Development of Momentary Appetite Capture (MAC): A versatile tool for monitoring appetite over long periods.

Understanding how an intervention impacts appetite in real-life settings and over several days remains a challenging and under-explored research question. To this end, we developed Momentary Appetite Capture (MAC), a form of ecological momentary assessment that combines automated text messaging with an online platform. Participants report their appetite using visual analogue scales (hunger, desire to eat, and fullness) and a virtual portion-size selection task. In two separate studies, we assessed the feasibility and test-retest reliability of MAC. Participants were prompted every 2 hours over a 14-hour window, and they repeated this assessment over two consecutive weekdays. For each participant, we calculated a daily time-averaged area under the curve (AUC) for each appetite measure. In Study One (N = 25) time-averaged AUC was significantly positively correlated across test days for hunger (r = 0.563, p = .003), desire to eat (r = 0.515, p = .008) and prospective portion size (r = 0.914, p < .001), but not for fullness (r = 0.342, p = .094). Participants completed 95% of MACs (380 of 400), and we used participant feedback to improve the MAC tool and study protocol for Study Two. In Study Two (N = 31), 94% of MACs were completed (468 of 496). Across days, time-averaged AUC was significantly positively correlated for hunger (r = 0.595, p = < .001), fullness (r = 0.501, p = .004), desire to eat (r = 0.585, p < .001), and prospective portion size (r = 0.757, p < .001). Together, these studies suggest that MAC could be an acceptable and reliable tool to track appetite throughout the day. In the future, MAC could be used to explore the impact of weight-loss interventions on natural fluctuations in appetite.

Exploring the acute effects of running on cerebral blood flow and food cue reactivity in healthy young men using functional magnetic resonance imaging.

Acute exercise suppresses appetite and alters food-cue reactivity, but the extent exercise-induced changes in cerebral blood flow (CBF) influences the blood-oxygen-level-dependent (BOLD) signal during appetite-related paradigms is not known. This study examined the impact of acute running on visual food-cue reactivity and explored whether such responses are influenced by CBF variability. In a randomised crossover design, 23 men (mean ± SD: 24 ± 4 years, 22.9 ± 2.1 kg/m2 ) completed fMRI scans before and after 60 min of running (68% ± 3% peak oxygen uptake) or rest (control). Five-minute pseudo-continuous arterial spin labelling fMRI scans were conducted for CBF assessment before and at four consecutive repeat acquisitions after exercise/rest. BOLD-fMRI was acquired during a food-cue reactivity task before and 28 min after exercise/rest. Food-cue reactivity analysis was performed with and without CBF adjustment. Subjective appetite ratings were assessed before, during and after exercise/rest. Exercise CBF was higher in grey matter, the posterior insula and in the region of the amygdala/hippocampus, and lower in the medial orbitofrontal cortex and dorsal striatum than control (main effect trial p ≤ .018). No time-by-trial interactions for CBF were identified (p ≥ .087). Exercise induced moderate-to-large reductions in subjective appetite ratings (Cohen's d = 0.53-0.84; p ≤ .024) and increased food-cue reactivity in the paracingulate gyrus, hippocampus, precuneous cortex, frontal pole and posterior cingulate gyrus. Accounting for CBF variability did not markedly alter detection of exercise-induced BOLD signal changes. Acute running evoked overall changes in CBF that were not time dependent and increased food-cue reactivity in regions implicated in attention, anticipation of reward, and episodic memory independent of CBF.

Developments in the design and delivery of self-management support for children and young people with diabetes: A narrative synthesis of systematic reviews.

