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Item Open Access Published version Peer-reviewed Increased GLP-1 response to oral glucose in pre-pubertal obese children.(De Gruyter, 2016-08-01) Giannini, Cosimo; Pietropaoli, Nicoletta; Polidori, Nella; Chiarelli, Francesco; Marcovecchio, Maria Loredana; Mohn, Angelika; Marcovecchio, Loredana [0000-0002-4415-316X]BACKGROUND: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. METHODS: Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: -0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated. RESULTS: In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001). CONCLUSIONS: Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.Item Open Access Accepted version Peer-reviewed Unmet needs in pediatric NAFLD research: what do we need to prioritize for the future?(Informa UK Limited, 2018-10) Hatton, Grace; Alterio, Tommaso; Nobili, Valerio; Mann, Jake P; Mann, Jake [0000-0002-4711-9215]Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that has complex pathophysiology and unquantified clinical significance. Though there have been major advances in the field, there is much yet to be understood. Areas covered: PubMed/MEDLINE and Embase were searched for articles related to pediatric NAFLD and nonalcoholic steatohepatitis (NASH) between January 1998 and January 2018. The areas considered to be 'unmet needs' were the relationship between the intestinal microbiome and perinatal events, clinical event risk stratification, and mechanisms underlying portal inflammation. Expert commentary: In utero and ex utero factors have been associated with NAFLD and also with the intestinal microbiome, but it is not yet known how intestinal dysbiosis can be reversed and whether intervention in high-risk neonates could alter their propensity for the metabolic syndrome. Children with NAFLD are at increased risk of cardiovascular, diabetic, and hepatic diseases, but it is unclear how best to stratify children into appropriate risk groups for targeted interventions. Finally, the immune processes underlying pediatric NASH are thought to differ to those in adult NASH, yet the events surrounding activation of periportal lymphocytes are poorly understood. Deepening our understanding of these topics may lead to novel therapeutic targets.Item Open Access Accepted version Peer-reviewed ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes.(Massachusetts Medical Society, 2018-02-08) Dunger, David B; Marcovecchio, M Loredana; Deanfield, John; Dunger, David [0000-0002-2566-9304]; Marcovecchio, Loredana [0000-0002-4415-316X]NAItem Open Access Published version Peer-reviewed Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress.(Elsevier BV, 2017-03-05) Di Pietro, Natalia; Marcovecchio, M Loredana; Di Silvestre, Sara; de Giorgis, Tommaso; Cordone, Vincenzo Giuseppe Pio; Lanuti, Paola; Chiarelli, Francesco; Bologna, Giuseppina; Mohn, Angelika; Pandolfi, Assunta; Marcovecchio, Loredana [0000-0002-4415-316X]Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation.Item Open Access Published version Peer-reviewed Vomiting in pregnancy is associated with a higher risk of low birth weight: a cohort study.(BioMed Central, 2018-05-04) Petry, Clive; Ong, Kenneth; Beardsall, Kathryn; Hughes, Ieuan; Acerini, Carlo; Dunger, David; Petry, Clive [0000-0002-6642-9825]; Ong, Kenneth [0000-0003-4689-7530]; Beardsall, Kathryn [0000-0003-3582-183X]; Acerini, Carlo [0000-0003-2121-5871]; Dunger, David [0000-0002-2566-9304]Background: Low birth weight has important short- and long-term health implications. Previously it has been shown that pregnancies affected by hyperemesis gravidarum in the mother are at higher risk of having low birth weight offspring. In this study we tested whether such risks are also evident with less severe nausea and vomiting in pregnancy. Methods: 1,238 women in the prospective Cambridge Baby Growth Study filled in pregnancy questionnaires which included questions relating to adverse effects of pregnancy and drugs taken during that time. Ordinal logistic regression models, adjusted for parity, ethnicity, marital and smoking status were used to relate the risk of giving birth to low birth weight (< 2.5 kg) babies to nausea and/or vomiting in pregnancy that were not treated with anti-emetics and did not report suffering from hyperemesis gravidarum. Results: Only 3 women in the cohort reported having had hyperemesis gravidarum although a further 17 women reported taking anti-emetics during pregnancy. Of those 1,218 women who did not take anti-emetics 286 (23.5 %) did not experience nausea or vomiting, 467 (38.3 %) experienced nausea but not vomiting and 465 experienced vomiting (38.2 %). Vomiting during pregnancy was associated with higher risk of