Strategies for identifying and predicting islet autoantigen T-cell epitopes in insulin-dependent diabetes mellitus

T cells recognize peptide epitopes bound to major histocompatibility complex molecules. Human T-cell epitopes have diagnostic and therapeutic applications in autoimmune diseases. However, their accurate definition within an autoantigen by T-cell bioassay, usually proliferation, involves many costly peptides and a large amount of blood, We have therefore developed a strategy to predict T-cell epitopes and applied it to tyrosine phosphatase IA-2, an autoantigen in IDDM, and HLA-DR4(*0401). First, the binding of synthetic overlapping peptides encompassing IA-2 was measured directly to purified DR4. Secondly, a large amount of HLA-DR4 binding data were analysed by alignment using a genetic algorithm and were used to train an artificial neural network to predict the affinity of binding. This bioinformatic prediction method was then validated experimentally and used to predict DR4 binding peptides in IA-2. The binding set encompassed 85% of experimentally determined T-cell epitopes. Both the experimental and bioinformatic methods had high negative predictive values, 92% and 95%, indicating that this strategy of combining experimental results with computer modelling should lead to a significant reduction in the amount of blood and the number of peptides required to define T-cell epitopes in humans.

Gestational diabetes mellitus: From consensus to action on screening and treatment

The 1998 consensus guidelines on the management of gestational diabetes mellitus from the Australasian Diabetes in Pregnancy Society emphasised that, “due to a lack of good quality randomised controlled clinical trials in the area of [gestational diabetes mellitus], these guidelines are based on what is a reasonable consensus of informed opinion in Australasia”.1 The clear benefits of treating women with gestational diabetes according to these guidelines have now been demonstrated by the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS).2 This study randomised 1000 women with gestational diabetes to either routine antenatal care or to an intervention that comprised home glucose monitoring, review by a diabetes educator, dietitian and physician, and insulin therapy if glycaemic targets were not met. Serious adverse perinatal outcomes occurred in 1% of the intervention group versus 4% of the routine-care group (adjusted relative risk, 0.33 [95% CI, 0.14–0.75]). The percentage of infants who were large for gestational age was lower in the intervention group (13% v 22%), with no increase in those who were small for gestational age. Although induction of labour was more common in the intervention group (39% v 29%), rates of caesarean delivery were similar (around 31%). Measures of maternal quality of life were more favourable in the intervention group. To prevent one serious perinatal outcome, 34 women needed to be treated. The 1998 guidelines were equivocal in regard to screening for gestational diabetes, allowing either for universal screening or for selective screening based on clinical risk factors in relatively lowrisk populations. In the light of the findings of ACHOIS, we believe that universal screening should now be accepted and implemented.

Quality of diabetes care and coronary heart disease absolute risk in patients with type 2 diabetes mellitus in Australian general practice

Objective: To examine the quality of diabetes care and prevention of cardiovascular disease (CVD) in Australian general practice patients with type 2 diabetes and to investigate its relationship with coronary heart disease absolute risk (CHDAR). Methods: A total of 3286 patient records were extracted from registers of patients with type 2 diabetes held by 16 divisions of general practice (250 practices) across Australia for the year 2002. CHDAR was estimated using the United Kingdom Prospective Diabetes Study algorithm with higher CHDAR set at a 10 year risk of >15%. Multivariate multilevel logistic regression investigated the association between CHDAR and diabetes care. Results: 47.9% of diabetic patient records had glycosylated haemoglobin (HbA1c) >7%, 87.6% had total cholesterol >= 4.0 mmol/l, and 73.8% had blood pressure (BP) >= 130/85 mm Hg. 57.6% of patients were at a higher CHDAR, 76.8% of whom were not on lipid modifying medication and 66.2% were not on antihypertensive medication. After adjusting for clustering at the general practice level and age, lipid modifying medication was negatively related to CHDAR (odds ratio (OR) 0.84) and total cholesterol. Antihypertensive medication was positively related to systolic BP but negatively related to CHDAR (OR 0.88). Referral to ophthalmologists/optometrists and attendance at other health professionals were not related to CHDAR. Conclusions: At the time of the study the diabetes and CVD preventive care in Australian general practice was suboptimal, even after a number of national initiatives. The Australian Pharmaceutical Benefits Scheme (PBS) guidelines need to be modified to improve CVD preventive care in patients with type 2 diabetes.

(Review) Body mass index and risk of diabetes mellitus in the Asia-Pacific region

Few prospective data from the Asia Pacific region are available relating body mass index to the risk of diabetes. Our objective was to provide reliable age, sex and region specific estimates of the associations between body mass index and diabetes. Twenty-seven cohort studies from Asia, New Zealand and Australia, including 154,989 participants, contributed 1,244,793 person-years of follow-up. Outcome data included a combination of incidence of diabetes (based on blood glucose measurements) and fatal diabetes events. Hazard ratios were calculated from Cox models, stratified by sex and cohort, and adjusted for age at risk and smoking. During follow-up (mean = 8 years), 75 fatal diabetes events and 242 new cases of diabetes were documented. There were continuous positive associations between baseline body mass index and risk of diabetes with each 2 kg/m(2) lower body mass index associated with a 27% (23-30%) lower risk of diabetes. The associations were stronger in younger age groups, and regional comparisons demonstrated slightly stronger associations in Asian than in Australasian cohorts (P = 0.04). This overview provides evidence of a strong continuous association between body mass index and diabetes in the Asia Pacific region. The results indicate considerable potential for reduction in incidence of diabetes with population-wide lowering of body mass index in this region.

Diet, lifestyle and the risk of Type 2 Diabetes Mellitus in women

Background Previous studies have examined individual dietary and lifestyle factors in relation to type 2 diabetes, but the combined effects of these factors are largely unknown. Methods We followed 84,941 female nurses from 1980 to 1996; these women were free of diagnosed cardiovascular disease, diabetes, and cancer at base line. Information about their diet and lifestyle was updated periodically. A low-risk group was defined according to a combination of five variables: a body-mass index (the weight in kilograms divided by the square of the height in meters) of less than 25; a diet high in cereal fiber and polyunsaturated fat and low in trans fat and glycemic load (which reflects the effect of diet on the blood glucose level); engagement in moderate-to-vigorous physical activity for at least half an hour per day; no current smoking; and the consumption of an average of at least half a drink of an alcoholic beverage per day. Results During 16 years of follow-up, we documented 3300 new cases of type 2 diabetes. Overweight or obesity was the single most important predictor of diabetes. Lack of exercise, a poor diet, current smoking, and abstinence from alcohol use were all associated with a significantly increased risk of diabetes, even after adjustment for the body-mass index. As compared with the rest of the cohort, women in the low-risk group (3.4 percent of the women) had a relative risk of diabetes of 0.09 (95 percent confidence interval, 0.05 to 0.17). A total of 91 percent of the cases of diabetes in this cohort (95 percent confidence interval, 83 to 95 percent) could be attributed to habits and forms of behavior that did not conform to the low-risk pattern. Conclusions Our findings support the hypothesis that the majority of cases of type 2 diabetes could be prevented by the adoption of a healthier lifestyle.

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.