Thyroid hormone sensitivity and diabetes onset: a longitudinal cross-lagged cohort.

Purpose: Thyroid hormones sensitivity is a newly proposed clinical entity closely related with metabolic health. Prior studies have reported the cross-sectional relationship between thyroid hormones sensitivity and diabetes; however, the longitudinal association is unclear to date. We aimed to explore the relationship between impaired thyroid hormone sensitivity at baseline and diabetes onset using a cohort design. Methods: This study enrolled 7283 euthyroid participants at the first visit between 2008 and 2009, and then annually followed until diabetes onset or 2019. Thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were measured to calculate thyroid hormone sensitivity by thyroid feedback quantile-based index (TFQI), Chinese-referenced parametric thyroid feedback quantile-based index (PTFQI), thyrotropin index (TSHI), thyrotroph thyroxine resistance index (TT4RI) and FT3/FT4 ratio. Cox proportional hazard model and cross-lagged panel analysis were used. Results: The mean baseline age was 44.2 ± 11.9 years, including 4170 (57.3%) male. During a median follow-up of 5.2 years, 359 cases developed diabetes. There was no significant association between thyroid hormones sensitivity indices and diabetes onset, and adjusted hazard ratios per unit (95% CIs) were 0.89 (0.65-1.23) for TFQI, 0.91 (0.57-1.45) for PTFQI, 0.95 (0.70-1.29) for TSHI, 0.98 (0.70-1.01) for TT4RI and 2.12 (0.17-5.78) for FT3/FT4 ratio. Cross-lagged analysis supported the temporal association from fasting glucose to impaired thyroid hormones sensitivity indices. Conclusions: Our findings could not demonstrate that thyroid hormones sensitivity status is a predictor of diabetes onset in the euthyroid population. Elevated fasting glucose (above 7.0 mmol/L) appeared to precede impaired sensitivity indices of thyroid hormones.

Prediabetes, intervening diabetes and subsequent risk of dementia: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes. METHODS: Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA1c 39-46 mmol/mol (5.7-6.4%) and subsequent incident diabetes as a self-reported physician diagnosis or use of diabetes medication. Incident dementia was ascertained via active surveillance and adjudicated. We quantified the association of prediabetes with dementia risk before and after accounting for the subsequent development of diabetes among ARIC participants without diabetes at baseline (1990-1992; participants aged 46-70 years). We also evaluated whether age at diabetes diagnosis modified the risk of dementia. RESULTS: Among 11,656 participants without diabetes at baseline, 2330 (20.0%) had prediabetes. Before accounting for incident diabetes, prediabetes was significantly associated with the risk of dementia (HR 1.12 [95% CI 1.01, 1.24]). After accounting for incident diabetes, the association was attenuated and non-significant (HR 1.05 [95% CI 0.94, 1.16]). Earlier age of onset of diabetes had the strongest association with dementia: HR 2.92 (95% CI 2.06, 4.14) for onset before 60 years; HR 1.73 (95% CI 1.47, 2.04) for onset at 60-69 years; and HR 1.23 (95% CI 1.08, 1.40) for onset at 70-79 years. CONCLUSIONS/INTERPRETATION: Prediabetes is associated with dementia risk but this risk is explained by the subsequent development of diabetes. Earlier age of onset of diabetes substantially increases dementia risk. Preventing or delaying progression of prediabetes to diabetes will reduce dementia burden.

Onset age of diabetes and incident dementia: A prospective cohort study.

