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The CONCEPTT trial compared real-time Continuous Glucose Monitoring (RT-CGM) to capillary glucose monitoring in pregnant women with type 1 diabetes. We analyzed CGM and glycated hemoglobin (HbA1c) ...

OBJECTIVE We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of β-cell regeneration in pregnancy with type 1 diabetes. RESEARCH DESIGN AND METHODS C-peptide was measured on maternal serum samples from 127 participants (12, 24, and 34 weeks) and cord blood during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay. RESULTS Three discrete patterns of maternal C-peptide trajectory were identified: pattern 1, undetectable throughout pregnancy, n = 74 (58%; maternal C-peptide CONCLUSIONS First maternal C-peptide appearance at 34 weeks was associated with midtrimester hyperglycemia, elevated cord blood C-peptide, and high rates of neonatal complications. This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related β-cell regeneration.

Objective: Type 1 diabetes in pregnancy is associated with increased birthweight and adiposity in offspring, which may contribute to increased future cardiometabolic risk. We assessed if the effects of maternal hyperglycemia on adiposity were mediated by altered lipid metabolism in pregnancy. Methods and Outcomes: 200 women in the Continuous Glucose Monitoring (CGM) in Pregnant women with Type 1 diabetes Trial (CONCEPTT) had a livebirth. Liquid chromatography-mass spectrometry of maternal serum (12, 24, 34 wks; n=174) and cord blood (n=93) measured 21metabolites. Anthropometry was performed at birth by trained staff. Statistical Analysis: Linear regression of CGM time above range 12, 24, 34 wks (>140 mg/dl; >7.8 mmol/l) with adjustment for maternal age, BMI, parity, ethnicity, education and intervention (birth gestation for offspring) . Significance limit was p=0.0for unselected analysis of all metabolites, p=0.for subset analysis with skinfolds. Results: Maternal hyperglycemia at 24 and 34 weeks was associated with increased triglycerides containing FA (16:0) , (16:1) , (18:0) and (18:1) in maternal serum, considered biomarkers of de novo lipogenesis. Maternal hyperglycemia was associated with abundant carnitines in cord blood, suggesting increased fetal beta oxidation. Lipogenesis-associated species (maternal serum) and carnitines (cord blood) were associated with offspring skinfold sum, independently of maternal hyperglycemia. However, maternal hyperglycemia retained a strong independent association with skinfold sum despite adjustment for potential lipid mediators. Conclusions: Maternal hyperglycemia is associated with features of de novo lipogenesis in the maternal metabolism and beta oxidation in the offspring. Altered lipid metabolism significantly contributes to offspring adiposity but does not appear to solely mediate the relationship between hyperglycemia and body composition in type 1 diabetes pregnancy. Disclosure C.L.Meek: Research Support; Dexcom, Inc. Z.A.Stewart: None. D.Feig: Advisory Panel; Novo Nordisk, Research Support; Apotex. A.Koulman: None. H.R.Murphy: Advisory Panel; Medtronic. Funding This project was funded by Diabetes UK (PG 2017/2278) . The CONCEPTT trial was funded by Juvenile Diabetes Research Foundation (JDRF) grants #17-2011-533, and grants under the JDRF Canadian Clinical Trial Network, a public-private partnership including JDRF and FedDev Ontario and supported by JDRF #80-2010-585. Medtronic supplied the CGM sensors and CGM systems at reduced cost. The study sponsor/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the European Foundation for the Study of Diabetes – Novo Nordisk Foundation Future Leaders’ Award (NNF19SA058974) . HRM conducts independent research supported by the National Institute for Health Research (Career Development Fellowship, CDF-2013-06-035) , and is supported by Tommy’s charity. SF and AK acknowledge funding from the BBSRC (BB/M027252/1) . DSF conducts independent research supported by the Canadian Institute for Health Research.

OBJECTIVE The optimal method of monitoring glycemia in pregnant women with type 1 diabetes remains controversial. This study aimed to assess the predictive performance of HbA1c, continuous glucose monitoring (CGM) metrics, and alternative biochemical markers of glycemia to predict obstetric and neonatal outcomes. RESEARCH DESIGN AND METHODS One hundred fifty-seven women from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) were included in this prespecified secondary analysis. HbA1c, CGM data, and alternative biochemical markers (glycated CD59, 1,5-anhydroglucitol, fructosamine, glycated albumin) were compared at ∼12, 24, and 34 weeks’ gestation using logistic regression and receiver operating characteristic (ROC) curves to predict pregnancy complications (preeclampsia, preterm delivery, large for gestational age, neonatal hypoglycemia, admission to neonatal intensive care unit). RESULTS HbA1c, CGM metrics, and alternative laboratory markers were all significantly associated with obstetric and neonatal outcomes at 24 weeks’ gestation. More outcomes were associated with CGM metrics during the first trimester and with laboratory markers (area under the ROC curve generally 140 mg/dL [>7.8 mmol/L]) were the most consistently predictive CGM metrics. HbA1c was also a consistent predictor of suboptimal pregnancy outcomes. Some alternative laboratory markers showed promise, but overall, they had lower predictive ability than HbA1c. CONCLUSIONS HbA1c is still an important biomarker for obstetric and neonatal outcomes in type 1 diabetes pregnancy. Alternative biochemical markers of glycemia and other CGM metrics did not substantially increase the prediction of pregnancy outcomes compared with widely available HbA1c and increasingly available CGM metrics (TIR and TAR).