having a low birth weight baby (odds ratio 3.5 (1.2, 10.8), p = 0.03). The risk associated with vomiting was found in the first (p = 0.01) and second (p = 0.01) trimesters but not the third (p = 1.0). The higher risk was not evident in those women who only experienced nausea (odds ratio 1.0 (0.3, 4.0), p = 1.0). Conclusions: Vomiting in early pregnancy, even when not perceived to be sufficiently severe to merit treatment, is associated with a higher risk of delivering a low birth weight baby. Early pregnancy vomiting might therefore be usable as a marker of higher risk of low birth weight in pregnancy. This may be of benefit in situations where routine ultrasound is not available to distinguish prematurity from fetal growth restriction, so low birth weight is used as an alternative.Item Open Access Accepted version Peer-reviewed Clinical Implications(Ovid Technologies (Wolters Kluwer Health), 2016-12) Petry, CJ; Petry, Clive [0000-0002-6642-9825]Item Open Access Published version Peer-reviewed Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort.(BMJ, 2018-04-04) Bravis, Vassiliki; Kaur, Akaal; Walkey, Helen C; Godsland, Ian F; Misra, Shivani; Bingley, Polly J; Williams, Alistair JK; Dunger, David B; Dayan, Colin M; Peakman, Mark; Oliver, Nick S; Johnston, Desmond G; ADDRESS-2 Management Committee, Patient Advocate Group and Investigators; Walkey, Helen C [0000-0003-3391-0759]OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results.Item Open Access Accepted version Peer-reviewed Thresholds for hypoglycaemic screening-a cause for concern?(BMJ, 2019-02) Ogilvy-Stuart, Amanda L; Harding, Jane E; Beardsall, Kathryn; Beardsall, Kathryn [0000-0003-3582-183X]The new Framework for Practice highlights the limited evidence for our current clinical practice (1). It is helpful in emphasising the importance of accurate measurement of glucose concentrations, listening to the concerns of parents and acknowledging that untreated hypoglycaemia can have devastating longterm consequences. However we have the following concerns: Screening thresholds The Framework recommends lowering a commonly accepted screening threshold in infants considered to be at risk of hypoglycaemia to a level that at any other time of life would be considered harmful. It fails to acknowledge the differences between screening and diagnostic thresholds; something neonatologists are very familiar with in the management of babies with jaundice. Phototherapy is provided to many babies with bilirubin levels well below a harmful level to prevent a harmful level being reached. Screening interventions are intended to prevent harmful events. Such thresholds will inevitably mean many individuals are treated ‘unnecessarily’ to avoid the risk of significant harm. In 2000 Cornblath et al published guidance on ‘operational thresholds’ in keeping with the current BAPM framework (2). However, and possibly reflecting concerns about the lack of evidence for the safety of this lower operational threshold, in 2017 in the UK, >80% of neonatal units still used <2.6mmol/ as their defined hypoglycaemic threshold (3). A threshold of <2.6mmol/l provides an opportunity for intervention before damaging neuroglycopaenia occurs.Item Open Access Accepted version Peer-reviewed Experiences of closed-loop insulin delivery among pregnant women with Type 1 diabetes.(Wiley, 2017-10) Farrington, C; Stewart, ZA; Barnard, K; Hovorka, R; Murphy, HR; Farrington, C [0000-0002-8625-2684]; Hovorka, R [0000-0003-2901-461X]AIMS: To explore the experiences of pregnant women with Type 1 diabetes, and the relationships between perceptions of glucose control, attitudes to technology and glycaemic responses with regard to closed-loop insulin delivery. METHODS: We recruited 16 pregnant women with Type 1 diabetes [mean ± sd age 34.1 ± 4.6 years, duration of diabetes 23.6 ± 7.2 years, baseline HbA1c 51±5 mmol/mol (6.8 ± 0.6%)] to a randomized crossover trial of sensor-augmented pump therapy vs automated closed-loop therapy. Questionnaires (Diabetes Technology Questionnaire, Hypoglycaemia Fear Survey) were completed before and after each intervention, with qualitative interviews at baseline and follow-up. RESULTS: Women described the benefits and burdens of closed-loop systems during pregnancy. Feelings of improved glucose control, excitement and empowerment were counterbalanced by concerns about device visibility, obsessive data checking and diminished attentiveness to hyper- and hypoglycaemia symptoms. Responding to questionnaires, eight participants felt less worry about overnight hypoglycaemia and that diabetes 'did not run their lives'; however, five reported that closed-loop increased time thinking about diabetes, and three felt it made sleep and preventing hyperglycaemia more problematic. Women slightly overestimated their glycaemic response to closed-loop therapy. Most became more positive in their technology attitudes throughout pregnancy. Women with more positive technology attitudes had higher degrees of overestimation, and poorer levels of glycaemic control. CONCLUSIONS: Women displayed complex psychosocial responses to closed-loop therapy in pregnancy. Perceptions of glycaemic response may diverge from biomedical data.Item Open Access Published version Peer-reviewed Examining the relationships between body image, eating attitudes, BMI, and physical activity in rural and urban South African young adult females using structural equation modeling.