BACKGROUND: Relationship between age at diagnosis of diabetes and dementia is lacking. The aim of the study was to investigate whether diabetes onset at a younger age was associated with a higher incidence of dementia. METHODS: 466,207 participants free of dementia in the UK biobank (UKB) were included in the analysis. Propensity score matching (PSM) was adopted to match diabetic and non-diabetic participants in different onset age of diabetes groups to evaluate onset age of diabetes and incident dementia. RESULTS: Compared with non-diabetic participants, diabetes participants had an adjusted hazard ratio (HR) of 1.87 (95 % confidence interval [CI]: 1.73-2.03) for all-cause dementia, 1.85 (95 % CI: 1.60-2.04) for Alzheimer's disease (AD), and 2.86 (95 % CI: 2.47-3.32) for vascular dementia (VD). Among diabetic participants who reported onset age, the adjusted HRs for incident all-cause dementia, AD, and VD were 1.20 (95 % CI: 1.14-1.25), 1.19 (95 % CI: 1.10-1.29), and 1.19 (95 % CI: 1.10-1.28), respectively, per 10 years decrease in age at diabetes onset. After PSM, strength of association between diabetes and all-cause dementia increased with decreasing onset age of diabetes (≥60 years: HR = 1.47, 95 % CI: 1.25-1.74; 45-59 years: HR = 1.66, 95 % CI: 1.40-1.96; <45 years: HR = 2.92, 95 % CI: 2.13-4.01) after multivariable adjustment. Similarly, diabetic participants with onset age <45 years had greatest HRs for incident AD and VD, compared with their matched controls. LIMITATIONS: Our results only reflect the characteristics of UKB participants. CONCLUSIONS: Younger age at diabetes onset was significantly associated with a higher risk of dementia in this longitudinal cohort study.

High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in Children.

Recently, it was shown that children at the onset of type 1 diabetes (T1D) have a higher proportion of oligomannose glycans in their total plasma protein N-glycome compared to their healthy siblings. The most abundant complement component, glycoprotein C3, contains two N-glycosylation sites occupied exclusively by this type of glycans. Furthermore, complement system, as well as C3, was previously associated with T1D. It is also known that changes in glycosylation can modulate inflammatory responses, so our aim was to characterize the glycosylation profile of C3 in T1D. For this purpose, we developed a novel high-throughput workflow for human C3 concanavalin A lectin affinity enrichment and subsequent LC-MS glycopeptide analysis which enables protein-specific N-glycosylation profiling. From the Danish Childhood Diabetes Register, plasma samples of 61 children/adolescents newly diagnosed with T1D and 84 of their unaffected siblings were C3 N-glycoprofiled. Significant changes of C3 N-glycan profiles were found. T1D was associated with an increase in the proportion of unprocessed glycan structures with more mannose units. A regression model including C3 N-glycans showed notable discriminative power between children with early onset T1D and their healthy siblings with area under curve of 0.879. This study confirmed our previous findings of plasma high-mannose glycan changes in a cohort of recent onset T1D cases, suggesting the involvement of C3 N-glycome in T1D development. Our C3 glycan-based discriminative model could be valuable in assessment of T1D risk in children.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

[This corrects the article .].

Early Initiation of Intermittently Scanned Continuous Glucose Monitoring in a Pediatric Population With Type 1 Diabetes: A Real World Study.

Background: Use of Continuous Glucose Monitoring (CGM) systems early in the course of diabetes has the potential to help glycemic management and to improve quality of life (QoL). No previous research has examined these outcomes in children-adolescents with type 1 diabetes (T1D) who use intermittently scanned CGM (isCGM) starting within the first month after diagnosis. Aim: To evaluate the impact of isCGM early after T1D diagnosis, on metabolic control and QoL, comparing a group who started the use of the device within one month from the onset with another one who started at least one year later. Subjects and Methods: Patients who used isCGM within 1 month from T1D diagnosis were enrolled in group A; those who didn't have the device during the first year were considered as control group (group B). HbA1c and total daily insulin were evaluated at 3 (T1), 6 (T2) and 12 (T3) months post-baseline (T0, diabetes onset), QoL after 1 year. In group A, isCGM glucose metrics were also recorded. Results: 85 patients were enrolled in group A and 67 patients in group B. In group A isCGM was well accepted during follow up: no patient dropped out; percentage of time with active sensor was in mean > 87%; number of scans/day remained stable. QoL was higher in group A than in group B both in children-adolescents (p<0.0001) and in parents (p 0.003). Group A presented lower HbA1c during the first year after diagnosis (p<0.001), and this data correlated with glucose management indicator (GMI), time in range (TIR) and mean glucose. The honeymoon period lasted more in group A than in B (p 0.028). Furthermore, the mean hypoglycemia duration decreased during follow-up (p 0.001) in group A. Conclusions: Early use of isCGM, starting within the first month after diagnosis, improves metabolic control and QoL in pediatric patients with T1D.

The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Increased Presentation of Diabetic Ketoacidosis and Changes in Age and Month of Type 1 Diabetes at Onset during the COVID-19 Pandemic in Spain.

