Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory.

AIMS/HYPOTHESIS: There is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs). METHODS: Selected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194). RESULTS: Eleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family. CONCLUSIONS/INTERPRETATION: The association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.

Associations between breast milk intake volume, macronutrient intake and infant growth in a longitudinal birth cohort: the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF).

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother-infant dyads (n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide (2H2O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks (ß + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months (ß + se - 2·27 + 0·7 for weight and -2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4-6 weeks were positively associated with early (0-6 weeks) but tended to be negatively related with later (3-12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

A one-year study of human milk oligosaccharide profiles in the milk of healthy UK mothers and their relationship to maternal FUT2 genotype.

Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over 1 year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated "dilute-and-shoot" method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. These data provide valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2'-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.

No relationship between prenatal or early postnatal androgen exposure and autistic traits: evidence using anogenital distance and penile length measurements at birth and 3 months of age.

BACKGROUND: Autism is more prevalent in males than in females. Hypotheses related to the extreme male brain theory of autism suggest that heightened androgen exposure during early development contributes to autistic traits. Whilst prior research focused mostly on the prenatal period, the current study tests the influences of androgen exposure during both the prenatal and the early postnatal periods on autistic traits during childhood. METHODS: Anthropometric measures that are putative biomarkers of early androgen exposure were employed. Anogenital distance (AGD) was measured at birth and 3 months of age in boys and girls. Penile length at birth and 3 months of age was also measured in boys. When the children were 9-13 years old, a parent-reported questionnaire (the 10-item children's version of the Autism Spectrum Quotient; AQ-10 Child) was used to assess autistic traits in 97 boys and 110 girls. RESULTS: There were no significant associations between any of the AGD or penile length measures and scores on the AQ-10 Child in boys, girls or the entire sample. CONCLUSIONS: The current study provides the first test of whether early measurements of AGD and/or penile length predict subsequent autistic traits. The current findings do not support a relationship between prenatal or early postnatal androgen exposure and autistic traits. The current study augments prior research showing no consistent relationship between early androgen exposure and autistic traits.

A Novel method for the identification and quantification of weight faltering.

OBJECTIVE: We describe a new method for identifying and quantifying the magnitude and rate of short-term weight faltering episodes, and assess how (a) these episodes relate to broader growth outcomes, and (b) different data collection intervals influence the quantification of weight faltering. MATERIALS AND METHODS: We apply this method to longitudinal growth data collected every other day across the first year of life in Gambian infants (n = 124, males = 65, females = 59). Weight faltering episodes are identified from velocity peaks and troughs. Rate of weight loss and regain, maximum weight loss, and duration of each episode were calculated. We systematically reduced our dataset to mimic various potential measurement intervals, to assess how these intervals affect the ability to derive information about short-term weight faltering episodes. We fit linear models to test whether metrics associated with growth faltering were associated with growth outcomes at 1 year, and generalized additive mixed models to determine whether different collection intervals influence episode identification and metrics. RESULTS: Three hundred weight faltering episodes from 119 individuals were identified. The number and magnitude of episodes negatively impacted growth outcomes at 1 year. As data collection interval increases, weight faltering episodes are missed and the duration of episodes is overestimated, resulting in the rate of weight loss and regain being underestimated. CONCLUSIONS: This method identifies and quantifies short-term weight faltering episodes, that are in turn negatively associated with growth outcomes. This approach offers a tool for investigators interested in understanding how short-term weight faltering relates to longer-term outcomes.

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes.

BACKGROUND: Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. METHODS: We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine). RESULTS: The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. CONCLUSIONS: The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .).

Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size.

OBJECTIVES: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood. SUBJECTS AND METHODS: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32). RESULTS: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (ß from -0.294 to -0.371; R2 from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (ß from -0.428 to -0.552; R2 from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR. CONCLUSIONS: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.

Factors predicting poor glycemic control in the first two years of childhood onset type 1 diabetes in a cohort from East London, UK: Analyses using mixed effects fractional polynomial models.