AIMS: Facilitated self-management support programmes have become central to the treatment of chronic diseases including diabetes. For many children and young people with diabetes (CYPD), the impact on glycated haemoglobin (HbA1c ) and a range of self-management behaviours promised by these programmes remain unrealised. This warrants an appraisal of current thinking and the existing evidence to guide the development of programmes better targeted at this age group. METHODS: Create a narrative review of systematic reviews produced in the last 3 years that have explored the impact on CYPD of the four key elements of self-management support programmes: education, instruction and advice including peer support; psychological counselling via a range of therapies; self-monitoring, including diaries and telemetric devices; and telecare, the technology-enabled follow-up and support by healthcare providers. RESULTS: Games and gamification appear to offer a promising means of engaging and educating CYPD. Psychological interventions when delivered by trained practitioners, appear to improve HbA1c and quality of life although effect sizes were small. Technology-enabled interactive diaries can increase the frequency of self-monitoring and reduce levels of HbA1c . Telecare provided synchronously via telephone produced significant improvements in HbA1c . CONCLUSIONS: The cost-effective flexibility of increasing the reliance on technology is an attractive proposition; however, there are resource implications for digital connectivity in underserved populations. The need remains to improve the understanding of which elements of each component are most effective in a particular context, and how to optimise the influence and input of families, caregivers and peers.

Views of children with diabetes from underserved communities, and their families on diabetes, glycaemic control and healthcare provision: A qualitative evidence synthesis.

AIMS: Children and young people with diabetes (CYPD) from socio-economically deprived and/or ethnic minority groups tend to have poorer glucose control and greater risk of diabetes-related complications. In this systematic review of qualitative evidence (qualitative evidence synthesis, QES), we aimed to explore the experiences and views of clinical encounters in diabetes care from the perspectives of CYPD and their family/carers from underserved communities and healthcare professionals in diabetes care. METHODS: We searched 6 databases to March 2022 with extensive search terms, and used a thematic synthesis following methods of Thomas and Harden. RESULTS: We identified 7 studies and described 11 descriptive themes based on primary and secondary constructs. From these, three "analytical themes" were developed. (1) "Alienation of CYPD" relates to their social identity and interaction with peers, family and health service practitioners in the context of diabetes self- and family/carer management and is impacted by communication in the clinical encounter. (2) "Empowerment of CYPD and family/carers" explores families' understanding of risks and consequences of diabetes and taking responsibility for self- and family/carer management in the context of their socio-cultural background. (3) "Integration of diabetes (into self and family)" focuses on the ability to integrate diabetes self-management into the daily lives of CYPD and family/carers beyond the clinical consultation. CONCLUSIONS: The analytical themes are interdependent and provide a conceptual framework from which to explore and strengthen the therapeutic alliance in clinical encounters and to foster greater concordance with treatment plans. Communicating the biomedical aspects of managing diabetes in the clinical encounter is important, but should be balanced with addressing socio-emotional factors important to CYPD and family/carers.

Current evidence for designing self-management support for underserved populations: an integrative review using the example of diabetes.

AIMS: With numerous and continuing attempts at adapting diabetes self-management support programmes to better account for underserved populations, its important that the lessons being learned are understood and shared. The work we present here reviews the latest evidence and best practice in designing and embedding culturally and socially sensitive, self-management support programmes. METHODS: We explored the literature with regard to four key design considerations of diabetes self-management support programmes: Composition - the design and content of written materials and digital tools and interfaces; Structure - the combination of individual and group sessions, their frequency, and the overall duration of programmes; Facilitators - the combination of individuals used to deliver the programme; and Context - the influence and mitigation of a range of individual, socio-cultural, and environmental factors. RESULTS: We found useful and recent examples of design innovation within a variety of countries and models of health care delivery including Brazil, Mexico, Netherlands, Spain, United Kingdom, and United States of America. Within Composition we confirmed the importance of retaining best practice in creating readily understood written information and intuitive digital interfaces; Structure the need to offer group, individual, and remote learning options in programmes of flexible duration and frequency; Facilitators where the benefits of using culturally concordant peers and community-based providers were described; and finally in Context the need to integrate self-management support programmes within existing health systems, and tailor their various constituent elements according to the language, resources, and beliefs of individuals and their communities. CONCLUSIONS: A number of design principles across the four design considerations were identified that together offer a promising means of creating the next generation of self-management support programme more readily accessible for underserved communities. Ultimately, we recommend that the precise configuration should be co-produced by all relevant service and patient stakeholders and its delivery embedded in local health systems.