Objective: To assess the impact of the COVID-19 pandemic and lockdown measures on the presenting characteristics (age at diagnosis, severity, monthly distribution) of newly diagnosed type 1 diabetes in Spanish children. Research Design and Methods: An ambispective observational multicenter study was conducted in nine Spanish tertiary-level hospitals between January 2015 and March 2021. Inclusion criteria: new cases of type 1 diabetes in children (0-14 years) recording age, sex, date of diagnosis, presence of diabetic ketoacidosis (DKA) at onset, and severity of DKA. Data were compared before and during the pandemic. Results: We registered 1444 new cases of type 1 diabetes in children: 1085 in the pre-pandemic period (2015-2019) and 359 during the pandemic (2020-March 2021). There was a significant increase in the group aged ≤4 years in the pandemic period (chi-squared = 10.986, df 2, p = 0.0041). In 2020-2021, cases of DKA increased significantly by 12% (95% CI: 7.2-20.4%), with a higher percentage of moderate and severe DKA, although this increase was not significant. In 2020, there was a sharp decrease in the number of cases in March, with a progressive increase from May through November, higher than in the same months of the period 2015-2019, highlighting the increase in the number of cases in June, September, and November. The first three months of 2021 showed a different trend to that observed both in the years 2015-2019 and in 2020, with a marked increase in the number of cases. Conclusions: A change in monthly distribution was described, with an increase in DKA at onset of type 1 diabetes. No differences were found in severity, although there were differences in the age distribution, with an increase in the number of cases in children under 4 years of age.

Children at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG.

AIMS/HYPOTHESIS: Individual variation in plasma N-glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N-glycomes in patients with recent onset type 1 diabetes, and to evaluate their discriminative potential in risk assessment. METHODS: In the first part of the study, plasma and IgG N-glycans were chromatographically analysed in a study population from the DanDiabKids registry, comprising 1917 children and adolescents (0.6-19.1 years) who were newly diagnosed with type 1 diabetes. A follow-up study compared the results for 188 of these participants with those for their 244 unaffected siblings. Correlation of N-glycan abundance with the levels and number of various autoantibodies (against IA-2, GAD, ZnT8R, ZnT8W), as well as with sex and age at diagnosis, were estimated by using general linear modelling. A disease predictive model was built using logistic mixed-model elastic net regression, and evaluated using a 10-fold cross-validation. RESULTS: Our study showed that onset of type 1 diabetes was associated with an increase in the proportion of plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. ZnT8R autoantibody levels were associated with higher IgG digalactosylated glycan with bisecting GlcNAc. Finally, an increase in the number of autoantibodies (which is a better predictor of progression to overt diabetes than the level of any individual antibody) was accompanied by a decrease in the proportions of some of the highly branched plasma N-glycans. Models including age, sex and N-glycans yielded notable discriminative power between children with type 1 diabetes and their healthy siblings, with AUCs of 0.915 and 0.869 for addition of plasma and IgG N-glycans, respectively. CONCLUSIONS/INTERPRETATION: We defined N-glycan changes accompanying onset of type 1 diabetes, and developed a predictive model based on N-glycan profiles that could have valuable potential in risk assessment. Increasing the power of tests to identify individuals at risk of disease development would be a considerable asset for type 1 diabetes prevention trials.

Risk of Incident Heart Failure in Individuals With Early-Onset Type 2 Diabetes.

CONTEXT: Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce. OBJECTIVE: We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes. METHODS: We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined. RESULTS: A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P < 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures. CONCLUSION: Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population.

Características de los debuts diabéticos en los niños ingresados en un hospital terciario durante diez años / Characteristics of diabetic debuts in children admitted to a tertiary hospital for ten years

