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As members will know, an ever increasing number of young people are being diagnosed with type 2 diabetes mellitus. This disease is more aggressive in children than in adults, and presents specific issues regarding screening, management and co-morbidities. It provides the topical theme of this issue of ESPE News On page 7, William Tamborlane explains how the formation of the Pediatric Diabetes Consortium in the USA came about initially to provide a type 2 diabetes registry, and how it has subsequently begun to address the limiting lack of medical treatment options that have been approved for use in youth. The Australasian Paediatric Endocrine Group has recently developed guidelines on screening, assessment and management of type 2 diabetes mellitus in young people (page 8). Alexia Peña Vargas outlines their importance in supporting patients, particularly those in high risk ethnic groups, including the indigenous Australasian population. Type 2 diabetes mellitus has complex and devastating co-morbidities, as Orit Pinhas Hamiel describes, as she details research that has taken place into the various complications across a wide range of studies (page 9). We also highlight some articles on type 2 diabetes mellitus from the recently published Yearbook of Paediatric Endocrinology (page 10). We hope that all these articles bring you up to date with the latest developments in this area. Of course, since the last issue of ESPE News, we have had the privilege of meeting virtually to exchange knowledge and expand our understanding at ESPE 2021 Online, which was incredibly valuable at a time when travel is still restricted. It provided an excellent programme of talks and posters (page 11). The Annual Meeting saw the presentation of the ESPE Awards for 2021 as well as those for 2020. You can read about the 2021 award recipients on pages 4 and 5. (The 2020 recipients were featured in issue 50.) We congratulate them all! The rest of this issue is packed with news, including details of the new ECPE Taskforce to support early career paediatric endocrinologists (see page 3). You can also enjoy hot topics, as well as the latest event and deadline information, as we move, hopefully and gradually, back towards normality. Sarah Ehtisham Editor, ESPE News [email protected]
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We welcome your nominations for the 2022 ESPE Awards. These celebrate and recognise the achievements of ESPE members at all stages of their research and clinical careers, wherever they are in the world. Nominate your colleagues by 10 December 2021 www.eurospe.org/grants-awards/award
The ESPE Annual Review for 2020 is now available online, providing an easily digestible round-up and celebration of everything ESPE achieved and was involved in last year. Take a look and you will see how much happened, despite the pandemic. Find the ESPE Annual Review at www.eurospe.org/about/ annual-review ESPE roles renamed from 2022 Historically, ESPE has used the term Secretary General where other societies use President. At the recent Annual Business Meeting, it was agreed to bring our terminology in line with the wider community. Thus, after the ESPE Annual Meeting in September 2022, the role of Secretary General will be known as President, while the current role of President will become Annual Meeting Host (with a Deputy Annual Meeting Host). You will begin to see these changes reflected in our communications. YOUR SOCIETY Annual Review 2020 eurospe.org Advancing excellence in paediatric endocrinology and diabetes ESPE Clinical Fellowship Spring Initiative on video This event in April 2021 celebrated 30 years of the ESPE Clinical Fellowship programme. It featured a diverse educational programme, with 3.5 hours of content, which is now freely available online as a bookmarked video for all to view. The event included a wide range of high quality presentations, including cases and research from ESPE Clinical Fellows. You can watch the event at https://vimeo.com/536237907/75d19e455
The European Commission’s plan to create a European Data Space includes the health sector. Its aim is to improve access to health data, to support healthcare delivery, research and policy-making. ESPE, along with the European Society of Endocrinology, the European Reference Network on Rare Endocrine Conditions (Endo-ERN) and the European Registries for Rare Endocrine Conditions (EuRRECa), issued a joint statement welcoming the initiative, but also urging the EU institutions to consider the following points:
This event in April 2021 celebrated 30 years of the ESPE Clinical
Fellowship programme. It featured a diverse educational
programme, with 3.5 hours of content, which is now freely
available online as a bookmarked video for all to view. The event
included a wide range of high quality presentations, including
cases and research from ESPE Clinical Fellows
ESPE’s mission is to advance excellence in paediatric endocrinology to benefit children worldwide. That is why ESPE needs to nurture its members in their early careers, so that future opinion leaders are appropriately represented and engaged within the Society. For this reason, the ESPE Council agreed to create an Early Career Paediatric Endocrinologist (ECPE) Taskforce. The project is led by Rasha Hamza (Egypt), as Chair of the ESPE Education and Training Committee. The Taskforce is chaired by Rade Vukovic (Serbia), and has five enthusiastic and accomplished members from different parts of the world. The ECPE Taskforce seeks to define how ESPE can best support young paediatric endocrinologists, research their needs, and maximise their engagement, integration and visibility within the Society. It is the first step towards developing a future, wider ECPE group, providing early career members with more chances to actively contribute to ESPE. Our predecessors in paediatric endocrinology paved the way for our successes, and we aim to do the same for those who follow
ESPE Andrea Prader Prize ESPE Young Investigator Awards This award for paediatricians who are still in training or have been no more than 5 years in a senior (principal investigator) role was presented to the following, in recognition of their scientific publications:
ESPE Outstanding Clinician Award ESPE International Award ESPE International Outstanding Clinician Award ESPE Research Award Sasha Howard Willem Staels ESPE NEWSLETTER / ISSUE 54 / WINTER 2021 You can find a link to a presentation about our winners at www.eurospe.org/grants-awards/espe-2021-award-winners Nominations are now open for our 2022 Awards Nominate your colleagues by 10 December 2021 www.eurospe.org/grants-awards
FCAH-ESPE Grants The following awards have been made for research into congenital adrenal hyperplasia (CAH):
ESPE Research Unit Lars Sävendahl (Stockholm, Sweden) and colleagues have been awarded the ESPE Research Unit, which supports collaborative research among members, for their project entitled ‘Humanin, a novel target to improve bone health in chronic inflammation’ (€100 000). ESPE Clinical Fellowships Due to the pandemic, selection of clinical fellows has been postponed throughout 2021. It is hoped that the selection process will take place in the coming months for the programme to run again in 2022. All applications have already been received for this allocation and no additional places are available.