Evaluating the benefit of early patient and public involvement for product development and testing with small companies.

INTRODUCTION: There is a growing understanding of the benefits of patient and public involvement (PPI), and its evaluation, in research. An online version of the CUBE PPI evaluation framework has been developed. We sought to use the CUBE to evaluate the value of early PPI with two small healthcare companies during product development. METHODS: Contributors were recruited online and had lived experience of either type 1 diabetes or obesity. Two 1-h sessions were run with a company developing a smartphone application to manage diabetes (DEE-EM): one with young people (YP; n = 5) and one with parents (n = 7). Two 1-h sessions were run with a company developing a weight-loss product, both with adults (n = 7 in each session). Sessions were facilitated by an independent University researcher and attended by company representatives, who presented their product. One facilitator led the evaluation of the session by giving a demonstration of the CUBE and asking simple questions in the YP session. RESULTS: A high proportion of contributors completed the CUBE (80.5% DEE-EM; 93% Oxford Medical Products). Responses were positive to all four CUBE dimensions (in italics). Contributors felt there were diverse ways to contribute to the sessions, and that they had a strong voice to add to the discussion. Balance was achieved regarding whose concerns (public or company) led the agenda, and contributors felt that both companies would make changes based on the discussion. The supportive attitude of both companies resulted in most contributors feeling comfortable participating in PPI sessions with the industry, while recognising the profit-making aspect of their work. CONCLUSIONS: PPI with small healthcare companies is both feasible and worthwhile. The CUBE framework facilitated the evaluation of the interaction between experts in different knowledge spaces. We provide recommendations for future projects, including considerations of who should participate and the level of implicit endorsement of the product that participation implies. PATIENT OR PUBLIC CONTRIBUTION: People with lived experience of type 1 diabetes or obesity were invited to contribute to one of four PPI sessions, which they then evaluated. One contributor agreed to contribute to the analysis of the evaluation data and interpretation and preparation of the manuscript.

Integrating COM-B and the person-based approach to develop an ACT based therapy programme to raise self-determination in adolescents with obesity.

BACKGROUND: This paper details the development of the Adolescent Intrinsic Motivation 'AIM2Change' intervention to support weight-management in young people previously unable to make changes whilst attending a tier 3 weight management service for children and young people. AIM2Change is an acceptance and commitment therapy based intervention that will be delivered one-to-one online over a seven-week period. METHODS: To develop this intervention, we have triangulated results from a qualitative research study, patient and public involvement groups (PPI) and a COM-B (capability, opportunity, motivation, behaviour) analysis, in a method informed by the person-based approach. RESULTS: The integrated development approach yielded a broad range of perspectives and facilitated the creation of a tailored intervention to meet the needs of the patient group whist remaining pragmatic and deliverable. CONCLUSIONS: The next steps for this intervention will be in-depth co-development of the therapy sessions with service users, before implementing a proof of concept trial.