Aims To determine whether the neonatal and delivery outcomes of gestational diabetes vary seasonally in the context of a relatively cool temperate climate. Methods A retrospect cohort of 23 735 women consecutively delivering singleton, live‐born term infants in a single tertiary obstetrics centre in the UK (2004–2008) was identified. A total of 985 (4.1%) met the diagnostic criteria for gestational diabetes. Additive dynamic regression models, adjusted for maternal age, BMI, parity and ethnicity, were used to compare gestational diabetes incidence and outcomes over annual cycles. Outcomes included: random plasma glucose at booking; gestational diabetes diagnosis; birth weight centile; and delivery mode. Results The incidence of gestational diabetes varied by 30% from peak incidence (October births) to lowest incidence (March births; P=0.031). Ambient temperature at time of testing (28 weeks) was strongly positively associated with diagnosis (P, What's new? Gestational diabetes (GDM) shows seasonal variation in hot climates, but there is no consensus on whether this impacts on neonatal or delivery outcomes.Birth weights and emergency Caesarean section rates vary seasonally in GDM‐affected pregnancies. The highest average birth weight and greatest risk of emergency Caesarean delivery occur when fewest births are complicated by GDM (March births).There are seasonal differences in GDM outcomes, and consideration should be given to the differing environmental, dietary and lifestyle factors faced by women with GDM throughout the year.

Despite recent advances in care, women with diabetes in pregnancy are still at increased risk of multiple pregnancy complications. Offspring exposed to hyperglycaemia in utero also experience long-term health sequelae, affecting neurocognitive and cardiometabolic status. Many of these adverse consequences can be prevented or ameliorated with good medical care, specifically to optimize glycaemic control. The accurate assessment of glycaemia in pregnancy is therefore vital to safeguard the health of mother and child. However, there is no consensus about the best method of monitoring glycaemic control in pregnancy. Short-term changes in insulin dosage and lifestyle, with altered appetite, insulin sensitivity and red cell turnover create difficulties in interpretation of standard laboratory measures such as HbA1c. The ideal marker would provide short-term feedback on daily or weekly glycaemic control, with additional capability to predict pregnancies at high risk of suboptimal outcomes. Several novel biochemical markers are available which allow assessment of dynamic changes in glycaemia over weeks rather than months. Continuous glucose monitoring devices have advanced in accuracy and provide new opportunities for robust assessment of glycaemia in pregnancy. Recent work from the continuous glucose monitoring in pregnant women with type 1 diabetes trial (CONCEPTT) has provided information about the ability of different markers of glycaemia to predict pregnancy outcomes.The aim of this review is to summarize the care for women with pre-existing diabetes in pregnancy and to highlight the important role of glycaemic monitoring in pregnancy.

Context Gestational diabetes (GDM) affects 20 million women/year worldwide and is associated with childhood obesity. Infants of affected mothers have increased adiposity from birth, which leads to obesity in later life. However, it remains unknown whether the effect of GDM upon neonatal body composition is due to hyperglycemia alone or is mediated by other pathways. Objective To investigate plasma lipid profiles in obese women according to GDM diagnosis, infant birthweight percentiles, and adiposity. Design Prospective cohort from UPBEAT trial (ISRCTN 89971375). Setting Hospital and community. Patients 867 obese pregnant women recruited in early pregnancy, assessed at 28 weeks for GDM. Offspring anthropometry was assessed at birth. Outcome (Prespecified) Neonatal birth percentile and abdominal circumference. Methods Lipidomic profiling in the fasting plasma oral glucose tolerance test sample using direct infusion mass spectrometry. Analysis included logistic/linear regression, unadjusted and adjusted for maternal age, body mass index, parity, ethnicity, UPBEAT trial arm, and fetal sex. The limit of significance was P = 0.05 for offspring anthropometry and P = 0.002 for lipidomic data. Results GDM in obese women was associated with elevated plasma concentrations of specific diglycerides [DG(32:0)] and triglycerides [TG(48:0), (50:1), (50:2)] containing fatty acids (16:0), (16:1), (18:0), and (18:1), consistent with increased de novo lipogenesis. In the whole cohort, these species were associated with birthweight percentile and neonatal abdominal circumference. Effects upon infant abdominal circumference remained significant after adjustment for maternal glycemia. Conclusions Increased de novo lipogenesis-related species in pregnant women with obesity and GDM are associated with measures of offspring adiposity and may be a target for improving lifelong health.

The COVID-19 pandemic has put diabetes at the forefront of conversation. The prevalence of type 2 diabetes in the United Kingdom is high1 and has links to adverse COVID-19 outcomes.2 Research investigating the links between these two public health issues are moving at pace. However, the pandemic has seen early career researchers (ECRs) in diabetes face professional and personal challenges that have the potential to slow down or derail bourgeoning careers. These challenges are not unique to ECRs working in the diabetes field—and they compound a challenging decade that included the fallout from an economic crisis and uncertainties arising from a protracted Brexit. In May 2021, 15 ECRs gathered online as part of the Diabetes UK annual Innovators in Diabetes (IDia) training programme. A discussion on the career challenges faced and possible solutions to facilitate a healthy future for diabetes ECRs was initiated and facilitated by senior leaders in diabetes research. This letter summarises the themes from that discussion.

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.

