Flash glucose monitoring in young people with type 1 diabetes-a qualitative study of young people, parents and health professionals: 'It makes life much easier'.

OBJECTIVES: Flash glucose monitoring for patients with T1 diabetes avoids frequent painful finger-prick testing, thus potentially improving frequency of glucose self-monitoring. Our study aimed to explore experiences of young people using Freestyle Libre sensors and their parents, and to identify benefits and challenges to National Health Service (NHS) staff of its adoption in their care provision. PARTICIPANTS: Young people with T1 diabetes, their parents and healthcare professionals were interviewed between February and December 2021. Participants were recruited via social media and through NHS diabetes clinic staff. DESIGN: Semistructured interviews were conducted online and analysed using thematic methods. Staff themes were mapped onto normalisation process theory (NPT) constructs. RESULTS: Thirty-four participants were interviewed: 10 young people, 14 parents and 10 healthcare professionals. Young people reported that life was much easier since changing to flash glucose monitoring, increasing confidence and independence to manage their condition. Parents' quality of life improved and they appreciated access to real-time data. Using the NPT concepts to understand how technology was integrated into routine care proved useful; health professionals were very enthusiastic about flash glucose monitoring and coped with the extra data load to facilitate more tailored patient support within and between clinic visits. CONCLUSION: This technology empowers young people and their parents to understand their diabetes adherence more completely; to feel more confident about adjusting their own care between clinic appointments; and provides an improved interactive experience in clinic. Healthcare teams appear committed to delivering improving technologies, acknowledging the challenge for them to assimilate new information required to provide expert advice.

Increased levels of anti-BSA antibodies in children with Down syndrome.

Introduction: Autoimmune diabetes occurs more often in the first 2 years of life in children with Down syndrome (DS) compared with the general population. We previously observed increased frequencies of islet autoantibodies, including insulin autoantibodies (IAA), in children with DS. Assays for IAA using 125I-labelled insulin require competition to overcome cross reactivity with antibodies to the cow's milk protein, bovine serum albumin (BSA). 125I-IAA assay results suggested that levels of antibodies to BSA may also be increased in children with DS. The aim of this study therefore was to determine whether the levels of anti-BSA antibodies differed in children with DS compared with controls. Methods: Samples were available from two populations with DS: one from the UK, (UK DS cohort n=106, 58 male, median age 12.5 years) and one from Estonia (Estonian DS cohort: n=121, 65 male, median age 9.75 years). A UK control population was provided by sex and age-matched healthy siblings of probands participating in the Bart's Oxford (BOX) family study of type 1 diabetes. A competitive-displacement radiobinding assay (RBA) and a Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA) were developed to measure and confirm anti-BSA antibody levels. HLA class II genotype was analysed by PCR using sequence specific primers (PCR-SSP). Results: Overall, levels of anti-BSA antibodies were increased in those with DS compared with controls (p<0.0001) but this was not HLA associated. Conclusion: Increased levels of anti-BSA antibodies may reflect a defect in immune maturation or increased gut permeability in children with DS, increasing their risk of developing autoimmunity.

National consensus to develop core outcomes for the evaluation of complications from excess weight (CEW) clinics: results of a national Delphi process.

OBJECTIVE: In 2021, centres across all seven NHS-England regions were selected to develop pilot clinics with the aim of treating children and young people (CYP) living with complications relating to excess weight (CEW). We led a process to develop core outcomes to enable the evaluation of these clinics. METHODS: A two-round Delphi process, virtual steering group meetings and two patient representation workshops were used to agree the most important outcomes for both clinicians/allied professionals and representative prospective service users. RESULTS: A total of 119 clinicians/allied professionals were invited to contribute to the Delphi process: 62 (52%) agreed and completed round 1 and 47 of these (76%) went on to complete round 2. Six young people (age range 13-17 years) and six parents were involved in two patient representation workshops and their experiences fed into virtual steering group meetings, via a representative.There were 44 outcomes assessed in round 1 and 21 outcomes assessed in round 2. There were 16 core outcomes selected: anthropometric, glucose tolerance/insulin resistance/type 2 diabetes, blood pressure, lipid profile, breathing problems, identification of aetiology, non-alcoholic fatty liver disease, idiopathic intracranial hypertension, anxiety, depression, self-esteem, quality of life, school attendance, dietary habits including disordered eating, exercise and activity habits. CONCLUSIONS: Use of an online Delphi process, patient representation workshops and virtual steering group meetings has enabled the development of core outcomes for clinical obesity services with eight physical health, five mental health and three self-management outcomes. Further work is needed to develop outcome measures to complete a core outcome set. These will be used to guide the evaluation of novel regional clinics for the treatment of complications of excess weight.

