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OBJECTIVE This study examined associations of maternal glycemia during pregnancy with childhood glucose outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS HAPO was an observational international investigation that established associations of maternal glucose with adverse perinatal outcomes. The HAPO Follow-up Study included 4,832 children ages 10–14 years whose mothers had a 75-g oral glucose tolerance test (OGTT) at ∼28 weeks of gestation. Of these, 4,160 children were evaluated for glucose outcomes. Primary outcomes were child impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Additional outcomes were glucose-related measures using plasma glucose (PG), A1C, and C-peptide from the child OGTT. RESULTS Maternal fasting plasma glucose (FPG) was positively associated with child FPG and A1C; maternal 1-h and 2-h PG were positively associated with child fasting, 30 min, 1-h, and 2-h PG, and A1C. Maternal FPG, 1-h, and 2-h PG were inversely associated with insulin sensitivity, whereas 1-h and 2-h PG were inversely associated with disposition index. Maternal FPG, but not 1-h or 2-h PG, was associated with child IFG, and maternal 1-h and 2-h PG, but not FPG, were associated with child IGT. All associations were independent of maternal and child BMI. Across increasing categories of maternal glucose, frequencies of child IFG and IGT, and timed PG measures and A1C were higher, whereas insulin sensitivity and disposition index decreased. CONCLUSIONS Across the maternal glucose spectrum, exposure to higher levels in utero is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes.

OBJECTIVE Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl. RESULTS A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11–1.42]) and fatal (1.49 [1.30–1.71]) CVD and with all-cause mortality (1.25 [1.11–1.40]), myocardial infarction (1.22 [1.02–1.45]), and amputations (1.36 [1.05–1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79–1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00–1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes. CONCLUSIONS Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes.

OBJECTIVE To assess the risk of neonatal hypoglycemia following diet-controlled and insulin-treated gestational diabetes mellitus (GDM) and how it relates to birth weight. RESEARCH DESIGN AND METHODS Prospective cohort study included term neonates born after GDM from January 2013 through December 2015 at the University Medical Center Utrecht (Utrecht, the Netherlands). Routine screening of neonatal blood glucose levels was performed at 1, 3, 6, 12, and 24 h after birth. Main outcome measures were neonatal hypoglycemia defined as blood glucose ≤36 mg/dL (severe) and ≤47 mg/dL (mild). RESULTS A total of 506 neonates were included, born after pregnancies complicated by GDM treated either with insulin (22.5%) or without insulin (77.5%). The incidence of mild and severe hypoglycemia was similar in the insulin-treated and diet-controlled groups (33 vs. 35%, P = 0.66; and 20 vs. 21%, P = 0.79). A birth weight >90th centile was seen in 17.2% of all infants. Although children with a birth weight >90th centile had the highest risk for hypoglycemia, the vast majority of hypoglycemia (78.6%) was detected in those with a birth weight CONCLUSIONS Routine screening for neonatal hypoglycemia following pregnancies complicated by GDM reveals high incidence of both mild and severe hypoglycemia for both diet-controlled and insulin-treated GDM and across the full range of birth weight centiles. We propose routine blood glucose screening for neonatal hypoglycemia within the first 12 h of life in all neonates after GDM, irrespective of maternal insulin use or birth weight.

OBJECTIVE The increasing importance of peers in adolescence and emerging adulthood has been widely acknowledged. However, longitudinal research linking the peer context to diabetes management and outcomes is scarce. The present longitudinal study in a large sample of youths with type 1 diabetes related both positive and negative peer variables to diabetes outcomes over a time interval of 1 year. RESEARCH DESIGN AND METHODS Our sample consisted of 467 adolescents (14–17 years of age) and emerging adults (18–25 years of age) with type 1 diabetes who participated in a two-wave longitudinal study. Questionnaires tapped into peer support, extreme peer orientation, parental responsiveness, diabetes-related distress, and treatment adherence. HbA1c values were obtained from the treating physicians of patients. Cross-lagged analysis from a structural equation modeling approach was performed to assess the directionality of effects. RESULTS Peer support negatively predicted diabetes-related distress over time. Extreme peer orientation positively predicted treatment distress over time. Parental responsiveness negatively predicted food distress over time. Treatment adherence negatively predicted extreme peer orientation, treatment distress, and HbA1c values over time. For emerging adults specifically, there was a reciprocal relationship between HbA1c values and extreme peer orientation because they positively predicted each other. CONCLUSIONS This study highlights the importance of peers in predicting the functioning of youths with type 1 diabetes. Additionally, treatment adherence at baseline was found to negatively predict extreme peer orientation, treatment distress, and worse glycemic control over time. In sum, the current study underscores the importance of the peer context for adolescents and emerging adults with type 1 diabetes.