Introducción. La diabetes mellitus tipo 1 constituye unade las patologías crónicas más frecuentes en la infancia. Suincidencia está sufriendo un incremento en los últimos años.Objetivo. Describir y analizar las características epidemiológicas, clínicas, analíticas y terapéuticas en el momentodel debut de la enfermedad, comparándolas entre gruposde edad de los pacientes que debutan con DM1 en nuestraprovincia.Pacientes y métodos. Estudio observacional retrospectivo mediante revisión de historias clínicas de pacientesmenores de 14 años con debut de diabetes tipo 1 entre 2007y 2017 en un hospital de tercer nivel. La muestra se dividiópor edades en tres grupos (0-4 años, 5-9 años,10-14 años).Resultados. Se recogieron 64 pacientes con edad mediade 8,15 años (DE 3,41), el 48,4% entre 5-9 años. No se hallarondiferencias de sexo ni patrón estacional, aunque los pacientesde menor edad debutaron más frecuentemente en invierno.No se observó aumento en la incidencia con el tiempo nidiferencias en los síntomas entre grupos. Debutaron concetoacidosis diabética el 36%, fundamentalmente leves.Encontramos un porcentaje menor de anticuerpos IAA yantiGAD de lo esperado y mayor frecuencia de antecedentesfamiliares positivos. Se observó correlación lineal positivaentre las cifras de bicarbonato y cuerpos cetónicos en sangrey las necesidades de insulina por kg de peso (p 0,025 y p0,05, respectivamente). Los niños de menor edad presentanniveles de HbA1c más bajos al inicio de la enfermedad.Conclusiones. En nuestro medio no se está produciendoun aumento en el número de casos de esta enfermedad, aunque los mismos se concentran a menor edad de la esperada (AU)

Introduction. Type 1 diabetes mellitus is one of the mostfrequent chronic pathologies in childhood. Its incidence hasincreased in the last years.Objective. To analyze the epidemiological, clinical,analytical and therapeutic characteristics at the time of thedisease’s onset, and to compare them between age groupsof those patients with Diabetes mellitus type 1 in our region.Patients and methods. Retrospective observational studyby reviewing the medical records of patients under 14 yearsof age with onset of type 1 diabetes between 2007 and 2017in a tertiary-level hospital. The sample was divided by ageinto three groups (0-4 years, 5-9 years,10-14 years).Results. 64 patients were studied, the mean age was8.15 years (SD 3.41), 48.4% of them between 5-9 years. Nodifferences in sex or seasonal pattern were found, althoughyounger children became ill more frequently in winter. There was no increase in incidence over time ordifferencesin symptoms between groups. 36% debuted with diabeticketoacidosis, mainly mild. We found a lower percentage ofIAA and antiGAD antibodies than expected and a higherfrequency of positive family history. A positive linear correlation was observed between the levels of bicarbonateand ketone bodies in blood and the insulin needs per kg ofweight (p 0.025 and p 0.05 respectively). Younger childrenhave lower HbA1c levels at the beginning of the disease.Conclusions. In our centre there is not an increase in thenumber of cases of this disease, although we found morecases at a younger age than expected. (AU)

Adult-onset type 1 diabetic patients with less severe clinical manifestation have less risk DR-DQ genotypes than childhood-onset patients.

BACKGROUND: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population. MATERIALS AND METHODS: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing. RESULTS: Adult-onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C-peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood-onset patients, adult-onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high-risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non-risk) genotypes. CONCLUSIONS: Adult-onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR-DQ haplotypes than childhood-onset patients, which suggested the association between less risk DR-DQ genotypes and the less severe clinical manifestation in adult-onset patients.

Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.

Islet/ß cell dysfunction and death caused by autoimmune-mediated injuries are major features of type 1 diabetes (T1D). Mesenchymal stromal cells (MSCs) have been used for the treatment of T1D in animal models and clinical trials. Based on the anti-inflammatory effects of alpha-1 antitrypsin (AAT), we generated human AAT engineered MSCs (hAAT-MSCs) by infecting human bone marrow-derived MSCs with the pHAGE CMV-a1aT-UBC-GFP-W lentiviral vector. We compared the colony forming, differentiation, and migration capacity of empty virus-treated MSCs (hMSC) and hAAT-MSCs and tested their protective effects in the prevention of onset of T1D in nonobese diabetic (NOD) mice. hAAT-MSCs showed increased self-renewal, better migration and multilineage differentiation abilities compared to hMSCs. In addition, polymerase chain reaction array for 84 MSC-related genes showed that 23 genes were upregulated, and 3 genes were downregulated in hAAT-MSCs compared to hMSCs. Upregulated genes include those critical for the stemness (ie, Wnt family member 3A [WNT3A], kinase insert domain receptor [KDR]), migration (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion protein 1 [VICAM-1], matrix metalloproteinase-2 [MMP2]), and survival (insulin-like growth factor 1 [IGF-1]) of MSCs. Pathway analysis showed that changed genes were related to growth factor activity, positive regulation of cell migration, and positive regulation of transcription. In vivo, a single intravenous infusion of hAAT-MSCs significantly limited inflammatory infiltration into islets and delayed diabetes onset in the NOD mice compared with those receiving vehicle or hMSCs. Taken together, overexpression of hAAT in MSCs improved intrinsic biological properties of MSCs needed for cellular therapy for the treatment of T1D.