Cross-sectional survey of child weight management service provision by acute NHS trusts across England in 2020/2021.

OBJECTIVE: With one in five children in England living with obesity, we mapped the geographical distribution and format of child weight management services provided by acute National Health Service (NHS) trusts across England, to identify breadth of service provision. DESIGN: A cross-sectional survey. SETTING: The survey was sent to acute NHS trusts (n=148) in England in 2020, via a freedom of information request. PARTICIPANTS: Responses were received from 139 of 148 (94%) acute NHS trusts, between March 2020 to March 2021. OUTCOME MEASURES: The survey asked each acute NHS trust whether they provide a weight management service for children living with obesity. For those trusts providing a service, data were collected on eligibility criteria, funding source, personnel involved, number of new patients seen per year, intervention duration, follow-up length and outcome measures. Service characteristics were reported using descriptive statistics. Service provision was analysed in the context of ethnicity and Index of Multiple Deprivation score of the trust catchment area. RESULTS: From the 139 survey respondents, 23% stated that they provided a weight management service for children living with obesity. There were inequalities in the proportion of acute NHS trusts providing a service across the different regions of England, ranging from 4% (Midlands) to 36% (London). For trusts providing a service, there was variability in the number of new cases seen per year, eligibility criteria, funding source, intervention format and outcome measures collected. A multidisciplinary approach was not routinely provided, with only 41% of services reporting ≥3 different staff disciplines. CONCLUSION: In 2020/2021, there were geographical inequalities in weight management service provision by acute NHS trusts for children living with obesity. Services provided lacked standardisation, did not routinely offer children multidisciplinary care and were insufficient in size to meet need.

Establishing breast feeding in infants with Down syndrome: the FADES cohort experience.

OBJECTIVE: To describe breastfeeding prevalence and maternal experience in infants with trisomy 21. DESIGN: Longitudinal cohort study. SETTING: Participants from UK recruited through websites, social media and local collaborators: neonatologists, community paediatricians and research nurses. SUBJECTS: Infants under the age of 8 months with Down syndrome (DS) recruited to the Feeding and Autoimmunity in Down Syndrome Evaluation Study between 1 September 2014 and 31 August 2017. Seventy participants: median age 20 weeks (IQR 13-29 weeks) at initial questionnaire. MAIN OUTCOME MEASURE: Breastfeeding prevalence at 6 weeks and 6 months among infants with DS. RESULTS: The prevalence of exclusive breast feeding among study participants was similar to the general population (13/61, 21% vs 23% at 6 weeks, 2/54, 4% vs 1% at 6 months). However, the prevalence of breast feeding (exclusive or combination feeding) among the study participants was higher than the general population (39/61 64% vs 55% at 6 weeks, 32/59 54% vs 34% at 6 months). CONCLUSION: Although there may be challenges in establishing breast feeding in infants with DS, our data suggest that exclusive breast feeding is possible for some, and the prevalence of breast feeding is comparable to the prevalence in the general population. TRIAL REGISTRATION NUMBER: ISRCTN12415856.

Childhood obesity as a safeguarding issue: positive experiences with the "new home" environment as a treatment for weight management.

OBJECTIVES: Childhood obesity can lead to acute and chronic comorbidities and adult obesity, highlighting the need for prompt intervention. Families and caregivers play a vital role in treatment and when primary interventions fail, this may become a child protection issue. CASE PRESENTATION: We present two cases of severe childhood obesity where targeted lifestyle interventions failed to impact weight status. Both cases feature child welfare involvement with patients coming into the care of the local authority (under s20 of the Children Act 1989). Foster placement resulted in significant weight loss and improved BMI achieved through reduced portions, healthier choices, restricted calories to recommended daily intake for age and increased activity. Physical and emotional wellbeing benefits were observed and improvements in obesity related comorbidities. CONCLUSIONS: Failure to reduce a child's weight alone does not constitute a child protection issue. In severe cases, where maximum intervention has failed and when the child has obesity related comorbidites or at a higher risk of developing them, home environment change should be considered in the child's best interest as a treatment for severe childhood obesity.

