–17 years of age (11). In designing the TODAY study, the UKPDS experience led to a decision to exclude islet antibody-positive individuals from the trial. This report examines islet autoimmunity in youth who were considered by pediatric endocrinologists to have type 2 diabetes based on their phenotypic presentation. Subjects were assessed for islet autoimmunity at the screening visit for the TODAY study; those with islet autoimmunity were excluded from participation. Clinical and laboratory differences between islet antibody-positive and antibody-negative participants at screening are described.     

Plasma carotenoids and tocopherols and cognitive function: a prospective study

As a site of high metabolic activity, the brain is particularly susceptible to oxidative damage. We explored the association between plasma antioxidants and cognition. In 858 female participants of the Nurses’ Health Study, aged 70+ years, we measured plasma carotenoids and tocopherols in 1989–1990, and assessed cognitive function by telephone beginning in 1995–2001; assessments were repeated twice at 2-year intervals. We used linear regression to estimate multivariable-adjusted mean cognitive performance at the initial assessment by quartile of antioxidants, and longitudinal models for analyzing cognitive decline over 4 years. Higher antioxidant levels were not associated with initial performance or decline. Mean difference in initial global composite score (averaging all six cognitive tests) for the top versus bottom quartile of total carotenoids was −0.05 standard units (95% confidence interval [CI] −0.19, 0.09), and 0.04 units for total tocopherols (95% CI −0.10, 0.18). Individual antioxidants were not associated with cognition. Overall, total plasma carotenoids or tocopherols were not related to cognition in women.     

Recent advances in the characterization of HIV-1 neutralization assays for standardized evaluation of the antibody response to infection and vaccination

In AIDS vaccine development the pendulum has swung towards a renewed emphasis on the potential role for neutralizing antibodies in a successful global vaccine. It is recognized that vaccine-induced antibody performance, as assessed in the available neutralization assays, may well serve as a “gatekeeper” for HIV-1 subunit vaccine prioritization and advancement. As a result, development of a standardized platform for reproducible measurement of neutralizing antibodies has received considerable attention. Here we review current advancements in our knowledge of the performance of different types of antibodies in a traditional primary cell neutralization assay and the newer, more standardized TZM-bl reporter cell line assay. In light of recently revealed differences (see accompanying article) in the results obtained in these two neutralization formats, parallel evaluation with both platforms should be contemplated as an interim solution until a better understanding of immune correlates of protection is achieved.     

The role of written action plans in childhood asthma

PURPOSE OF REVIEW: The aim of this article is to examine the evidence for the effectiveness of a written action plan as an important element of guided self-management and to identify key features associated with its effectiveness in children and adolescents. RECENT FINDINGS: Various written action plans are available for use; however, few have been specifically designed or validated for children. Strong, but limited pediatric evidence confirms that the addition of a written action plan to guided self-management education significantly improves outcome. Use of daily controller medication, with no step-up therapy other than as needed inhaled beta2-agonist, best prevents asthma exacerbations. Symptom-based appear superior to peak-flow based written action plans. The paucity of pediatric trials does not permit the identification of other keys features that enhance the dispensing of written action plans by healthcare professionals or uptake of recommendations by children, adolescents and their parents. SUMMARY: Written action plans are effective tools to facilitate self-management. While step-up therapy is not superior to daily controller medication, symptom-based are superior to peak-flow based action plans for preventing exacerbations, other keys features associated with effectiveness have yet to be identified.     