Funder: NIHR Cambridge Biomedical Research Centre, Aims: There is seasonal variation in the incidence of gestational diabetes (GDM) and delivery outcomes of affected patients. We assessed whether there was also evidence of temporal variation in maternal treatment requirements and early neonatal outcomes. Methods: We performed a retrospective analysis of women diagnosed with GDM (75 g oral glucose tolerance test, 0 h ≥ 5.1; 1 h ≥ 10.0; 2 h ≥ 8.5 mmol/L) in a UK tertiary obstetric centre (2015–2019) with a singleton infant. Data regarding demographic characteristics, total insulin requirements and neonatal outcomes were extracted from contemporaneous electronic medical records. Linear/logistic regression models using month of the year as a predictor of outcomes were used to assess annual variation. Results: In all, 791 women (50.6% receiving pharmacological treatment) and 790 neonates were included. The likelihood of requiring insulin treatment was highest in November (p < 0.05). The average total daily insulin dose was higher at peak (January) compared to average by 19 units/day (p < 0.05). There was no temporal variation in neonatal intensive care admission, or neonatal capillary blood glucose. However, rates of neonatal hypoglycaemia (defined as

Funder: NIHR School for Primary Care Research; Id: http://dx.doi.org/10.13039/501100013374, Funder: Cancer Research UK; Id: http://dx.doi.org/10.13039/501100000289, Funder: Action Medical Research; Id: http://dx.doi.org/10.13039/501100000317, Funder: European Foundation for the Study of Diabetes; Id: http://dx.doi.org/10.13039/501100001648, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265, Funder: Diabetes UK; Id: http://dx.doi.org/10.13039/501100000361, Aims: To explore the views of women with a history of gestational diabetes mellitus (GDM) on suggested practical approaches to support diabetes screening attendance after GDM, which is recommended but poorly attended. Methods: We conducted semi‐structured interviews with 20 participants in Cambridgeshire, UK who had been diagnosed with GDM and were 3–48 months postpartum. Interviews covered whether participants had been screened and why, plans for future screening and their views on potential interventions to facilitate attendance (at the first postpartum test and annual testing). Framework analysis was used to analyse the transcripts. The interview schedule, suggested interventions and thematic framework were based on a recent systematic review. Results: Sixteen participants had undergone screening since pregnancy, explaining that they had an appointment arranged and wanted reassurance that they did not have diabetes. The participants who had not been tested were not aware that it was recommended. Only 13 had planned to attend subsequent tests at the start of the interview. Eight themes to support future attendance were discussed. The majority of the participants agreed that changing the processes for arranging tests, offering choice in test location and combining appointments would facilitate attendance. Child‐friendly clinics, more opportunities to understand GDM and the role of postpartum testing, stopping self‐testing and increasing their GP’s awareness of their pregnancy received inconsistent feedback. The nature of the test used did not appear to influence attendance. Conclusions: The participants wanted to be screened for diabetes after GDM. We have identified interventions that could be relatively simply incorporated into routine practice to facilitate screening attendance, such as flexibility in the appointment location or time and sending invitations for tests.

Aims: We assessed metabolomic signatures in maternal and cord blood associated with suboptimal outcomes in the continuous glucose monitoring in women with type 1 diabetes in pregnancy trial (CONCEPTT). Methods: Serum samples from 162 mothers (12, 24 and 34 weeks’ gestation) and 93 cord blood samples were analysed for 1049 metabolites and 1041 lipids using ultra-performance liquid chromatography-tandem mass spectroscopy. We used adjusted and unadjusted logistic regression of metabolomic variables using adjudicated outcomes: extremely-large-for-gestational-age (ELGA; >97.5th centile), pre-eclampsia and neonatal hypoglycaemia with modified Bonferroni false discovery rate p≤0.001. Results: All materno-fetal complications studied were associated with reliance on non-carbohydrate sources of fuel. Lipids through beta oxidation were the main fuel source in ELGA (24 and 34 weeks), neonatal hypoglycaemia (12 weeks only) and pre-eclampsia (12 and 24 weeks). Marked protein catabolism was evident in neonatal hypoglycaemia (34 weeks) and pre-eclampsia (24 and 34 weeks). Cord blood in ELGA infants showed evidence of simultaneous beta oxidation and de novo lipogenesis, a biologically futile cycle of creating and destroying lipids, which consumes excess energy and substrate. Cord blood from infants with neonatal hypoglycaemia showed evidence of pronounced protein catabolism providing glucogenic amino acids for gluconeogenesis. Conclusions: Reliance on lipid or protein sources for fuel was associated with ELGA, neonatal hypoglycaemia and pre-eclampsia. Carbohydrate metabolism was insufficient to meet cellular energy demands, possibly due to insufficient insulin, insufficient dietary carbohydrate or both. Improving outcomes in type 1 diabetes pregnancy may require greater focus on normalising carbohydrate metabolism through optimal carbohydrate intake and matched insulin dosing. Disclosure C. L. Meek: None. Z. Stewart: None. S. Furse: None. J. M. Yamamoto: None. D. Feig: Advisory Panel; Self; Novo Nordisk. A. Koulman: None. H. R. Murphy: None. Funding JDRF (17/2011/533, 80/2010/585); Diabetes UK (DUK-HKF 17/0005712, DUK-PG 17/0005633.BBSRC BB/M027252/1)