Clinical characteristics and 10-year outcomes of diabetes in adults with advancing age at onset: A population cohort.

PURPOSE: The risk of diabetes mellitus increases with age but its characteristics, treatment patterns, and outcomes in people with onset at different ages are little studied. The aim of this study is Investigate longitudinal clinical characteristics, complications, anti-diabetes medication usage, and diabetes-related outcomes among people diagnosed at different ages. METHODS: This retrospective cohort study using Taiwan National Health Insurance Research Database claims data from 2000 to 2013, recruited 123,172 ≥ 40-year-olds with newly diagnosed diabetes, stratified by age at diagnosis: 40-64 years (62.2 %), 65-74 (21.9 %), 75-84 (12.9 %), and ≥ 85 (3.0 %). Baseline characteristics, 10-year follow-up of anti-diabetes drug usage, and cumulative incidence of diabetes-related complications and outcomes, stratified by age. RESULTS: Compared to people with younger-onset, those diagnosed when older had more multimorbidity, higher prevalence of diabetes-related complications, and proportionally lower anti-diabetes drug usage (all p < 0.01). During 10-year follow-up, people diagnosed when older had higher risks for cardiovascular and cerebrovascular disease, nephropathy, and peripheral artery disease, but lower cumulative incidence of retinopathy and peripheral neuropathy (all p < 0.001). People with later versus earlier onset had higher rates of all-cause mortality, cardiovascular mortality, major adverse cardiovascular events, and diabetes-related hospitalization (all p < 0.001). CONCLUSION: Over 10-year follow-up, people who are older versus younger at diabetes diagnosis have higher cumulative incidence of macrovascular complications but lower rates of microvascular complications (except nephropathy); they also have higher cumulative incidence of diabetes-related hospitalization, all-cause mortality, and cardiovascular morbidity and mortality.

After Gestational Diabetes: Impact of Pregnancy Interval on Recurrence and Type 2 Diabetes.

The contribution of pregnancy interval after gestational diabetes (GDM) to type 2 diabetes (T2DM) onset is a poorly understood but potentially modifiable factor for T2DM prevention. The purpose of this study was to assess the impact of GDM recurrence and/or delivery interval on follow-up care and T2DM onset in a sample of continuously insured women with a term livebirth within 3 years of a GDM-affected delivery. This is a secondary analysis of a cohort of 12,622 women with GDM, 2006-2012, drawn from a national administrative data system (OptumLabs Data Warehouse). We followed 1091 women with GDM who had a subsequent delivery within 3 years of their index delivery. GDM recurred in 49.3% of subsequent pregnancies regardless of the interval to the next conception. Recurrence tripled the odds of early T2DM onset within 3 years of the second delivery. Women with GDM recurrence had greater likelihood of glucose testing in that 3-year interval, but not transition to primary care for continued monitoring, as required by both American Congress of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) guidelines. In multivariable analysis, we found a trend toward increased likelihood of T2DM onset for short interpregnancy intervals (≤1 year vs. 3 year, 0.08). Pregnancy interval may play a previously unrecognized role in progression to T2DM. T2DM onset after GDM can be prevented or mitigated, but many women in even this insured sample did not receive recommended follow-up monitoring and preventive care, even after a GDM recurrence. The postpartum visit may be an ideal time to inform patients about T2DM prevention opportunities, and discuss potential benefits of optimal spacing of future pregnancies.

Onset of T2DM after gestational diabetes: What the prevention paradox tells us about risk.