BACKGROUND/OBJECTIVE: Poor early glycemic control in childhood onset type 1 diabetes (T1D) is associated with future risk of acute and chronic complications. Our aim was to identify the predictors of higher glycated hemoglobin (HbA1c) within 24 months of T1D diagnosis in children and adolescents. METHODS: Mixed effects models with fractional polynomials were used to analyze longitudinal data of patients <19 years of age, followed from T1D diagnosis for up to 2 years, at three diabetes clinics in East London, United Kingdom. RESULTS: A total of 2209 HbA1c observations were available for 356 patients (52.5% female; 64.4% non-white), followed from within 3 months of diagnosis during years 2005 to 2015, with a mean ± SD of 6.2 ± 2.5 HbA1c observations/participant. The mean age and HbA1c at diagnosis were 8.9 ± 4.3 years and 10.7% ±4.3% (or expressed as mmol/mol HbA1c mean ± SD 92.9 ± 23.10 mmol/mol) respectively. Over the 2 years following T1D diagnosis, HbA1c levels were mostly above the National Institute for Health, Care and Excellence (NICE), UK recommendations of 7.5% (<58 mmol/mol). Significant (P < .05) predictors of poorer glycemic control were: Age at diagnosis (12-18 years), higher HbA1c at baseline (>9.5%, ie, >80 mmol/mol), clinic site, non-white ethnicity, and period (pre-year 2011) of diagnosis. Additionally in univariable analyses, frequency of clinic visits, HbA1c at diagnosis, and type of insulin treatment regimen showed association with poor glycemic control (P < .05). CONCLUSIONS: Major risk factors of poorer glycemic control during 3-24 months following childhood onset T1D are: diagnosis prior to 2011, higher HbA1c levels at baseline, age at diagnosis, non-white ethnicity, and clinic site.

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <-3 and > 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation.

AIMS: High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed. METHODS AND RESULTS: Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05). CONCLUSION: Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.

Reduced size at birth and persisting reductions in adiposity in recent, compared with earlier, cohorts of infants born to mothers with gestational diabetes mellitus.

AIMS/HYPOTHESIS: This study aimed to explore the infancy growth trajectories of 'recent' and 'earlier' offspring of mothers with gestational diabetes mellitus (OGDM), each compared with the same control infants, and investigate whether 'recent' OGDM still exhibit a classical phenotype, with macrosomia and increased adiposity. METHODS: Within a prospective observational birth cohort, 98 'earlier' OGDM born between 2001 and 2009 were identified using 75 g oral glucose tolerance testing at 28 weeks gestation, 122 recent OGDM born between 2011 and 2013 were recruited postnatally through antenatal diabetes clinics, and 876 normal birthweight infants of mothers with no history of diabetes were recruited across the full study period as the control group. All infants followed the same study protocol (measurements at birth, 3, 12 and 24 months, including weight, length and skinfold thickness indicating adiposity, and detailed demographic data). In all cases, GDM was defined using the International Association of Diabetes and Pregnancy Study Group criteria. RESULTS: Earlier OGDM had higher birthweight SD scores (SDS) than control infants. Conversely, recent OGDM had similar birthweight- and length SDS to control infants (mean ± SD, 0.1 ± 1.0 and- 0.1 ± 0.9, respectively), but lower mean skinfold thickness SDS (-0.4 ± 0.6 vs 0.0 ± 0.9; p < 0.001). After birth, earlier OGDM showed reduced gains in weight and length between 3 and 12 months. In contrast, recent OGDM had increased weight and skinfold thickness gains until 3 months, followed by reduced gains in those variables from 3 to 12 months, compared with control infants. At 24 months, recent OGDM had lower adiposity than control infants (mean skinfold thickness SDS -0.3 ± 0.7 vs 0.0 ± 0.8; p < 0.001). At all time points recent OGDM had lower growth measurements than earlier OGDM. CONCLUSIONS/INTERPRETATION: Recent OGDM showed different growth trajectories to the earlier group, namely normalisation of birthweight and reduced adiposity at birth, followed by initial rapid weight gain but subsequent reduced adiposity postnatally. While avoidance of macrosomia at birth may be advantageous, the longer-term health implications of these changing growth trajectories are uncertain.

Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.

BACKGROUND: The achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older. METHODS: In this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA. We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7·5-10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living. Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period. Eligible subjects were randomly assigned using central randomisation software. Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA1c. The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9-10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual. FINDINGS: From May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group). The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001). In the closed-loop group, HbA1c was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period. In the control group, the HbA1c values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change -0·83 percentage points, -1·40 to -0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change -10·3 percentage points, -13·2 to -7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change -0·4%, 95% CI -1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI -0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI -0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group. INTERPRETATION: Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes. FUNDING: JDRF, NIHR, and Wellcome Trust.

Human Milk Short-Chain Fatty Acid Composition is Associated with Adiposity Outcomes in Infants.

BACKGROUND: Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. OBJECTIVE: We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. METHODS: In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. RESULTS: NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B  = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). CONCLUSIONS: These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.

Mixed-meal tolerance test to assess residual beta-cell secretion: Beyond the area-under-curve of plasma C-peptide concentration.

AIMS: Residual beta-cell secretion in type 1 diabetes is commonly assessed by area-under-curve of plasma C-peptide concentration (AUCCpep ) following mixed-meal tolerance test (MMTT). We aimed to investigate alternative measures of beta-cell responsiveness. METHODS: We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUCCpep with (a) validated mechanistic index of postprandial beta-cell responsiveness MI accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C-peptide concentration corrected for baseline plasma glucose concentration. RESULTS: Postprandial responsiveness MI was correlated with age and BMI SDS (Rs = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUCCpep (Rs = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUCCpep (Rs = 0.94, P < 0.01). CONCLUSIONS: Postprandial responsiveness MI may be more relevant to glucose control than AUCCpep . Baseline C-peptide corrected for baseline glucose appears to be a suitable surrogate of AUCCpep if MMTT is not performed.

Effect of early glycemic control on HbA1c tracking and development of vascular complications after 5 years of childhood onset type 1 diabetes: Systematic review and meta-analysis.

OBJECTIVE: A systematic review and meta-analysis was conducted to investigate if glycemic control measured by glycated hemoglobin (HbA1c) levels near diagnosis are predictive of future glycemic outcomes and vascular complications in childhood onset type 1 diabetes (T1D). METHODS: Evidence was gathered using electronic databases (MEDLINE, EMBASE, Web of Science, CINAHL, Scopus, and Cochrane Library up to February 2017) and snowballing techniques. Studies investigating the association between the exposure "early glycemic control" and main outcome: "tracking of early control" and secondary outcome: risk of future complications; in children and young people aged 0 to 19 years at baseline; were systematically double-reviewed, quality assessed, and outcome data extracted for synthesis and meta-analysis. FINDINGS: Five studies (N = 4227 participants) were eligible. HbA1c levels were sub-optimal throughout the study period but tended to stabilize in a "track" by 6 months after T1D diagnosis. The group with low HbA1c <53 mmol/mol (<7%) at baseline had lower long-term HbA1c levels than the higher HbA1c group. The estimated standardized mean difference between the sub groups showed a reduction of HbA1c levels on average by 1.6% (range -0.95% to -2.28%) from baseline. Only one study investigated the association between early glycemic control and development of vascular complications in childhood onset T1D. INTERPRETATIONS: Glycemic control after the first few months of childhood onset T1D, remains stable but sub-optimal for a decade. The low and high HbA1c levels at baseline seem to "track" in their respective tracks during the 10-year follow-up, however, the initial difference between groups narrows over time. PROSPERO: CRD42015024546 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024546.

Reliability and validity of last menstrual period for gestational age estimation in a low-to-middle-income setting.