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes. Maternal adaptations are driven by placental hormones, although the full identity of these is lacking. This study unbiasedly characterized the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed on cultured primary trophoblast and fluorescence-activated sorted endocrine trophoblasts from mice and a placental secretome map was generated. Proteins secreted from the placenta were detectable in the circulation of mice and showed a higher relative abundance in pregnancy. Bioinformatic analyses showed that placental secretome proteins are involved in metabolic, immune and growth modulation, are largely expressed by human placenta and several are dysregulated in pregnancy complications. Moreover, proof-of-concept studies found that secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) were increased in women prior to diagnosis of gestational diabetes. Thus, placental secretome analysis could lead to the identification of new placental biomarkers of pregnancy complications., This work was supported by a Royal Society Dorothy Hodgkin Research Fellowship, Academy of Medical of Sciences Springboard Grant, Isaac Newton Trust Grant and Lister Institute Research Prize grant to ANSP (grant numbers DH130036 / RG74249, SBF002/1028 / RG88501, RG97390 and RG93692, respectively). TN was supported by an EU Marie Skłodowska-Curie Fellowship (PlaEndo/703160) and an Early Career Grant from the Society for Endocrinology. CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the EFSD-Novo Nordisk Foundation Future Leader’s Award (NNF19SA058974). Work in the FR/FMG laboratory was supported by the Wellcome Trust (106262/Z/14/Z,106263/Z/14/Z), the MRC (MRC_MC_UU_12012/3 and MRC -Enhancing UK clinical research grant MR/M009041/1) and the Cambridge Biomedical Research Centre (NIHR-BRC Gastrointestinal Diseases theme).

Guanylin, a peptide implicated in regulation of intestinal fluid secretion, is expressed in the mucosa, but the exact cellular origin remains controversial. In a new transgenic mouse model fluorescent reporter protein expression driven by the proguanylin promoter was observed throughout the small intestine and colon in goblet and Paneth(-like) cells and, except in duodenum, in mature enterocytes. In Ussing chamber experiments employing both human and mouse intestinal tissue, proguanylin was released predominantly in the luminal direction. Measurements of proguanylin expression and secretion in cell lines and organoids indicated that secretion is largely constitutive and requires ER to Golgi transport but was not acutely regulated by salt or other stimuli. Using a newly-developed proguanylin assay, we found plasma levels to be raised in humans after total gastrectomy or intestinal transplantation, but largely unresponsive to nutrient ingestion. By LC-MS/MS we identified processed forms in tissue and luminal extracts, but in plasma we only detected full-length proguanylin. Our transgenic approach provides information about the cellular origins of proguanylin, complementing previous immunohistochemical and in-situ hybridisation results. The identification of processed forms of proguanylin in the intestinal lumen but not in plasma supports the notion that the primary site of action is the gut itself.

Childhood obesity is an area of intense concern internationally and is influenced by events during antenatal and postnatal life. Although pregnancy complications, such as gestational diabetes and large-for-gestational-age birthweight have been associated with increased obesity risk in offspring, very few successful interventions in pregnancy have been identified. We describe a study protocol to identify if a reduced calorie diet in pregnancy can reduce adiposity in children to 3 years of age. The dietary intervention in gestational diabetes (DiGest) study is a randomised, controlled trial of a reduced calorie diet provided by a whole-diet replacement in pregnant women with gestational diabetes. Women receive a weekly dietbox intervention from enrolment until delivery and are blinded to calorie allocation. This follow-up study will assess associations between a reduced calorie diet in pregnancy with offspring adiposity and maternal weight and glycaemia. Anthropometry will be performed in infants and mothers at 3 months, 1, 2 and 3 years post-birth. Glycaemia will be assessed using bloodspot C-peptide in infants and continuous glucose monitoring with HbA1c in mothers. Data regarding maternal glycaemia in pregnancy, maternal nutrition, infant birthweight, offspring feeding behaviour and milk composition will also be collected. The DiGest follow-up study is expected to take 5 years, with recruitment finishing in 2026.

Background Gastrointestinal hormones regulate intestinal transit, control digestion, influence appetite and promote satiety. Altered production or action of gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), may contribute to the biological basis of obesity and altered glucose homeostasis. However, challenges in analytical methodology and lack of clarity on expected values for healthy individuals have limited progress in this field. The aim of this study was to describe expected concentrations of gastrointestinal and pancreatic hormones in healthy volunteers following a standardized meal test (SMT) or 75 g oral glucose tolerance test (OGTT). Methods A total of 28 healthy volunteers (12 men, 16 women; mean age 31.3 years; mean body mass index 24.9 kg/m2) were recruited to attend a hospital clinic on two occasions. Volunteers had blood sampling in the fasting state and were given, in randomized order, an oral glucose tolerance test (OGTT) and standardized mixed liquid meal test with venepuncture at timed intervals for 4 h after ingestion. Analytical methods for gut and pancreatic hormones were assessed and optimized. Concentrations of gut and pancreatic hormones were measured and used to compile ranges of expected values. Results Ranges of expected values were created for glucose, insulin, glucagon, GLP-1, GIP, PYY and free fatty acids in response to a standardized mixed liquid meal or OGTT. Intact proinsulin and C-peptide levels were also measured following the OGTT. Conclusions These ranges of expected values can now be used to compare gut hormone concentrations between healthy individuals and patient groups.