Perceptions of non-successful families attending a weight-management clinic.

OBJECTIVE: This study seeks to understand family's perceptions of their care at a paediatric weight management service, with a view to informing service improvement. DESIGN: A qualitative service review conducted via semistructured interviews with parents (n=11) and children (n=3) who attended the clinic. The recruitment was open to all, but those who were not succeeding in their weight-loss goals self-selected to participate. Self-Determination Theory was used as a framework to explore families' experiences of the clinic. SETTING: Recruitment occurred during clinical appointments and interviews were conducted over the phone in the days following the appointments. PATIENTS: The service sees paediatric patients with a body mass index >99th percentile, with comorbidities or safeguarding concerns. INTERVENTIONS: The clinic's service includes appointments typically every 2 months, with a multidisciplinary team including consultant endocrinologists, a dietician, a clinical psychologist, a social worker and a clinical nurse specialist. MAIN OUTCOME MEASURES: Families' feedback on the multi-disciplinary team (MDT) clinic, and their perceptions of how improvements could be made. RESULTS: Families perceive a lack of autonomy, competency and feel a lack of connectivity both in their lives broadly and within their experience at the clinic. CONCLUSIONS: Interventions in families struggling with weight improvements should see the clinical team placing more emphasis on working alongside parents to develop young people's sense of self-determination. Expectations must be set that success originates from changes outside of clinical appointments and that the clinical team is in place to support the family's development of sustainable, self-determined lifestyle habits.

Reducing cardiovascular disease risk among families with familial hypercholesterolaemia by improving diet and physical activity: a randomised controlled feasibility trial.

OBJECTIVE: Familial hypercholesterolaemia (FH) elevates low-density lipoprotein cholesterol (LDL-C) and increases cardiovascular disease (CVD) risk. This study aimed to provide evidence for the feasibility of conducting a randomised controlled trial to evaluate the efficacy of an intervention designed to improve diet and physical activity in families with FH. DESIGN: A parallel, randomised, waitlist-controlled, feasibility pilot trial. SETTING: Three outpatient lipid clinics in the UK. PARTICIPANTS: Families that comprised children (aged 10-18 years) and their parent with genetically diagnosed FH. INTERVENTION: Families were randomised to either 12-week usual care or intervention. The behavioural change intervention aimed to improve dietary, physical activity and sedentary behaviours. It was delivered to families by dietitians initially via a single face-to-face session and then by four telephone or email follow-up sessions. OUTCOME MEASURES: Feasibility was assessed via measures related to recruitment, retention and intervention fidelity. Postintervention qualitative interviews were conducted to explore intervention acceptability. Behavioural (dietary intake, physical activity and sedentary time) and clinical (blood pressure, body composition and blood lipids) outcomes were collected at baseline and endpoint assessments to evaluate the intervention's potential benefit. RESULTS: Twenty-one families (38% of those approached) were recruited which comprised 22 children and 17 adults with FH, and 97% of families completed the study. The intervention was implemented with high fidelity and the qualitative data revealed it was well accepted. Between-group differences at the endpoint assessment were indicative of the intervention's potential for improving diet in children and adults. Evidence for potential benefits on physical activity and sedentary behaviours was less apparent. However, the intervention was associated with improvements in several CVD risk factors including LDL-C, with a within-group mean decrease of 8% (children) and 10% (adults). CONCLUSIONS: The study's recruitment, retention, acceptability and potential efficacy support the development of a definitive trial, subject to identified refinements. TRIAL REGISTRATION NUMBER: ISRCTN24880714.

Exploring how lifestyle weight management programmes for children are commissioned and evaluated in England: a mixed methodology study.