Evaluating future risk of NAFLD in adolescents: a prediction and decision curve analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest liver condition in the western world and is directly linked to obesity and the metabolic syndrome. Elevated body mass index is regarded as a major risk factor of NAFL (steatosis) and NAFLD fibrosis. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we sought to investigate whether other variables from adolescence could improve prediction of future NAFL and NAFLD fibrosis risk at 24 years, above BMI and sex. METHODS: Aged 24 years, 4018 ALSPAC participants had transient elastography (TE) and controlled attenuation parameter (CAP) measurement using Echosens 502 Touch. 513 participants with harmful alcohol consumption were excluded. Logistic regression models examined which variables measured at 17 years were predictive of NAFL and NAFLD fibrosis in young adults. Predictors included sex, BMI, central adiposity, lipid profile, blood pressure, liver function tests, homeostatic model assessment for insulin resistance (HOMA-IR), and ultrasound defined NAFL at 17 years (when examining fibrosis outcomes). A model including all these variables was termed "routine clinical measures". Models were compared using area under the receiver operator curve (AUROC) and Bayesian Information Criterion (BIC), analysis, which penalises model complexity. Models were tested in all participants and those with overweight or obese standardised BMIs (BMI SDS) centiles at the 17-year time point. A decision curve analysis (DCA) was performed to evaluate the clinical utility of models in overweight and obese adolescents predicting NAFLD fibrosis at a threshold probability of 0.1. RESULTS: The "routine clinical measures" model had the highest AUROC for predicting NAFL in all adolescent participants (AUROC 0.79 [SD 0.00]) and those with an overweight/obese BMI SDS centile (AUROC 0.77 [SD 0.01]). According to BIC analysis, insulin resistance was the best predictor of NAFL in all adolescents, whilst central adiposity was the best predictor in those with an overweight/obese BMI SDS centile. The "routine clinical measures" model also had the highest AUROC for predicting NAFLD fibrosis in all adolescent participants (AUROC 0.78 [SD 0.02]) and participants with an overweight/obese BMI SDS centile (AUROC 0.84 [SD 0.03]). However, following BIC analysis, BMI was the best predictor of NAFLD fibrosis in all adolescents including those with an overweight/obese BMI SDS centile. A decision curve analysis examining overweight/obese adolescent participants showed the model that had the greatest net benefit for increased NAFLD fibrosis detection, above a treat all overweight and obese adolescents' assumption, was the "routine clinical measures" model. However, the net benefit was marginal (0.0054 [0.0034-0.0075]). CONCLUSION: In adolescents, routine clinical measures were not superior to central adiposity and BMI at predicting NAFL and NAFLD fibrosis respectively in young adulthood. Additional routine clinical measurements do provide incremental benefit in detecting true positive fibrosis cases, but the benefit is small. Thus, to reduce morbidity and mortality associated with NASH cirrhosis in adults, the ultimate end point of NAFLD, the focus must be on obesity management at a population level.

The feasibility, acceptability, and benefit of interventions that target eating speed in the clinical treatment of children and adolescents with overweight or obesity: A systematic review and meta-analysis.

Eating at a faster speed is positively correlated with having a higher BMI. Modifying eating speed may offer a treatment opportunity for those with overweight and obesity. This review sought to understand the feasibility, acceptability, and benefit to using eating speed interventions in paediatric clinical weight-management settings. The PICO Framework was used. Clinical studies of eating speed interventions as a treatment for paediatric patients with overweight or obesity were included. No limits to search date were implemented. A systematic search of MEDLINE, PsychINFO and EMBASE via OVID, Web of Science and JBI, Database of systematic reviews and Implementation reports, along with trial registers NICE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials was conducted. Two authors were responsible for screening, extraction, and evaluation of the risk of bias. Fifteen papers reporting twelve interventions addressing eating-speed were identified, involving a total of 486 active participants (range 7-297). Study design was weak with only one full RCT and there were some concerns over quality and risk of bias (Cochrane RoB 2.0). Limited sample sizes and different measured outcomes did not allow powered evaluations of effect for all outcomes. There is some indication, overall, that addressing eating speed has the potential to be a beneficial adjunct to clinical obesity treatment, although the pooled effect estimate did not demonstrate a difference in BMISDS status following eating speed interventions compared to control [pooled mean difference (0.04, 95% CI -0.39 to 0.46, N = 3)]. Developments to improve the engagement to, and acceptability of, interventions are required, alongside rigorous high-quality trials to evaluate effectiveness.

How full am I? The effect of rating fullness during eating on food intake, eating speed and relationship with satiety responsiveness.