Food cue exposure can trigger eating. Food cue reactivity (FCR) is a conditioned response to food cues and includes physiological responses and activation of reward-related brain areas. FCR can be affected by hunger and weight status. The appetite-regulating hormones ghrelin and leptin play a pivotal role in homeostatic as well as hedonic eating. We examined the association between ghrelin and leptin levels and neural FCR in the fasted and sated state and the association between meal-induced changes in ghrelin and neural FCR, and in how far these associations are related to BMI and HOMA-IR. Data from 109 participants from three European centers (age 50±18 y, BMI 27±5 kg/m2) who performed a food viewing task during fMRI after an overnight fast and after a standardized meal were analyzed. Blood samples were drawn prior to the viewing task in which high-caloric, low-caloric and non-food images were shown. Fasting ghrelin was positively associated with neural FCR in the inferior and superior occipital gyrus in the fasted state. This was partly attributable to BMI and HOMA-IR. These brain regions are involved in visual attention, suggesting that individuals with higher fasting ghrelin have heightened attention to food cues. Leptin was positively associated with high calorie FCR in the medial prefrontal cortex (PFC) in the fasted state and to neural FCR in the left supramarginal gyrus in the fasted versus sated state, when correcting for BMI and HOMA-IR, respectively. This PFC region is involved in assessing anticipated reward value, suggesting that for individuals with higher leptin levels high-caloric foods are more salient than low-caloric foods, but foods in general are not more salient than non-foods. There were no associations between ghrelin and leptin and neural FCR in the sated state, nor between meal-induced changes in ghrelin and neural FCR. In conclusion, we show modest associations between ghrelin and leptin and neural FCR in a relatively large sample of European adults with a broad age and BMI range. Our findings indicate that people with higher leptin levels for their weight status and people with higher ghrelin levels may be more attracted to high caloric foods when hungry. The results of the present study form a foundation for future studies to test whether food intake and (changes in) weight status can be predicted by the association between (mainly fasting) ghrelin and leptin levels and neural FCR.

Understanding the mechanisms of hunger, satiety and how nutrients affect appetite control is important for successful weight management across the lifecourse. The primary aim of this study was to describe acute appetite control across the lifecourse, comparing age groups (children, adolescents, adults, elderly), weight categories, genders and European sites (Scotland and Greece). Participants (n = 391) consumed four test drinks, varying in composition (15% (normal protein, NP) and 30% (high protein, HP) of energy from protein) and quantity (based on 100% basal metabolic rate (BMR) and 140% BMR), on four separate days in a double-blind randomized controlled study. Ad libitum energy intake (EI), subjective appetite and biomarkers of appetite and metabolism (adults and elderly only) were measured. The adults&rsquo, appetite was significantly greater than that of the elderly across all drink types (p &lt, 0.004) and in response to drink quantities (p &lt, 0.001). There were no significant differences in EI between age groups, weight categories, genders or sites. Concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were significantly greater in the elderly than the adults (p &lt, 0.001). Ghrelin and fasting leptin concentrations differed significantly between weight categories, genders and sites (p &lt, 0.05), while GLP-1 and PYY concentrations differed significantly between genders only (p &lt, 0.05). Compared to NP drinks, HP drinks significantly increased postprandial GLP-1 and PYY (p &lt, 0.001). Advanced age was concomitant with reduced appetite and elevated anorectic hormone release, which may contribute to the development of malnutrition. In addition, appetite hormone concentrations differed between weight categories, genders and geographical locations.

Aim: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA 1c, during the COVID-19 pandemic. Methods: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004–2008; 826 consecutive gestational diabetes pregnancies, 2014–2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver-operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA 1c performance. Results: Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks [area under the receiver-operating characteristic curve for both criteria 0.81 (95% CI 0.79–0.83)], fasting plasma glucose [National Institute of Health and Clinical Excellence: area under the receiver-operating characteristic curve 0.75 (95% CI 0.65–0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver-operating characteristic curve 0.92 (95% CI 0.85–0.98)] and HbA 1c at 28 weeks' gestation [National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75–0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77–0.91)]. Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA 1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2–5.4 mmol/l (sensitivity 18–41%; specificity 97–98%). Conclusions: Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA 1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.

Gestational diabetes, the most common medical disorder in pregnancy, is defined as glucose intolerance resulting in hyperglycaemia that begins or is first diagnosed in pregnancy. Gestational diabetes is associated with increased pregnancy complications and long-term metabolic risks for the woman and the offspring. However, the current diagnostic and management strategies recommended by national and international guidelines are mainly focused on short-term risks during pregnancy and delivery, except the Carpenter-Coustan criteria, which were based on the risk of future incidence of type 2 diabetes post-gestational diabetes. In this Personal View, first, we summarise the evidence for long-term risk in women with gestational diabetes and their offspring. Second, we suggest that a shift is needed in the thinking about gestational diabetes; moving from the perception of a short-term condition that confers increased risks of large babies to a potentially modifiable long-term condition that contributes to the growing burden of childhood obesity and cardiometabolic disorders in women and the future generation. Third, we propose how the current clinical practice might be improved. Finally, we outline and justify priorities for future research.