AIM: Gestational age estimation by ultrasonography is the gold standard for dating pregnancies. However, the availability of prenatal ultrasonography in low-to-middle-income countries is limited. This study aimed to assess the reliability and validity of last menstrual period (LMP) as a gestational age dating method among women in Johannesburg, South Africa. METHODS: A total of 741 pregnant women were enrolled into a longitudinal study (June 2013 to July 2016). Gestational age was determined by LMP and ultrasonography. Differences in ultrasound-based and LMP-based gestational age estimates were assessed according to the American College of Obstetrics and Gynecologists' guidelines and women were classified as having discrepant results or not. Multiple statistical analyses determined the level of agreement between the two methods and validity of LMP estimates. RESULTS: Compared to ultrasound, dating by LMP assessed gestational age as 0.2 days longer. Women with discrepant results were of significantly lower weight and household socioeconomic status than those without discrepancies. While there was a substantial agreement (k = 0.64; 95% confidence interval, CI: 0.54, 0.71, P < 0.001) between the two methods, LMP only had a 29.0% (95% CI: 14.2, 48.0) sensitivity in identifying late-term neonates and a 33.3% (95% CI: 4.33, 77.7) sensitivity in identifying post-term neonates. CONCLUSION: In the absence of ultrasound, LMP is a reliable alternative for gestational age dating during early pregnancy. However, it is not sensitive in identifying late- and post-term pregnancies and should not be relied upon to make clinical decisions regarding elective cesarean section or induction of labor for supposed prolonged pregnancies.

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes.

AIMS/HYPOTHESIS: We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. METHODS: A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as 'high-risk' for future albuminuria and the lower two tertiles were deemed 'low-risk'. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1-Q5) for associations with log10 ACR and ACR risk groups. RESULTS: Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2-Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1-Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. CONCLUSIONS/INTERPRETATION: Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.

Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes.

OBJECTIVE: To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D). STUDY DESIGN: Renal outcomes included estimated glomerular filtration rate (eGFR) and albumin-creatinine excretion ratio (ACR). Differences in urinary and serum inflammatory markers also were assessed in relation to social determinants of health. Regression analysis was used to evaluate the association between the Ontario Marginalization Index (ON-Marg) as a measure of the social determinants of health, patient characteristics, ACR, eGFR, and renal filtration status (hyperfiltration vs normofiltration). RESULTS: Participants with T1D (n = 199) with a mean age of 14.4 ± 1.7 years and diabetes duration of 7.2 ± 3.1 years were studied. Mean eGFR was 122.0 ± 19.4 mL/min/1.73 m2. Increasing marginalization was positively associated with eGFR (P < .0001) but not with ACR (P = .605). Greater marginalization was associated with greater median levels of urinary interleukin (IL)-2, IL-12 (p40), macrophage-derived chemokine, monocyte chemoattractant protein-3, and tumor necrosis factor-ß and serum IL-2. ON-Marg was significantly associated with eGFR after we controlled for age, sex, body mass index z score, ethnicity, serum glucose, and hemoglobin A1c in linear regression. A similar association between hyperfiltration and ON-Marg score was observed in multivariable logistic regression. CONCLUSION: Increasing marginalization is significantly associated with both eGFR and hyperfiltration in adolescents with T1D and is associated with significant changes in urinary inflammatory biomarkers. These findings highlight a potentially important interaction between social and biological determinants of health in adolescents with T1D.

Associations between the maternal circulating lipid profile in pregnancy and fetal imprinted gene alleles: a cohort study.

BACKGROUND: Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. METHODS: Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n = 200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n = 567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. RESULTS: The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R = 0.14, p = 2.9 × 10- 3, n = 386) and maternally-transmitted fetal FAM99A rs7131362 (R = 0.18, p = 6.2 × 10- 3, n = 351; association with maternal-untransmitted allele R = 0.08, p = 0.07, n = 328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10- 3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). CONCLUSIONS: Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.