OBJECTIVE: To assess how lifestyle weight management programmes for children aged 4-16 years in England are commissioned and evaluated at the local level. DESIGN: This was a mixed-methods study comprising an online survey and semistructured telephone interviews. SETTING: An online survey was sent to all local authorities (LAs) in England regarding lifestyle weight management services commissioned for children aged 4-16 years. Online survey data were collected between February and May 2016 and based on services commissioned between April 2014 and March 2015. Semistructured telephone interviews with LA staff across England were conducted between April and June 2016. PARTICIPANTS: Commissioners or service providers working within the public health department of LAs. MAIN OUTCOME MEASURES: The online survey collected information on the evidence base, costs, reach, service usage and evaluation of child lifestyle weight management services. The telephone interviews explored the nature of child weight management contracts commissioned by LAs, the type of outcome data collected and whether these data were shared with other LAs or organisations, the challenges faced by these services, and the perceived 'markers of success' for a programme. RESULTS: The online survey showed that none of the participating LAs was aware of any peer-reviewed evidence supporting the effectiveness of their specific commissioned service. Despite this, the telephone interviews revealed that there was no national formal sharing of data to enable oversight of the effectiveness of commissioned services across LAs in England to help inform future commissioning decisions. Challenges with long-term data collection, service engagement, funding and the pressure to reduce the prevalence of obesity were frequently mentioned. CONCLUSIONS: Robust, independent, cost-effectiveness analyses of obesity strategies are needed to determine the appropriate allocation of funding to lifestyle weight management treatment services, population-level preventative approaches or development of whole system approaches by an LA.

Treatment adherence and BMI reduction are key predictors of HbA1c 1 year after diagnosis of childhood type 2 diabetes in the United Kingdom.

BACKGROUND/OBJECTIVE: Type 2 Diabetes (T2DM) is increasing in childhood especially among females and South-Asians. Our objective was to report outcomes from a national cohort of children and adolescents with T2DM 1 year following diagnosis. METHODS: Clinician reported, 1-year follow-up of a cohort of children (<17 years) diagnosed with T2DM reported through the British Paediatric Surveillance Unit (BPSU) (April 2015-April 2016). RESULTS: One hundred (94%) of 106 baseline cases were available for review. Of these, five were lost to follow up and one had a revised diagnosis. Mean age at follow up was 15.3 years. Median BMI standard deviation scores (SDS) was 2.81 with a decrease of 0.13 SDS over a year. HbA1c <48 mmol/mol (UK target) was achieved in 38.8%. logHbA1c was predicted by clinician reported compliance and attendance concerns (ß = 0.12, P = <0.0001) and change in body mass index (BMI) SDS at 1-year (ß = 0.13, P=0.007). In over 50%, clinicians reported issues with compliance and attendance. Mean clinic attendance was 75%. Metformin was the most frequently used treatment at baseline (77%) and follow-up (87%). Microalbuminuria prevalence at 1-year was 16.4% compared to 4.2% at baseline and was associated with a higher HbA1c compared to those without microalbuminuria (60 vs 49 mmol/mol, P = 0.03). CONCLUSIONS: Adherence to treatment and a reduction in BMI appear key to better outcomes a year after T2DM diagnosis. Retention and clinic attendance are concerning. The prevalence of microalbuminuria has increased 4-fold in the year following diagnosis and was associated with higher HbA1c.

Is Child Abuse Associated with Adolescent Obesity? A Population Cohort Study.

BACKGROUND: Child abuse is associated with obesity in adulthood through multiple mechanisms. However, little is known about the relationship between abuse and obesity during adolescence. The aim of this study was to investigate, using a birth cohort, whether there is an association between child abuse and overweight or obesity in adolescence. METHODS: This study utilizes data from the Avon Longitudinal Study of Parents and Children, a prospective cohort study based in South West England. Using data from the 4205 children with complete data at 13 and 16 years, we analyzed body mass index (BMI) and anonymous parental report of abuse. Abuse was categorized as emotional, physical, or sexual. A sub-sample of 3429 had BMI recorded at 18 years, enabling a longitudinal analysis of BMI trajectories. RESULTS: Using linear and logistic regression analysis, adjusting for sex and family adversity, no association was found between child abuse and BMI, BMI Z-scores, overweight, or obesity, at 13 or 16 years, with all confidence intervals straddling the null. There was weak evidence of a negative association between physical and emotional abuse and BMI trajectories between 13 and 18 years. CONCLUSIONS: No relationship was found between child abuse and adolescent obesity in this cohort. This challenges the assumption that adolescent obesity is linked to previous child abuse, as demonstrated for obesity in adult life. A further longitudinal study utilizing both parental and child reports with data record linkage, to improve reporting of abuse, and including neglect as an abuse category, would be desirable.