Aim Complications of gestational diabetes (GDM) can be mitigated if the diagnosis is recognized. However, some at‐risk women do not complete antenatal diagnostic oral glucose tolerance testing (OGTT). We aimed to understand reasons contributing to non‐completion, particularly to identify modifiable factors. Methods Some 1906 women attending a tertiary UK obstetrics centre (2018–2019) were invited for OGTT based on risk‐factor assessment. Demographic information, test results and reasons for non‐completion were collected from the medical record. Logistic regression was used to analyse factors associated with non‐completion. Results Some 242 women (12.3%) did not complete at least one OGTT, of whom 32.2% (n = 78) never completed testing. In adjusted analysis, any non‐completion was associated with younger maternal age [≤ 30 years; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6–3.4; P, What’s new? Gestational diabetes is associated with significant complications if untreated, yet a proportion of at‐risk women invited for antenatal screening do not complete testing. There is a lack of evidence to guide improvements in antenatal screening completion.Younger women and those from minority ethnic groups were less likely to complete testing. Key barriers to completion cited by women related to the demands of the testing protocol, ability to attend appointments, and mental health or social issues.Modification of testing protocols, increased support for vulnerable groups, and fuller explanation regarding test indications and risk could improve screening rates.

This chapter outlines the basic science and theory of metabolic medicine required for MRCP Part 1, before addressing the clinical aspects of metabolic medicine for MRCP Part 2. To ensure effective revision, material is presented in short sections with bullet lists, tables and boxes to highlight key facts.

Pregnancy requires adaptation of maternal physiology to enable normal fetal development. These adaptations are driven, in part, by the production of placental hormones. Failures in maternal adaptation and placental function lead to pregnancy complications including abnormal birthweight and gestational diabetes. However, we lack information on the full identity of hormones secreted by the placenta that mediate changes in maternal physiology. This study used an unbiased approach to characterise the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones that are important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed using mass spectrometry on cultured primary trophoblast and fluorescence-activated sorted endocrine cells from pregnant mouse dams, and a placenta secretome map containing 319 proteins was generated. Gene ontology analyses showed that a high proportion of placental secretome proteins are involved in metabolic and immune modulation, signalling and growth. The majority of proteins identified are also expressed by human placenta and several have been reported to be dysregulated in pregnancy complications. Moreover, in proof of concept studies, we found that the relative abundance of secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) was increased in women at 12 weeks of pregnancy, prior to diagnosis of gestational diabetes. Finally, we identified several transcription factors that may be important for controlling hormone production by the placenta and associate with pregnancy outcome. Thus, our observations suggest that analysis of the placental secretome could lead to the identification of new placental biomarkers of pregnancy complications. ### Competing Interest Statement The authors have declared no competing interest.

Wernicke’s encephalopathy is caused by thiamine deficiency and has a range of presenting features, including gait disturbance, altered cognitive state, nystagmus and other eye movement disorders. In the past, Wernicke’s encephalopathy was described almost exclusively in the alcohol-dependent population. However, in current times, Wernicke’s encephalopathy is also well recognized in many other patient groups, including patients following bariatric surgery, gastrointestinal surgery, cancer and pancreatitis. Early recognition of Wernicke’s encephalopathy is vital, as prompt treatment can restore cognitive or ocular function and can prevent permanent disability. Unfortunately, Wernicke’s encephalopathy is often undiagnosed – presumably because it is relatively uncommon and has a variable clinical presentation. Clinical biochemists have a unique role in advising clinicians about potential nutritional or metabolic causes of unexplained neurological symptoms and to prompt consideration of thiamine deficiency as a potential cause in high-risk patient groups. The aim of this review is to summarize the clinical features, diagnosis and treatment of Wernicke’s encephalopathy and to highlight some non-traditional causes, such as after bariatric surgery.

Background Offspring of women with type 1 diabetes are at increased risk of fetal growth patterns which are associated with perinatal morbidity. Our aim was to compare rates of large- and small-for-gestational age (LGA; SGA) defined according to different criteria, using data from the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT). Methods This was a pre-specified analysis of CONCEPTT involving 225 pregnant women and liveborn infants from 31 international centres (ClinicalTrials.gov NCT01788527; registered 11/2/2013). Infants were weighed immediately at birth and GROW, INTERGROWTH and WHO centiles were calculated. Relative risk ratios, sensitivity and specificity were used to assess the different growth standards with respect to perinatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress, neonatal intensive care unit (NICU) admission and a composite neonatal outcome. Results Accelerated fetal growth was common, with mean birthweight percentiles of 82.1, 85.7 and 63.9 and LGA rates of 62, 67 and 30% using GROW, INTERGROWTH and WHO standards respectively. Corresponding rates of SGA were 2.2, 1.3 and 8.9% respectively. LGA defined according to GROW centiles showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission. Infants born > 97.7th centile were at highest risk of complications. SGA defined according to INTERGROWTH centiles showed slightly stronger associations with perinatal outcomes. Conclusions GROW and INTERGROWTH standards performed similarly and identified similar numbers of neonates with LGA and SGA. GROW-defined LGA and INTERGROWTH-defined SGA had slightly stronger associations with neonatal complications. WHO standards underestimated size in preterm infants and are less applicable for use in type 1 diabetes. Trial registration This trial is registered with ClinicalTrials.gov. number NCT01788527. Trial registered 11/2/2013.