Age-related differences in spatiotemporal markers of gait stability during dual task walking

Increased stride-to-stride variability during walking characterizes gait instability and predicts falling in older adults. Walking while performing cognitive tasks (dual task walking) is also associated with increased risk of falling. The purpose of the study was to examine whether gait velocity and stride-to-stride variability in gait velocity differ in older adults compared with middle-aged and younger adults during normal and dual task walking conditions. Sixty older (n=20, mean age=81 years), middle-aged (n=20, mean age=48 years), and young adults (n=20, mean age=25 years) participated in the study. Gait parameters were quantified with GAITRite instrumentation. In the dual task condition, participants spelled five-letter words in reverse while walking across the walkway. Across groups, gait velocity was slower (p<0.001) and stride-to-stride variability in gait velocity was greater (p=0.001) in dual task walking. Older subjects walked more slowly than did middle-aged and younger subjects and the difference in gait velocity was greatest in the dual task condition (p<0.05). Variability in stride velocity was increased in older subjects compared with middle-aged and younger subjects (p<0.05). Additionally, in older subjects, impaired walking performance was associated with impaired cognitive performance in dual task walking. The gait changes observed in dual task walking characterize decreased gait stability and indicate that cognitively demanding tasks during walking have a destabilizing effect on gait and may place older people at a greater risk of falling.     

Diuretic abuse in eating disorders: Treatment protocol and case report

Abstract

Eating disorders are often complicated by the misuse of laxatives, diet pills, and diuretics. Although little attention has been paid to the problem of diuretic abuse as a method of weight control, diuretic abuse has been reported since 1968 in patients with anorexia nervosa (Wolff et al., 1968). A recent review article has documented the extent of diuretic use in eating disordered patients (Bulik, 1992). In a 1981 report of 34 bulimic patients, 29% (10 patients) reported having used diuretics for the purpose of weight control (Pyle, Mitchell,&Eckert, 1981). A subsequent 1985 study of 275 bulimic women found that 33.9% (90 women) used diuretics for weight loss reasons, 10.2% taking them at least once each day (Mitchell, Hatsukami, Eckert,&Pyle, 1985).     

Percutaneous radiofrequency ablation of hepatocellular lesions in segment II of the liver: a risk factor for cardiac tamponade

Percutaneous radiofrequency ablation (PRFA) is a minimally invasive procedure used for the treatment of small hepatocellular carcinomas. PRFA is regarded as a much safer alternative to surgical resection or orthotopic liver transplantation. However, serious complications, including cardiac tamponade, have been reported. Two cases of severe cardiac tamponade during PRFA were successfully treated.     

Tacrolimus and nonsteroidal anti-inflammatory drugs: an association to be avoided

BACKGROUND: Tacrolimus (FK) and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute nephrotoxicity. The expanding use of tacrolimus and the intense consumption of NSAIDS increase the chances of their simultaneous use. METHODS: Rats receiving a nonselective COX inhibitor (diclofenac, D) and FK or a selective COX-2 inhibitor (rofecoxib, RO) and FK were treated with FK (2 mg/kg/day), D (10 mg/kg/day), RO (3 mg/kg/day), FK+D, FK+RO and vehicle for 7 days on low-salt diet. RESULTS: Both associations significantly impaired glomerular filtration rate (GFR; 0.63 +/- 0.06 ml/min/100 g in FK+D, 0.83 +/- 0.06 ml/min/100 g in FK+RO) which did not occur with single drug therapy (0.98 +/- 0.03 ml/min/100 g in D, 1.06 +/- 0.04 ml/min/100 g in RO, 0.99 +/- 0.05 ml/min/ 100 g in FK) or vehicle (1.10 +/- 0.05 ml/min/100 g). GFR decrease was significantly higher with FK+D. GFR impairment occurred without RBF or RVR major changes. Mild tubular vacuolization and dilatation and acute degenerative changes were observed in tubular cells. FK+D animals showed a marked weight loss, not observed in the other groups. FK+NSAIDs association decreased FK blood levels (1.73 +/- 0.3 ng/ml in FK+D, 1.8 +/- 0.3 ng/ml in FK+RO, 3.2 +/- 0.4 ng/ml in FK, p < 0.05). CONCLUSIONS: The association of FK and nonselective or COX-2 selective NSAIDs in salt-depleted animals caused a significant GFR impairment and decreased FK blood levels.