Incidence and Clinical Associations of Childhood Acute Pancreatitis.

OBJECTIVES: To establish the UK incidence and clinical associations of acute pancreatitis (AP) in children aged 0 to 14 years. METHODS: Monthly surveillance of new cases of AP in children under 15 years of age through the British Pediatric Surveillance Unit conducted from April 2013 to April 2014 (inclusive) followed by 1-year administrative follow-up for all valid cases. RESULTS: Ninety-four cases (48 boys) fulfilled the diagnostic criteria. The median age at diagnosis was 11.2 years (range 1.3-14.9). White children accounted for 61% of the cases compared with 28% from Asian and 5% from African ethnicities. Pakistani children accounted for 18 of 26 (69%) Asian patients and 19% of the total cohort. The incidence of AP in children in the United Kingdom was 0.78 per 100 000/year (95% confidence interval [CI] 0.62-0.96). The incidence in Pakistani children (4.55; 95% CI 2.60-7.39) was sevenfold greater than white children (0.63; 95% CI 0.47-0.83). Of the 94 cases, 35 (37%) were idiopathic; other associations were: drug therapy, 18 (19%); gallstones, 12 (13%); hereditary, 7 (7%); organic acidemias, 7 (7%); anatomic anomalies, 5 (5%); viral infections, 3 (3%); systemic diseases, 2 (2%); and trauma 1 (1%). The most common drug associations were asparaginase (28%), azathioprine (17%), and sodium valproate (17%). CONCLUSIONS: Although still relatively uncommon in the United Kingdom, on average there is >1 case of childhood AP diagnosed every week. The associations of AP have changed significantly since the 1970-80s. Overrepresentation of Pakistani children is worthy of further investigation.

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.

BACKGROUND: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. METHODS: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. RESULTS: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. CONCLUSIONS: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.

Attitudes to Exercise and Diabetes in Young People with Type 1 Diabetes Mellitus: A Qualitative Analysis.

AIMS: To investigate young people's attitudes to, and understanding of, physical activity on glycaemic control in Type 1 Diabetes Mellitus. METHODS: Four focus groups with 11-14 and 15-16 year olds were conducted with twelve young people with Type 1 Diabetes, from within a larger study investigating physical activity and fitness. Qualitative analysis of the focus group data was performed using Interpretative Phenomenological Analysis. RESULTS: Four superordinate themes were identified: Benefits of Exercise, Knowledge and Understanding, Information and Training and "You can do anything". Young people felt that exercising helped them to manage their diabetes and had a beneficial psychological and physical impact on their bodies. They reported a lack of knowledge and understanding about diabetes among school staff and other young people. The overwhelming sense from young people was that although diabetes impacts upon their lives, with preparation, physical activity can take place as normal. CONCLUSIONS: Whilst young people had an awareness of the physical and psychological benefits of exercise in managing their diabetes, they experienced difficulties at school. Professional support and discussions with young people, giving tailored strategies for managing Type 1 Diabetes during exercise are needed. Healthcare teams should ensure that the support and educational needs of school staff are met. Providing more opportunities to empower young people to take on the responsibility for their Type 1 Diabetes care is merited. Young people felt diabetes did not stop them from participating in activities; it is simply a part of them that needs managing throughout life.

Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes.

BACKGROUND: Survivors of childhood acute lymphoblastic leukaemia (ALL) treated with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have a high cardiometabolic risk despite lacking overt clinical obesity. This study characterised body composition using different methodologies and explored associations with reduced insulin sensitivities in a group of ALL survivors treated with/without HSCT/TBI. PROCEDURE: Survivors of childhood ALL treated with HSCT/TBI (n = 20,10 M) were compared with Chemotherapy-only (n = 31), and an obese non-leukaemic controls (n = 30). All subjects (aged 16-26 years) were investigated with: auxology (BMI, waist and hip circumferences), DEXA (total and regional fat, fat-free mass), abdominal MRI (subcutaneous, visceral, intramuscular fat), oral glucose tolerance tests (impaired glucose tolerance or diabetes, insulin sensitivity) and serum adiponectin. RESULTS: HSCT/TBI Group displayed a higher prevalence of abnormal glucose tolerance (45%); lower insulin sensitivity; lower lean mass with higher prevalence of reduced fat-free mass index (from DEXA); higher visceral and intramuscular, and lower subcutaneous fat on MRI, compared with the Chemotherapy-only and Obese controls. BMI was lowest in HSCT/TBI Group. Waist-to-hip and android-to-gynoid ratios were similar between HSCT/TBI and Obese Groups. Insulin sensitivity adjusted for visceral fat mass was lower in the HSCT/TBI than the Chemotherapy-only and Obese groups. Adiponectin in the HSCT/TBI Group was lower than the Chemotherapy-only group, and correlated negatively with time post HSCT/TBI. CONCLUSIONS: HSCT/TBI survivors have an increased risk of abnormal glucose tolerance and reduced insulin sensitivity with reduced subcutaneous and increased visceral fat distribution, increased total fat mass and reduced lean mass.