(Public Library of Science (PLoS), 2017) Prioreschi, Alessandra; Wrottesley, Stephanie V; Cohen, Emmanuel; Reddy, Ankita; Said-Mohamed, Rihlat; Twine, Rhian; Tollman, Stephen M; Kahn, Kathleen; Dunger, David B; Norris, Shane A; Prioreschi, Alessandra [0000-0002-6913-0706]The persistence of food insecurity, malnutrition, increasing adiposity, and decreasing physical activity, heightens the need to understand relationships between body image satisfaction, eating attitudes, BMI and physical activity levels in South Africa. Females aged 18-23 years were recruited from rural (n = 509) and urban (n = 510) settings. Body image satisfaction was measured using Stunkard's silhouettes, and the 26-item Eating Attitudes questionnaire (EAT-26) was used to evaluate participants' risk of disordered eating. Minutes per week of moderate to vigorous physical activity (MVPA) was assessed using the Global Physical Activity Questionnaire (GPAQ). Significant linear correlates were included in a series of regressions run separately for urban and rural participants. Structural equation modeling (SEM) was used to test the relationships between variables. Urban females were more likely to be overweight and obese than rural females (p = 0.02), and had a greater desire to be thinner (p = 0.02). In both groups, being overweight or obese was positively associated with a desire to be thinner (p<0.01), and negatively associated with a desire to be fatter (p<0.01). Having a disordered eating attitude was associated with body image dissatisfaction in the urban group (β = 1.27, p<0.01, CI: 0.38; 2.16), but only with a desire to be fatter in the rural group (β = 0.63, p = 0.04, CI: 0.03; 1.23). In the SEM model, body image dissatisfaction was associated with disordered eating (β = 0.63), as well as higher MVPA participation (p<0.01). These factors were directly associated with a decreased risk of disordered eating attitude, and with a decreased desire to be thinner. Findings indicate a shift in both settings towards more Westernised ideals. Physical activity may provide a means to promote a healthy body image, while reducing the risk of disordered eating. Given the high prevalence of overweight and obesity in both rural and urban women, this study provides insights for future interventions aimed at decreasing adiposity in a healthy way.Item Open Access Accepted version Peer-reviewed Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report.(American Diabetes Association, 2016-07) Maahs, David M; Buckingham, Bruce A; Castle, Jessica R; Cinar, Ali; Damiano, Edward R; Dassau, Eyal; DeVries, J Hans; Doyle, Francis J; Griffen, Steven C; Haidar, Ahmad; Heinemann, Lutz; Hovorka, Roman; Jones, Timothy W; Kollman, Craig; Kovatchev, Boris; Levy, Brian L; Nimri, Revital; O'Neal, David N; Philip, Moshe; Renard, Eric; Russell, Steven J; Weinzimer, Stuart A; Zisser, Howard; Lum, John W; Hovorka, Roman [0000-0003-2901-461X]Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes.Item Open Access Accepted version Peer-reviewed Randomised Controlled Trial of Real Time Continuous Glucose Monitoring in Neonatal Intensive Care REACT(BMJ Publishing Group) Beardsall, K; Beardsall, Kathryn [0000-0003-3582-183X]Background: Hyperglycaemia is common in the very preterm infant and has been associated with adverse outcomes. Preventing hyperglycaemia without increasing the risk of hypoglycaemia has proved challenging. The development of real time continuous glucose monitors (rCGM) to inform treatment decisions provides an opportunity to reduce this risk. We aimed to assess the feasibility of rCGM combined with a specifically designed paper based guideline to target glucose control in the preterm infant. Methods: The REACT Randomised controlled Trial (Real Time Continuous Glucose Monitoring in Neonatal Intensive Care) is an international multicentre randomised controlled trial. Two hundred preterm infants ≤1200g, and ≤24 hours of age will be randomly allocated to either real time continuous glucose monitoring, or standard care (with blinded CGM data collection). The