Lipidomics is of increasing interest in studies of biological systems. However, high-throughput data collection and processing remains non-trivial, making assessment of phenotypes difficult. We describe a platform for surveying the lipid fraction for a range of tissues. These techniques are demonstrated on a set of seven different tissues (serum, brain, heart, kidney, adipose, liver, and vastus lateralis muscle) from post-weaning mouse dams that were either obese (> 12 g fat mass) or lean (

Funder: Wellcome Trust, Gestational diabetes mellitus (GDM) annually affects 35,000 pregnancies in the United Kingdom, causing suboptimal health outcomes to the mother and child. Obesity and excessive gestational weight gain are risk factors for GDM. The Institute of Medicine recommends weight targets for women that are overweight and obese, however, there are no clear guidelines for women with GDM. Observational data suggest that modest weight loss (0.6-2 kg) after 28 weeks may reduce risk of caesarean section, large-for-gestational-age (LGA), and maternal postnatal glycaemia. This protocol for a multicentre randomised double-blind controlled trial aims to identify if a fully controlled reduced energy diet in GDM pregnancy improves infant birthweight and reduces maternal weight gain (primary outcomes). A total of 500 women with GDM (National Institute of Health and Care Excellence (NICE) 2015 criteria) and body mass index (BMI) ≥25 kg/m2 will be randomised to receive a standard (2000 kcal/day) or reduced energy (1200 kcal/day) diet box containing all meals and snacks from 28 weeks to delivery. Women and caregivers will be blinded to the allocations. Food diaries, continuous glucose monitoring, and anthropometry will measure dietary compliance, glucose levels, and weight changes. Women will receive standard antenatal GDM management (insulin/metformin) according to NICE guidelines. The secondary endpoints include caesarean section rates, LGA, and maternal postnatal glucose concentrations.

AIM: Excessive gestational weight gain increases risk of gestational diabetes mellitus (GDM) but it remains unclear whether weight control after GDM diagnosis improves outcomes. We assessed whether: (1) total gestational weight gain during pregnancy (0-36 weeks); (2) early gestational weight gain (0-28 weeks, before GDM diagnosis); or (3) late gestational weight gain (28-36 weeks, after diagnosis) are associated with maternal-fetal outcomes. METHODS: Some 546 women with GDM who delivered viable singleton infants at a single UK obstetric centre (October 2014 to March 2017) were included in this retrospective observational study. RESULTS: Higher total gestational weight gain was associated with Caesarean section [n = 376; odds ratio (OR) 1.05; confidence intervals (CI) 1.02-1.08, P < 0.001] and large for gestational age (OR 1.08; CI 1.03-1.12, P < 0.001). Higher late gestational weight gain (28-36 weeks; n = 144) was associated with large for gestational age (OR 1.17; CI 1.01-1.37, P < 0.05), instrumental deliveries (OR 1.26; CI 1.03-1.55, P < 0.01), higher total daily insulin doses (36 weeks; beta coefficient 4.37; CI 1.92-6.82, P < 0.001), and higher post-partum 2-h oral glucose tolerance test concentrations (beta coefficient 0.12; CI 0.01-0.22, P < 0.05). Women who avoided substantial weight gain after GDM diagnosis had 0.7 mmol/l lower postnatal 2-h glucose and needed half the amount of insulin/day at 36 weeks compared with women with substantial weight gain after diagnosis. There were no significant associations between early gestational weight gain (0-28 weeks) and pregnancy outcomes. CONCLUSIONS: These findings suggest that controlling gestational weight gain should be a priority following GDM diagnosis to optimize pregnancy outcomes and improve maternal postnatal glucose homeostasis. The period after diagnosis of GDM (often 28 weeks gestation) is not too late to offer lifestyle advice or intervention to improve weight management and pregnancy outcomes.

Objective: Gestational diabetes (GDM) incidence reportedly demonstrates seasonal variation. We aimed to assess if season also affects maternal-fetal outcomes in GDM. Methods: 23,735 women who consecutively delivered singleton, live-born, term infants in a tertiary obstetrics center (2004-08; 4.6% GDM) were included. Additive dynamic regression models (age, BMI, parity, ethnicity adjusted) compared GDM incidence and outcomes (GDM diagnosis, birth weight, delivery mode) over annual cycles. Results: GDM incidence varied by 30% from peak (October births) to nadir (March births; p Conclusions: Substantial seasonal variation exists in GDM diagnoses and maternal-fetal outcomes in GDM-affected pregnancies. Birth weight is highest when GDM diagnoses are lowest, implying either over-diagnosis in summer or more challenging glycemic control in winter. Considering seasonal variation gives new opportunities for intensive individualized therapy to improve outcomes. Figure: Effect of season on birthweight centiles in GDM; p Disclosure C.L. Meek: None. B.O. Devoy: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. C. Patient: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. C. Aiken: None. Funding Diabetes UK (17/0005712 to C.L.M.)

Aims/Objectives: To describe the maternal-fetal metabolomic and lipidomic profiles and examine associations with neonatal birthweight in type 1 diabetes pregnancy. Methods: A longitudinal prospective study of 162 CONCEPTT mothers. 1049 maternal metabolites and 1041 lipids were analyzed at 12, 24 and 34 weeks gestation, in addition to 93 cord-blood samples using ultra-performance liquid chromatography-tandem mass spectroscopy. The effects on neonatal birth weight, classified as appropriate for gestational age (AGA) 10-90th percentile, large for gestational age (LGA) >90th percentile and extreme LGA (ELGA) >97.7th percentile were examined through ANOVA, principle component analysis and hierarchical clustering, adjusting for maternal BMI. Results: Significant gestational changes in the maternal metabolome and lipidomic profiles were observed. Metabolite changes associated with birthweight were modest in LGA, albeit more apparent in ELGA. At 24 and 34 weeks, glucose levels were significantly elevated and 1,5-anhydroglucitol (1,5-AG) significantly reduced in ELGA mothers. Triglycerides did not differ between AGA and LGA. Throughout pregnancy, many lipid classes were lower in LGA mothers, with modest increases in free fatty acids and acylcarnitine species at 34 weeks in ELGA. The distribution of lipid classes was significantly different between maternal and cord-blood samples, with most cord-blood lipids comparable between AGA, LGA and ELGA. There were some differences in the cord-blood steroid hormones and acylcarnitine species of ELGA neonates. Conclusions: Gestational changes in maternal-fetal metabolomic and lipidomic profiles are largely conserved across birthweight categories. Some differences in glucose handling, lipid homeostasis, steroid hormones and acylcarnitine species were apparent in maternal-fetal samples of ELGA neonates. Disclosure Z.A. Stewart: None. J.M. Yamamoto: None. C.L. Meek: None. J. Sanchez: None. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. Funding Diabetes UK; JDRF