OBJECTIVE To evaluate whether low HDL cholesterol (HDL-c) levels are a risk factor for cardiovascular disease and mortality in patients with type 2 diabetes and whether it remains a residual risk factor when attaining low LDL cholesterol (LDL-c) treatment goals or when LDL-c is treated with intensive lipid-lowering therapy. RESEARCH DESIGN AND METHODS We performed a prospective cohort study of 1,829 patients with type 2 diabetes included in the Second Manifestations of ARTerial disease (SMART) cohort. Cox proportional hazard models were used to evaluate the risk of HDL-c on cardiovascular events and all-cause mortality. Analyses were performed in strata of LDL-c levels (2.5 mmol/L) and lipid-lowering therapy intensity and were adjusted for age, sex, BMI, smoking, alcohol, LDL-c, triglycerides, systolic blood pressure, estimated glomerular filtration rate, glucose, and HbA1c. RESULTS A total of 335 new cardiovascular events and 385 deaths occurred during a median follow-up of 7.0 years (interquartile range 3.9–10.4). No relation was found between plasma HDL-c and cardiovascular events (hazard ratio [HR] 0.97, 95% CI 0.93–1.01) or all-cause mortality (HR 0.99, 95% CI 0.96–1.03). Subgroup analysis supported effect modification by plasma LDL-c levels. In patients with LDL-c levels 2.5 mmol/L (HR 0.96, 95% CI 0.91–1.00). CONCLUSIONS In high-risk patients with type 2 diabetes with LDL-c levels

OBJECTIVE To investigate whether women with type 2 diabetes (T2D) develop a more advanced stage of breast cancer and whether treatment with insulin (analogs) is associated with specific breast cancer characteristics. RESEARCH DESIGN AND METHODS For this nested case-control study, women with breast cancer diagnosed in 2002–2014 were selected from the linked Netherlands Cancer Registry–PHARMO Database Network (N = 33,377). T2D was defined as receiving two or more dispensings of noninsulin blood glucose–lowering drugs prior to breast cancer diagnosis. Women with T2D were matched to women without diabetes. Among women with T2D, insulin users and nonusers were compared. Multivariable ordinal logistic regression was used to investigate the association between T2D/insulin and breast cancer characteristics, including TNM classification (tumor size, lymph node status, metastasis), morphology, grade, estrogen receptor and progesterone receptor (PR), human epidermal growth factor receptor 2, and molecular subtype. RESULTS Women with T2D (n = 1,567) were more often diagnosed with a more advanced tumor stage (odds ratio 1.28 [95% CI 13–1.44]) and a higher grade (1.22 [1.08–1.39]) though less often with a PR-negative breast tumor (0.77 [0.67–0.89]) than women without diabetes (n = 6,267). No associations were found for the other breast cancer characteristics. Women with T2D using insulin (n = 388) were not diagnosed with different breast cancer characteristics compared with women with T2D not using insulin (n = 1,179). CONCLUSIONS Our study suggests that women with T2D are at increased risk to be diagnosed with a more aggressive type of breast cancer than women without diabetes. No evidence was found that the use of insulin (analogs) is associated with developing more advanced breast cancer tumors.

OBJECTIVE To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study.RESEARCH DESIGN AND METHODS We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors.RESULTS When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors.CONCLUSIONS Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted. OBJECTIVE: To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study.RESEARCH DESIGN AND METHODS: We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors.RESULTS: When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors.CONCLUSIONS: Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.