primary outcome is time in target 2.6-10mmol/l during the study intervention assessed using continuous glucose monitoring. Secondary outcomes include efficacy relating to glucose control, utility including staff acceptability, safety outcomes relating to incidence and prevalence of hypoglycaemia and health economic analyses. Ethics and Dissemination: The REACT Trial has been approved by the NHS Health Research Authority National Research Ethics Service Committee East of England – Cambridge Central; Medical Ethics Review Committee, VU University Medical Centre, Amsterdam, The Netherlands and the Research Ethics Committee, Sant Joan de Déu Research Foundation, Barcelona, Spain. Recruitment began in July 2016 and will continue until mid 2018. Dissemination plans include presentations at scientific conferences, scientific publications and efforts at stakeholder engagement. Trial Registration The Trial has been adopted by the National Institute of Health Research Clinical Research Network portfolio (ID: 18826) and is registered with the ISRCTN registry (ID: 12793535).Item Open Access Published version Peer-reviewed Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis.(BMJ, 2018-04-18) Bekiari, Eleni; Kitsios, Konstantinos; Thabit, Hood; Tauschmann, Martin; Athanasiadou, Eleni; Karagiannis, Thomas; Haidich, Anna-Bettina; Hovorka, Roman; Tsapas, Apostolos; Hovorka, Roman [0000-0003-2901-461X]OBJECTIVE: To evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, and grey literature up to 2 February 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment. Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L). Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin. The Cochrane Collaboration risk of bias tool was used to assess study quality. RESULTS: 40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system. Only nine studies were at low risk of bias. Proportion of time in the near normoglycaemic range (3.9-10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%). Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (-8.52%, -11.14% to -5.9%) or below 3.9 mmol/L (-1.49%, -1.86% to -1.11%) over 24 hours, compared with control treatment. Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%). Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems. CONCLUSIONS: Artificial pancreas systems are an efficacious and safe approach for treating outpatients with type 1 diabetes. The main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials.Item Open Access Accepted version Peer-reviewed Evaluations of Lifestyle, Dietary, and Pharmacologic Treatments for Pediatric Non-Alcoholic Fatty Liver Disease—a Systematic Review(Elsevier, 2019-07) Mann, J; Tang, George Yizhou; Nobili, Valerio; Armstrong, Matthew James; Mann, Jake [0000-0002-4711-9215]Background & Aims: There are no approved treatments for pediatric non-alcoholic fatty liver disease (NAFLD) and there is a lack of consensus on the best outcome measure for randomized controlled trials. We performed a systematic review of treatments tested for pediatric NAFLD, the degree of heterogeneity in trial design, and endpoints analyzed in these studies. Methods: We searched publication databases and clinical trial registries through January 7, 2018 for randomized controlled trials (published and underway) of children (<18 years) with NAFLD. We assessed improvements in histologic features, radiologic and biochemical markers of reduced fibrosis, metabolic syndrome parameters, and adverse events. The quality of the trials was assessed using a modified version of the Cochrane risk of bias tool. Results: Our final analysis included 21 randomized controlled trials, comprising 1307 participants (mean age, 12.6 years; 63% male; mean duration of intervention, 8 months). Most studies evaluated weight loss with lifestyle intervention (n=8), oral polyunsaturated fatty acid treatment (PUFAs, n=6), or oral antioxidant treatment (n=7). Biomarkers of NAFLD decreased with weight loss, but most studies did not include histologic data. Trials of antioxidants were heterogeneous; some reported reduced histologic features of steatohepatitis with no effect on triglycerides or insulin resistance. PUFAs and probiotics reduced radiologic markers of steatosis, insulin resistance, and levels of triglycerides. Only 38% of the trials had biopsy-proven NAFLD as an inclusion criterion. There was heterogeneity in trial primary endpoints; 10 studies (48%) used levels of aminotransferases or ultrasonography findings as a primary endpoint and only 3 trials (14%) used histologic features as the primary endpoint. We identified 13 randomized controlled trials that are underway in children with NAFLD. None of the protocols include collection of liver biopsies; 9 trials (69%) will use magnetic resonance imaging quantification of steatosis as a primary outcome. Conclusion: In a systematic review of published and active randomized controlled trials of children with NAFLD, we found a large amount of heterogeneity in study endpoints and inclusion criteria. Few trials included histologic analyses. Antioxidants appear to reduce some features of steatohepatitis. Effects of treatment with lifestyle modification, PUFAs, or probiotics have not been validated with histologic analysis. Trials that are underway quantify steatosis magnetic resonance imaging—outcomes are anticipated.Item Open Access Published version Peer-reviewed Biomarkers of diabetic kidney disease.