Modifying eating behaviours may be an effective strategy to limit excess food intake, such as eating slower and mindfully. We hypothesized that regularly rating fullness whilst eating a standard meal in one course would increase post-meal satiety and reduce intake in a subsequent course during the same sitting. A between-subjects design was employed (n = 65; 75% female; mean age = 26.7 (s.d. = 9.5); mean body mass index = 22.4 (s.d. = 3.3)), with three conditions of within-meal visual-analogue-scale ratings: 'Fullness' (rated fullness); 'Taste' (rated pleasantness of taste of food); 'Control' (rated comfort of room). Fasted participants ate a pasta meal (327 kcal) followed by cookies ad libitum. Appetite ratings were measured at baseline, following each course and for 3-h post-meal. Satiety responsiveness was measured using the Adult Eating Behaviour Questionnaire, Intuitive Eating Scale and by calculating the satiety quotient of the pasta course alone and the whole meal. The primary outcomes were fullness ratings post-pasta course [mean (s.d.): Fullness = 67.1 (21.9); Taste = 64.4 (13.7); Control = 60.2 (21.5)] and cookie intake [mean kcal (s.d.): Fullness = 249 (236); Taste = 279 (231); Control = 255 (208)]. Eating speed was included as a secondary, control outcome [mean (s.d.): Fullness = 59.3 (9.0); Taste = 59.2 (17.7); Control = 60.7 (19.6)]. No evidence for a difference in outcomes was identified between conditions (p > 0.05). Future work could involve testing the impact of rating fullness during multiple meals over a longer period. Secondly, this study explored whether levels of satiety responsiveness influenced the impact of the manipulation on outcomes; however only weak evidence for a relationship with eating speed was found. Finally, only a weak relationship was found between the satiety responsiveness measures, suggesting that different aspects of the underlying construct are being captured.

When do children learn how to select a portion size?

The reduction of portion sizes supports weight-loss. This study looks at whether children have a conceptual understanding of portion size, by studying their ability to manually serve a portion size that corresponds to what they eat. In a clinical setting, discussion around portion size is subjective thus a computerised portion size tool is also trialled, with the portion sizes chosen on the screen being compared to amounts served manually. Children (n = 76) age 5-6, 7-8 and 10-11 were asked to rate their hunger (VAS scale), liking (VAS scale) and 'ideal portion size for lunch' of eight interactive meal images using a computerised portion size tool. Children then manually self-served and consumed a portion of pasta. Plates were weighed to allow for the calculation of calories served and eaten. A positive correlation was found between manually served food portions and the amount eaten (r = 0.53, 95%CI [0.34, 0.82, P < .001), indicating that many children were able to anticipate their likely food intake prior to meal onset. A regression model demonstrates that age contributes to 9.4% of the variance in portion size accuracy (t(68) = -2.3, p = .02). There was no relationship between portion size and either hunger or liking. The portion sizes chosen on the computer at lunchtime correlated to the amount manually served overall (r = .34, 95%CI [0.07, 0.55], p < .01), but not in 5-6-year-old children. Manual portion-size selection can be observed in five-year olds and from age seven, children's 'virtual' responses correlate with their manual portion selections. The application of the computerised portion-size tool requires further development but offers considerable potential.

Change in obesity-related metabolic abnormalities associated with body mass index improvement through life-style intervention: A meta-regression.

The reduction in body mass index standard deviation score (BMI-SDS) associated with improvement in biomarkers relating to metabolic health in obese children is unknown. We aimed to establish the change in BMI-SDS associated with improved inflammation, liver function, and insulin resistance to inform clinical guidelines for pediatric weight management interventions and to assess the efficacy of future trials. A large-scale systematic review was conducted to identify relevant studies. Studies of children with a diagnosis of obesity according to defined BMI thresholds, participating in lifestyle interventions to reduce obesity, were included. Studies must have reported baseline (pre-) and postintervention (or change of) BMI-SDS and either fasting glucose, homeostatic model of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), C-reactive protein (CRP), or interleukin-6 (IL-6). A series of meta-regressions were conducted to establish links between BMI-SDS change scores and change in metabolic markers of health. Sixty-eight articles were identified. From the meta-regression analyses, across all study subsets, greater mean falls in all four parameters, (HOMA-IR, Glucose, ALT, and CRP) were observed with greater mean loss of BMI-SDS, but the trends were only statistically significant for HOMA-IR and CRP (P = .003; P = .021). However, we could not find minimum changes in BMI-SDS that would ensure a fall in these outcomes. At this time, we are unable to recommend a definitive value of BMI-SDS reduction needed to improve the markers of metabolic health. Future trials should aim to report additional indices of derived BMI values, which may better reflect changes in actual adiposity.