Insulin and BMI as predictors of adult type 2 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Fasting insulin concentrations are increasingly being used as a surrogate for insulin resistance and risk for type 2 diabetes (T2DM), although associations with adult outcomes are unclear. Our objective was to determine whether fasting insulin concentrations in childhood associate with later T2DM. METHODS: Fasting insulin values were available from 2478 participants in the longitudinal Cardiovascular Risk in Young Finns Study at baseline age 3 to 18 years, along with data on adult T2DM (N = 84, mean age = 39.6 years). RESULTS: Among 3- to 6-year-olds, a 1-SD increase in fasting insulin was associated with a relative risk (RR) of 2.04 (95% confidence interval [CI], 1.54-2.70) for later T2DM, which remained significant after we adjusted for BMI and parental history of T2DM. For those aged 9 to 18 years, a 1-SD increase in insulin was associated with an RR of 1.32 (95% CI, 1.06-1.65) for T2DM, but this became nonsignificant after we adjusted for BMI and parental history of T2DM. In the latter age group, a 1-SD increase in BMI was associated with an RR of 1.45 (95% CI, 1.21-1.73) for T2DM, with adjustment for insulin and parental history of T2DM not improving this association. BMI in younger children was not associated with later T2DM. In life course analyses, those with T2DM had higher fasting insulin levels in early childhood and later adulthood but not in peripubertal years. CONCLUSIONS: Elevated fasting insulin concentrations in early childhood, but not adolescence, are independently associated with an elevated risk of T2DM in adulthood.

KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

High intensity interval running enhances measures of physical fitness but not metabolic measures of cardiovascular disease risk in healthy adolescents.

BACKGROUND: With accumulating evidence suggesting that CVD has its origins in childhood, the purpose of this study was to examine whether a high intensity training (HIT) intervention could enhance the CVD risk profile of secondary school aged adolescents in a time efficient manner. METHODS: Participants in the study were adolescent school children (64 boys, 25 girls, 16.7 ± 0.6 years). The intervention group (30 boys, 12 girls) performed three weekly exercise sessions over 7 weeks with each session consisting of either four to six repeats of maximal sprint running within a 20 m area with 30 s recovery. The control group were instructed to continue their normal behaviour. All participants had indices of obesity, blood pressure and nine biochemical risk markers for cardiovascular disease recorded as well as four physical performance measures at baseline and post-intervention. Feedback was provided through informal discussion throughout the intervention period as well as post-intervention focus groups. Statistical differences between and within groups were determined by use of paired samples t-tests and ANCOVA. RESULTS: Significant enhancements (P ≤ 0.05) in vertical jump performance, 10 m sprint speed and cardiorespiratory fitness was evident in the intervention group whereas a significant decrease in both agility and vertical jump performance was evident in the control group. Participants in the intervention group also experienced a significant decrease in systolic blood pressure post-intervention. Limited changes occurred with respect to the biochemical markers although both groups did experience a significant increase in LDL post-intervention whilst the control group experienced a significant decrease in total cholesterol. No apparent differences were evident between groups post intervention for any of the biochemical markers. Feedback indicated that participants endorsed the use of the intervention as an effective means of exercise. CONCLUSIONS: Our results demonstrate that high intensity exercise interventions may be used in the school setting for adolescents as a means of improving measures of physical fitness. Further investigations involving a larger cohort of participants, taken from different schools, is recommended. TRIAL REGISTRATION: NCT01027156.

Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome.

OBJECTIVE: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes. RESEARCH DESIGN AND METHODS: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay. RESULTS: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort. CONCLUSIONS: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.