(Springer Science and Business Media LLC, 2018-05) Colhoun, Helen M; Marcovecchio, M Loredana; Marcovecchio, Loredana [0000-0002-4415-316X]Diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in diabetes. The quest for both prognostic and surrogate endpoint biomarkers for advanced DKD and end-stage renal disease has received major investment and interest in recent years. However, at present no novel biomarkers are in routine use in the clinic or in trials. This review focuses on the current status of prognostic biomarkers. First, we emphasise that albuminuria and eGFR, with other routine clinical data, show at least modest prediction of future renal status if properly used. Indeed, a major limitation of many current biomarker studies is that they do not properly evaluate the marginal increase in prediction on top of these routinely available clinical data. Second, we emphasise that many of the candidate biomarkers for which there are numerous sporadic reports in the literature are tightly correlated with each other. Despite this, few studies have attempted to evaluate a wide range of biomarkers simultaneously to define the most useful among these correlated biomarkers. We also review the potential of high-dimensional panels of lipids, metabolites and proteins to advance the field, and point to some of the analytical and post-analytical challenges of taking initial studies using these and candidate approaches through to actual clinical biomarker use.Item Open Access Published version Peer-reviewed The association between age at menarche and later risk of gestational diabetes is mediated by insulin resistance.(Springer Science and Business Media LLC, 2018-08) Petry, Clive J; Ong, Ken K; Hughes, Ieuan A; Acerini, Carlo L; Dunger, David B; Petry, Clive J [0000-0002-6642-9825]; Ong, Ken K [0000-0003-4689-7530]; Hughes, Ieuan A [0000-0002-8787-1575]; Acerini, Carlo L [0000-0003-2121-5871]; Dunger, David B [0000-0002-2566-9304]AIMS: Associations have been reported between age at menarche and the later risk of gestational diabetes. However, it is not known whether these associations reflect differences in insulin sensitivity and/or pancreatic β-cell function in pregnancy. METHODS: We examined this question in women enrolled in the prospective Cambridge Baby Growth Study who recalled their age at menarche in questionnaires during pregnancy. Polynomial logistic and linear regression models were used to relate menarche timing to the risk of gestational diabetes, both unadjusted and adjusted for the Homeostasis Model Assessments of insulin resistance (HOMA IR) and pancreatic β-cell function (HOMA B) at week 28 of pregnancy. RESULTS: Age at menarche showed a U-shaped association with gestational diabetes risk (linear term: p = 9.5 × 10-4; quadratic term: p = 1.0 × 10-3; n = 889; overall model p = 8.1 × 10-3). Age at menarche showed a negative linear association with insulin resistance (HOMA IR: β = -0.13, p = 5.2 × 10-4, n = 771), which explained the relationship between age at menarche and gestational diabetes risk (adjusted linear term going from p = 0.03-0.08; adjusted quadratic term going from p = 0.04-0.08; n = 771). Age at menarche also showed a negative linear association with β-cell function (HOMA B: β = -0.11, p = 2.8 × 10-3, n = 771) but this did not attenuate the relationship between age at menarche and gestational diabetes (adjusted linear term p = 0.02; adjusted quadratic term p = 0.03, n = 771). CONCLUSIONS: These results suggest that the associations between age at menarche and risk of gestational diabetes and raised pregnancy glucose concentrations may be mediated by insulin resistance.Item Open Access Published version Peer-reviewed Serum Phthalate and Triclosan Levels Have Opposing Associations With Risk Factors for Gestational Diabetes Mellitus.