This study investigates the effect of severity of gestational diabetes (GDM) on likelihood of post-delivery glucose testing and early onset Type 2 diabetes (T2DM). We asked if clinical focus on relative risk (RR), i.e. greater probability of T2DM onset in a higher-severity group, contributes to missed opportunities for prevention among women with lower-severity GDM. A sample of 12,622 continuously-insured women with GDM (2006-2015) was drawn from a large national dataset (OptumLabs® Data Warehouse) and followed for 3-years post-delivery. Higher-severity GDM was defined as addition of hypoglycemic therapy to standard of care for GDM. We found that women with higher-severity (n = 2627) were twice as likely as lower-severity women (n = 9995) to obtain glucose testing post-delivery. Moreover, 357 (13.6%) of the higher-severity women developed T2DM by year-3 vs. 600 (6.0%) lower-severity women. In an analysis of the population attributable fraction (PAF), defined as the contribution of excess risk to population prevalence, lower-severity women contributed more cases to diabetes rates than higher-risk women (PAF 79% vs. 21%), despite an increased RR in the higher-severity group (13.6% vs. 6.0%, RR 2.26, 95%CI 2.00, 2.56). Projecting out to the 327,950 U.S. deliveries in 2014, we estimate that 9277 higher-severity women (13.6%) and 15,584 lower-severity women (6.0%), will have developed T2DM by 2018. These data demonstrate that lower-severity GDM contributes substantially to the diabetes epidemic. Greater awareness of clinical and cost implications of gaps in follow-up for lower-severity GDM may strengthen the likelihood of post-delivery testing and primary care referral, and thus reinforce the path to prevention.

Impact of age at diagnosis and duration of type 2 diabetes on mortality in Australia 1997-2011.

AIMS/HYPOTHESIS: Current evidence suggests that type 2 diabetes may have a greater impact on those with earlier diagnosis (longer duration of disease), but data are limited. We examined the effect of age at diagnosis of type 2 diabetes on the risk of all-cause and cause-specific mortality over 15 years. METHODS: The data of 743,709 Australians with type 2 diabetes who were registered on the National Diabetes Services Scheme (NDSS) between 1997 and 2011 were examined. Mortality data were derived by linking the NDSS to the National Death Index. All-cause mortality and mortality due to cardiovascular disease (CVD), cancer and all other causes were identified. Poisson regression was used to model mortality rates by sex, current age, age at diagnosis, diabetes duration and calendar time. RESULTS: The median age at registration on the NDSS was 60.2 years (interquartile range [IQR] 50.9-69.5) and the median follow-up was 7.2 years (IQR 3.4-11.3). The median age at diagnosis was 58.6 years (IQR 49.4-67.9). A total of 115,363 deaths occurred during 7.20 million person-years of follow-up. During the first 1.8 years after diabetes diagnosis, rates of all-cause and cancer mortality declined and CVD mortality was constant. All mortality rates increased exponentially with age. An earlier diagnosis of type 2 diabetes (longer duration of disease) was associated with a higher risk of all-cause mortality, primarily driven by CVD mortality. A 10 year earlier diagnosis (equivalent to 10 years' longer duration of diabetes) was associated with a 1.2-1.3 times increased risk of all-cause mortality and about 1.6 times increased risk of CVD mortality. The effects were similar in men and women. For mortality due to cancer (all cancers and colorectal and lung cancers), we found that earlier diagnosis of type 2 diabetes was associated with lower mortality compared with diagnosis at an older age. CONCLUSIONS/INTERPRETATION: Our findings suggest that younger-onset type 2 diabetes increases mortality risk, and that this is mainly through earlier CVD mortality. Efforts to delay the onset of type 2 diabetes might, therefore, reduce mortality.