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.

BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Insulin-like growth factor-II in adipocyte regulation: depot-specific actions suggest a potential role limiting excess visceral adiposity.

The IGF system has an important role in growth and development. IGF-II is a recognized fetal growth promoter. However, its physiological postnatal role remains uncertain, although it is maintained in the circulation at a substantially high level throughout life. IGF-II has been strongly linked to obesity in genetic studies, and more recent evidence suggests a metabolic role. We examined fat depot differences in IGF-II's action on differentiation and metabolism. We speculate a specific effect on visceral adipocytes in relation to the differential distribution of insulin receptors between visceral and subcutaneous fat depots. We used a previously established adipocyte, cell culture system of matched pairs of visceral and subcutaneous fat biopsies from 20 normal weight children undergoing routine surgery for nonmalignant, nonseptic conditions. Preadipocytes were differentiated for 14 days in the presence or absence of IGF-II. Oil Red O staining, Western blotting, and reverse transcription polymerase chain reaction techniques were employed to assess levels of adipogenesis markers and levels of the insulin receptor and insulin receptor isoforms. Our data indicate that IGF-II promotes preadipocyte differentiation in subcutaneous preadipocytes but showed a protective, opposing effect restricting visceral preadipocyte differentiation, confirmed by reductions in the differentiation markers peroxisome proliferator-activated receptor gamma and adiponectin and in triglyceride staining. Additionally, IGF-II reduced mRNA expression of the insulin receptor in adipocytes and downregulated insulin receptor isoform A and glucose transporter 4 abundance and corresponding glucose uptake in visceral adipocytes. In conclusion, IGF-II is a regulator of preadipocyte differentiation and metabolism by acting as a differential modulator of fat accumulation favoring less visceral fat deposition in children.

Using neuroimaging to investigate the impact of Mandolean® training in young people with obesity: a pilot randomised controlled trial.

BACKGROUND: Slowing eating rate using the Mandolean® previously helped obese adolescents to self-select smaller portion sizes, with no reduction in satiety, and enhanced ghrelin suppression. The objective of this pilot, randomised trial was to investigate the neural response to food cues following Mandolean® training using functional Magnetic Resonance Imaging (fMRI), and measures of ghrelin, PYY, glucose and self-reported appetite. METHOD: Twenty-four obese adolescents (11-18 years; BMI ≥ 95th centile) were randomised (but stratified by age and gender) to receive six-months of standard care in an obesity clinic, or standard care plus short-term Mandolean® training. Two fMRI sessions were conducted: at baseline and post-intervention. These sessions were structured as an oral glucose tolerance test, with food cue-reactivity fMRI, cannulation for blood samples, and appetite ratings taken at baseline, 30 (no fMRI), 60 and 90 min post-glucose. As this was a pilot trial, a conservative approach to the statistical analysis of the behavioural data used Cliff's delta as a non-parametric measure of effect size between groups. fMRI data was analysed using non-parametric permutation analysis (RANDOMISE, FSL). RESULTS: Following Mandolean® training: (i) relatively less activation was seen in brain regions associated with food cue reactivity after glucose consumption compared to standard care group; (ii) 22% reduction in self-selected portion size was found with no reduction in post-meal satiety. However, usage of the Mandolean® by the young people involved was variable and considerably less than planned at the outset (on average, 28 meals with the Mandolean® over six-months). CONCLUSION: This pilot trial provides preliminary evidence that Mandolean® training may be associated with changes in how food cues in the environment are processed, supporting previous studies showing a reduction in portion size with no reduction in satiety. In this regard, the study supports targeting eating behaviour in weight-management interventions in young people. However, given the variable usage of the Mandolean® during the trial, further work is required to design more engaging interventions reducing eating speed. TRIAL REGISTRATION: ISRCTN, ISRCTN84202126 , retrospectively registered 22/02/2018.