(Frontiers Media SA, 2018) Fisher, Benjamin G; Frederiksen, Hanne; Andersson, Anna-Maria; Juul, Anders; Thankamony, Ajay; Ong, Ken K; Dunger, David B; Hughes, Ieuan A; Acerini, Carlo L; Fisher, Benjamin [0000-0001-5497-9689]; Ong, Kenneth [0000-0003-4689-7530]; Dunger, David [0000-0002-2566-9304]; Acerini, Carlo [0000-0003-2121-5871]Certain phthalates and bisphenol A (BPA) have been associated with insulin resistance and type 2 diabetes in non-pregnant adults, but studies of gestational diabetes mellitus (GDM) have reported conflicting results for phthalates and no associations with BPA. Our aim was to investigate the relationship between maternal serum levels of phthalate metabolites and phenols at 10-17 weeks of gestation and glucose homeostasis at 28 weeks of gestation. 232 women aged ≥16 years without type 1 or 2 diabetes with singleton male pregnancies were recruited from a single UK maternity centre between 2001 and 2009 as part of a prospective observational study (Cambridge Baby Growth Study). Serum levels of 16 phthalate metabolites and 9 phenols (including BPA) were measured using liquid chromatography/tandem mass spectrometry. Oral glucose tolerance tests were performed at 28 weeks. 47/232 (20.3%) women had GDM. First-trimester triclosan (TCS) was inversely associated with incident GDM (adjusted odds ratio per log increase in concentration 0.54, 95% confidence interval 0.34-0.86, p = 0.010). Amongst women without GDM, first-trimester mono-(2-ethylhexyl) phthalate and mono(carboxyisooctyl) phthalate levels were positively associated with 120-min plasma glucose (adjusted β 0.268 and 0.183, p = 0.0002 and 0.010, respectively) in mid-pregnancy. No other monotonic associations were detected between phthalate or phenol levels and fasting or stimulated plasma glucose, β-cell function, insulin resistance, or 60-min disposition index. Our results support a glycaemia-raising effect of phthalates during pregnancy, consistent with findings in non-pregnant populations and suggest a possible protective effect of exposure to TCS against GDM.Item Open Access Published version Peer-reviewed Patients' and caregivers' experiences of using continuous glucose monitoring to support diabetes self-management: qualitative study.(2018-02-20) Lawton, J; Blackburn, M; Allen, J; Campbell, F; Elleri, D; Leelarathna, L; Rankin, D; Tauschmann, M; Thabit, H; Hovorka, Roman; Leelarathna, L [0000-0001-9602-1962]; Thabit, H [0000-0001-6076-6997]; Hovorka, Roman [0000-0003-2901-461X]Item Open Access Published version Peer-reviewed Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength(Elsevier) Kelley, Kevin W; Ben Haim, Lucile; Schirmer, Lucas; Tyzack, Giulia; Tolman, Michaela; Miller, John; Tsai, Hui-Hsin; Chang, Sandra M; Molofsky, Anna V; Yang, Yongjie; Patani, Rickie; Lakatos, Andras; Ullian, Erik M; Rowitch, DH; Lakatos, Andras [0000-0002-1301-2292]; Rowitch, David [0000-0002-0079-0060]Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast a-motor neurons (FaMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FaMN size and function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FaMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation might uncouple symptoms of muscle weakness from MN cell death in diseases like ALS.Item Open Access Published version Peer-reviewed Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes(Elsevier, 2017-12-12) Krencik, R; Seo, K; van Asperen, JV; Basu, N; Cvetkovic, C; Barlas, S; Chen, R; Ludwig, C; Wang, C; Ward, ME; Gan, L; Horner, PJ; Rowitch, DH; Ullian, EM; Rowitch, David [0000-0002-0079-0060]© 2017 The Authors Human astrocytes network with neurons in dynamic ways that are still poorly defined. Our ability to model this relationship is hampered by the lack of relevant and convenient tools to recapitulate this complex interaction. To address this barrier, we have devised efficient coculture systems utilizing 3D organoid-like spheres, termed asteroids, containing pre-differentiated human pluripotent stem cell (hPSC)-derived astrocytes (hAstros) combined with neurons generated from hPSC-derived neural stem cells (hNeurons) or directly induced via Neurogenin 2 overexpression (iNeurons). Our systematic methods rapidly produce structurally complex hAstros and synapses in high-density coculture with iNeurons in precise numbers, allowing for improved studies of neural circuit function, disease modeling, and drug screening. We conclude that these bioengineered neural circuit model systems are reliable and scalable tools to accurately study aspects of human astrocyte-neuron functional properties while being easily accessible for cell-type-specific manipulations and observations. In this article, Krencik and colleagues show that high-density cocultures of pre-differentiated human astrocytes with induced neurons, from pluripotent stem cells, elicit mature characteristics by 3–5 weeks. This provides a faster and more defined alternative method to organoid cultures for investigating human neural circuit function.