Follow-up after gestational diabetes: a fixable gap in women's preventive healthcare.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a known harbinger of future type 2 diabetes mellitus (T2DM), hypertension, and cardiac disease. This population-based study was designed to identify gaps in follow-up care relevant to prevention of T2DM in a continuously insured sample of women diagnosed with GDM. RESEARCH DESIGN AND METHODS: We analyzed data spanning 2005-2015 from OptumLabs Data Warehouse, a comprehensive, longitudinal, real-world data asset with deidentified lives across claims and clinical information, to describe patterns of preventive care after GDM. Women with GDM were followed, from 1 year preconception through 3 years postdelivery to identify individual and healthcare systems characteristics, and report on GDM-related outcomes: postpartum glucose testing, transition to primary care for monitoring, GDM recurrence, and T2DM onset. RESULTS: Among 12 622 women with GDM, we found low rates of glucose monitoring in the recommended postpartum period (5.8%), at 1 year (21.8%), and at 3 years (51%). A minority had contact with primary care postdelivery (5.7% at 6 months, 13.2% at 1 year, 40.5% at 3 years). Despite increased population risk (GDM recurrence in 52.2% of repeat pregnancies, T2DM onset within 3 years in 7.6% of the sample), 70.1% of GDM-diagnosed women had neither glucose testing nor a primary care visit at 1 year and 32.7% had neither at 3 years. CONCLUSIONS: We found low rates of glucose testing and transition to primary care in this group of continuously insured women with GDM. Despite continuous insurance coverage, many women with a pregnancy complication that portends risk for future chronic illness fail to obtain follow-up testing and may have difficulty navigating between clinician specialties. Results point to a need for action to close the gap between obstetrics and primary care to ensure receipt of preventive monitoring as recommended by both the American Diabetes Association and the American Congress of Obstetricians and Gynecologists.

Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY).

AIMS/HYPOTHESIS: We sought to assess the frequency, determinants and prognosis for future diabetes in individuals with islet autoimmunity and whether these factors differ depending on the age of onset of islet autoimmunity. METHODS: A prospective cohort (n = 2547) of children from the general population who had a high-risk HLA genotype and children who had a first-degree relative with type 1 diabetes were followed for up to 21 years. Those with the persistent presence of one or more islet autoantibodies were categorised as early-onset (<8 years of age, n = 143, median 3.3 years) or late-onset (≥8 years of age, n = 64, median 11.1 years), and were followed for a median of 7.4 and 4.7 years, respectively. Progression to diabetes was evaluated by Kaplan-Meier analysis with logrank test. Factors associated with progression to diabetes were analysed using the parametric accelerated failure time model. RESULTS: Children with late-onset islet autoimmunity were more likely to be Hispanic or African-American than non-Hispanic white (p = 0.004), and less likely to be siblings of individuals with type 1 diabetes (p = 0.04). The frequencies of the HLA-DR3/4 genotype and non-HLA gene variants associated with type 1 diabetes did not differ between the two groups. However, age and HLA-DR3/4 were important predictors of rate of progression to both the presence of additional autoantibodies and type 1 diabetes. Late-onset islet autoimmunity was more likely to present with a single islet autoantibody (p = 0.01) and revert to an antibody-negative state (p = 0.01). Progression to diabetes was significantly slower in children with late-onset islet autoimmunity (p < 0.001). CONCLUSIONS/INTERPRETATION: A late onset of islet autoimmunity is more common in African-American and Hispanic individuals. About half of those with late-onset islet autoimmunity progress to show multiple islet autoantibodies and develop diabetes in adolescence or early adulthood. Further investigation of environmental determinants of late-onset autoimmunity may lead to an understanding of and ability to prevent adolescent and adult-onset type 1 diabetes.

Mechanisms of diabetic autoimmunity: I--the inductive interface between islets and the immune system at onset of inflammation.

The mechanisms of autoimmune reactivity onset in type 1 diabetes (T1D) remain elusive despite extensive experimentation and discussion. We reconsider several key aspects of the early stages of autoimmunity at four levels: islets, pancreatic lymph nodes, thymic function and peripheral immune homeostasis. Antigen presentation is the islets and has the capacity to provoke immune sensitization, either in the process of physiological neonatal ß cell apoptosis or as a consequence of cytolytic activity of self-reactive thymocytes that escaped negative regulation. Diabetogenic effectors are efficiently expanded in both the islets and the lymph nodes under conditions of empty lymphoid niches during a period of time coinciding with a synchronized wave of ß cell apoptosis surrounding weaning. A major drive of effector cell activation and expansion is inherent peripheral lymphopenia characteristic of neonates, though it remains unclear when is autoimmunity triggered in subjects displaying hyperglycemia in late adolescence. Our analysis suggests that T1D evolves through coordinated activity of multiple physiological mechanisms of stimulation within specific characteristics of the neonate immune system.