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Large, rare chromosomal deletions associated with severe early-onset obesity.

Obesity is a highly heritable and genetically heterogeneous disorder. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 x 10(-5)). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.

Reduced beta-cell reserve and pancreatic volume in survivors of childhood acute lymphoblastic leukaemia treated with bone marrow transplantation and total body irradiation.

BACKGROUND: Impaired glucose tolerance (IGT) and diabetes mellitus (DM) occur more frequently after bone marrow transplantation and total body irradiation (BMT/TBI), but the mechanism is unclear. This study investigates insulin sensitivity, ß-cell reserve and pancreatic volume in adult survivors of childhood acute lymphoblastic leukaemia (ALL). METHOD: Survivors (aged 16-26 years) of ALL treated with BMT/TBI (10-14·4 Gy) Group 1 (n = 20, 10 m) were compared with a chemotherapy-only Group 2 (n = 28, 11 m). Participants underwent assessments of insulin sensitivity by whole body composite-insulin-sensitivity-index (ISIcomp ) from oral glucose tolerance tests (OGTTs); first (AIRarg , AIRg , AUCin10 ) and second (AUC in second phase ) phase insulin responses from arginine-intravenous glucose tolerance tests; and pancreatic volume by abdominal magnetic resonance imaging (MRI). Data were analysed by odds ratio, Chi-square or Fisher's exact tests, Student's t-tests, analysis of covariance (ancova) and Pearson's or partial correlations (5% significance). RESULTS: Abnormal OGTTs were documented in Group 1 (DM = 2, IGT = 7). Insulin secretion adjusted for insulin sensitivity was lower in Group 1 than Group 2 as a whole [LogAIRarg (P = 0·008), logAIRg (P = 0·013) and logAUCin10 (P = 0·014)] and after exclusion of those with abnormal glucose tolerance [logAIRarg (P = 0·011), logAIRg (P = 0·007) and logAUCin10 (P = 0·006)]. Group 1 had lower pancreatic volume than Group 2 [52·0 (14·2) vs 72·8 (23·5), P = 0·001] cm(3) , and results were consistent after adjustment for size by body surface area (P = 0·019). Pancreatic volume correlated with logAIRarg adjusted log ISIcomp (partial correlation = 0·34, P = 0·025). CONCLUSIONS: Adult survivors of childhood BMT/TBI for ALL demonstrated reduced ß-cell reserve and smaller pancreatic volume, both likely additional aetiological factors, with reduced insulin sensitivity, in their increased risk of diabetes.

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a ß cell phenotype.

BACKGROUND: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. METHODS AND RESULTS: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. CONCLUSIONS: The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.

Daily Duration of Eating for Children and Adolescents: A Systematic Review and Meta-Analysis.

Time-limited eating is a dietary intervention whereby eating is limited to a specific window of time during the day. The usual eating windows of adults, and how these can be manipulated for dietary interventions, is well documented. However, there is a paucity of data on eating windows of young people, the manipulation of which may be a useful intervention for reducing obesity. This paper reviewed the existing literature on the eating windows of children and adolescents, aged 5-18 years, plus clock times of first and last intakes and variations by subgroup. Two databases (Medline and Embase) were searched for eligible papers published between February 2013 and February 2023, with forward searching of the citation network of included studies on Web of Science. Articles were screened, and data extracted, in duplicate by two independent reviewers. Ten studies were included, with both observational and experimental designs. Narrative synthesis showed large variations in eating windows with average values ranging from 9.7 h to 16.4 h. Meta-analysis, of five studies, showed a pooled mean daily eating window of 11.3 h (95% CI 11.0, 11.7). Large variations in eating windows exist across different study populations; however, the pooled data suggest that it may be possible to design time-limited eating interventions in paediatric populations aimed at reducing eating windows. Further high-quality research, investigating eating windows and subsequent associations with health outcomes, is needed.