Type 1 diabetes (T1D) in pregnancy is associated with increased neonatal morbidity, which improves with optimal glycemic control. Aim: To compare lab and CGM glucose summary measures as predictors of neonatal outcomes in T1D pregnancy. Methods: 225 CONCEPTT participants had 6-day CGM and blood analysis of glycemic markers in 1st trimester, 24 and 34 weeks (Average glucose; % time in target 63-140 mg/dl, coefficient of variation (CV)); HbA1c; glycated CD59 (gCD59); 1,5-anhydroglucitol (1,5AG); glycated albumin). Outcomes: large for gestational age (LGA), neonatal hypoglycemia (NH) and neonatal intensive care unit (NICU) admission. Statistics: Unadjusted logistic regression. Results: All glucose summary measures excluding CV predicted neonatal outcomes (Table). Glycemic control at all timepoints from 1st trimester was important for LGA, but emerged later for NH (24 and 34 weeks) and NICU (mainly 24 weeks). Both CGM time in target and average glucose and lab markers HbA1c, 1,5AG and gCD59 predicted all three outcomes studied. Time in target was the best CGM predictor. The best lab predictors were HbA1c, 1,5AG and gCD59. HbA1c was the strongest predictor of LGA and NH, but only predicted NICU admission late in pregnancy. Conclusions: In women with T1D, both CGM and lab glucose summary measures can predict neonatal outcomes from 1st trimester. Disclosure C.L. Meek: None. D. Tundidor: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. J.M. Yamamoto: None. E.M. Scott: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Abbott, Eli Lilly and Company. D. Ma: None. J. Halperin: Stock/Shareholder; Self; Mellitus, LLC. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. R. Corcoy: None. Funding JDRF; Canadian Clinical Trials Network; National Institute for Health Research; European Foundation for the Study of Diabetes/Sanofi; Diabetes UK (17/0005712 to C.L.M.); Asahi Kasei Pharma Corporation; GlycoMark, Inc.

Gestational diabetes is a common pregnancy disorder which is generally managed with diet, exercise, metformin or insulin treatment and which usually resolves after delivery of the infant. Identifying and treating gestational diabetes improves maternal and fetal outcomes and allows for health promotion to reduce the mother’s risk of type 2 diabetes in later life. However, there remains considerable controversy about the optimal method of identification and diagnosis of women with gestational diabetes. The NICE-2015 diagnostic criteria (75 g oral glucose tolerance test (OGTT) 0 h ≥5.6 mmol/L; 2 h ≥7.8 mmol/L) are based upon cost-effectiveness estimates using observational data, while the WHO-2013 criteria (75 g OGTT 0 h ≥5.1 mmol/L; 1 h ≥10.0 mmol/L; 2 h ≥8.5 mmol/L) identify women and infants at risk of adverse outcomes according to prospective data. There is also considerable controversy about testing for gestational diabetes using universal or risk factor-based screening, and when and how testing should be performed. The aim of this review is to provide a summary of the clinical biochemistry aspects to these debates and to highlight the importance of appropriate identification of gestational diabetes and subsequent type 2 diabetes in this population.

The authors would like to correct an error in a recent published paper [...]

Rationale Diagnosis of pancreatic neuroendocrine tumours requires the study of patient plasma with multiple immunoassays, using multiple aliquots of plasma. The application of mass spectrometry based techniques could reduce the cost and amount of plasma required for diagnosis. Methods Plasma samples from two patients with pancreatic neuroendocrine tumours were extracted using an established acetonitrile‐based plasma peptide enrichment strategy. The circulating peptidome was characterised using nano and high flow rate liquid chromatography/mass spectrometry (LC/MS) analyses. To assess the diagnostic potential of the analytical approach, a large sample batch (68 plasmas) from control subjects, and aliquots from subjects harbouring two different types of pancreatic neuroendocrine tumour (insulinoma and glucagonoma), were analysed using a 10‐min LC/MS peptide screen. Results The untargeted plasma peptidomics approach identified peptides derived from the glucagon prohormone, chromogranin A, chromogranin B and other peptide hormones and proteins related to control of peptide secretion. The glucagon prohormone derived peptides that were detected were compared against putative peptides that were identified using multiple antibody pairs against glucagon peptides. Comparison of the plasma samples for relative levels of selected peptides showed clear separation between the glucagonoma and the insulinoma and control samples. Conclusions The combination of the organic solvent extraction methodology with high flow rate analysis could potentially be used to aid diagnosis and monitor treatment of patients with functioning pancreatic neuroendocrine tumours. However, significant validation will be required before this approach can be clinically applied.