OBJECTIVE To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure–related variables. RESEARCH DESIGN AND METHODS We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age ± SD, 60 ± 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemia was assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA1c), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure–related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects. RESULTS After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory −0.087, processing speed −0.196, executive function and attention −0.182; P values CONCLUSIONS Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance.

OBJECTIVE We investigated whether islet autoantibody profile, HLA-DQ genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb+) in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Persistently islet autoAb+ siblings and offspring (n = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay. RESULTS The 20-year progression rate of multiple-autoAb+ relatives (n = 194) was higher than that for single-autoAb+ participants (n = 268) (88% vs. 54%; P < 0.001). Relatives positive for IAA and GADA (n = 54) progressed more slowly than double-autoAb+ individuals carrying IA-2A and/or ZnT8A (n = 38; P = 0.001). In multiple-autoAb+ relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes (P < 0.001); in single-autoAb+ relatives, it identified younger age (P < 0.001), HLA-DQ2/DQ8 genotype (P < 0.001), and IAA (P = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (P = 0.042), HLA-DQ2/DQ8 genotype (P = 0.009), and the development of additional autoAbs (P = 0.012) were associated with more rapid progression to diabetes. CONCLUSIONS In single-autoAb+ relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and HLA-DQ2/DQ8 genotype. The majority of multiple-autoAb+ individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, HLA-DQ genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.

OBJECTIVE To determine trends in hospitalization for hypoglycemia in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in England. RESEARCH DESIGN AND METHODS Adults with T1DM or T2DM were identified from 398 of the 684 practices within the Clinical Practice Research Datalink, for which linkage to the Hospital Episode Statistics was possible. Hypoglycemia as the primary reason for hospitalization between 1998 and 2013 was extracted. Trends were estimated using joinpoint regression models for adults with T1DM, young and middle-aged adults with T2DM (18–64 years), and elderly adults with T2DM (≥65 years), respectively. RESULTS Among 23,246 adults with T1DM, 1,591 hypoglycemia hospitalizations occurred during 121,262 person-years. Among 241,441 adults with T2DM, 3,738 hypoglycemia hospitalizations occurred during 1,344,818 person-years. In adults with T1DM, the incidence increased 3.74% (95% CI 1.70–5.83) annually from 1998 to 2013. In young and middle-aged adults with T2DM, the annual incidence increase was 4.12% (0.61–7.75) from 1998 to 2013. In elderly adults with T2DM, the incidence increased 8.59% (5.76–11.50) annually from 1998 to 2009, and decreased 8.05% (−14.48 to −1.13) annually from 2009 to 2013, but the incidence was still higher in 2013 than 1998 (adjusted rate ratio 3.01 [1.76–5.14]). Trends in HbA1c level did not parallel trends of hypoglycemia hospitalization for both diabetes types. A possible reason for declined hypoglycemia trend in 2009–2013 in elderly adults with T2DM may be continuously decreased sulfonylurea use after 2009, which was not seen in young and middle-aged adults with T2DM. CONCLUSIONS Hypoglycemia requiring hospitalization has been an increasing burden in adults with T1DM and T2DM in England in the previous two decades, with the exception of the decline in elderly adults with T2DM starting in 2009.

OBJECTIVE Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease. RESEARCH DESIGN AND METHODS The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed. RESULTS Of the 6,979 participants in CARMELINA, CARMELINA-COG included 1,545 (mean ± SD age, 68 ± 8 years; MMSE, 28.3 ± 1.7; estimated glomerular filtration rate, 52 ± 23 mL/min/1.73 m2; and HbA1c, 7.8 ± 0.9% [61.4 ± 10.1 mmol/mol]). Over a median treatment duration of 2.5 years, accelerated cognitive decline occurred in 28.4% (linagliptin) vs. 29.3% (placebo) (odds ratio 0.96 [95% CI 0.77, 1.19]). Consistent effects were observed across subgroups by baseline characteristics. Absolute cognitive performance changes were also similar between treatment groups. CONCLUSIONS In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

OBJECTIVE We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS A registry-based group of siblings/offspring (aged 0–39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A*24, -B*18, and -B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS Unlike HLA-B*18 or -B*39, HLA-A*24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8+ relatives with IA-2 or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not -B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and -B*18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.