ESPE Hormone Research in Paediatrics Prizes Prizes for papers published in Hormone Research in Paediatrics were presented to the following:
Let ESPE support your career ESPE Research Unit Grant This collaborative research grant aims to foster, facilitate, co-ordinate and identify topics for high quality research in paediatric endocrinology, for both physicians and scientists. The grant of €100 000 is for 2 years (up to €50 000 per year). It covers salary, materials and consumables, small items of equipment, collaborative visits and overheads that should be less than 10% of the total value. Preliminary applications 1 November 2021–15 February 2022 Those fulfilling the preliminary criteria will need to submit a final application by 20 April 2022 Find full details at www.eurospe.org/grants-awards/grants/ research-unit
ESPE Research Fellowship The Research Fellowship enables talented early career scientists, investigators and paediatric endocrinologists to conduct research at leading institutions worldwide. €125 000 is available for up to 2 years of research training in a centre of excellence, for those intending to pursue a career in paediatric endocrinology. It will also cover living expenses. An additional €15 000 is available for consumables (reasonable travel and laboratory expenses). Applications accepted 1 January–20 April 2022 Find full details at www.eurospe.org/grants-awards/grants/ research-fellowship
The ESPE e-Learning portal provides learning modules on almost all aspects of paediatric endocrinology and diabetes mellitus. The General Content section features 78 chapters and over 120 real life problem-solving cases, concisely describing physiology, pathophysiology and practical approaches to management and treatment in English. The Resource Limited Countries (RLC) section is targeted towards frontline healthcare providers in these areas, and provides 24 chapters and 24 real life problem-solving cases in five languages (English, French, Spanish, Chinese and Swahili). A recent article highlights the development of our RLC resource: see JMIR Formative Research 2020 4 e18555. New additions Problem-solving cases have been added to the Courses section, under ESPE Maghreb School: ‘An infant with dehydration’ and ‘Persistent convulsions in a 12-month-old girl’. The content is in English and French. See www.espe-elearning.org Registration is free of charge
Bringing you recent highlights from the world of research
Some studies have shown an increased risk of early pubarche, early menarche and polycystic ovary syndrome (PCOS) in girls born small for gestational age. However, little is known about the association between preterm birth and PCOS. This Finnish study by Paalanne et al. included 74 women born very or moderately preterm (<34 weeks of gestation), 127 women born late preterm (34–36 weeks of gestation) and 184 women born at full term. Their mean age was 23.2 years. Women born preterm had higher testosterone, lower sex hormone-binding globulin and a higher free androgen index than controls. Furthermore, women born late preterm had a threefold increased risk of having PCOS according to clinical and biochemical signs. Women born late preterm also had a significantly higher waist circumference than controls and were more hyperinsulinaemic and insulin-resistant than women born at term. These are contributing factors to hyperandrogenism and pathogenic features of PCOS. This study supports the association of early life factors, including prematurity, with the development of PCOS in later life
Idiopathic diabetes is a subcategory of type 1 diabetes mellitus (T1DM) characterised by the absence of autoantibodies. The underlying molecular mechanisms are still poorly understood. Over a 2-year period, Abdel-Karim and colleagues carried out a prospective study of 1157 patients with T1DM who were under the age of 18 years. Autoantibodies (GAD65, IAA, IA-2A and ZnT8) were measured and, in cases where they were absent, genetic evaluation was performed to rule out monogenic diabetes. It was found that 53 patients (4%) had idiopathic T1DM, and around 33% of these had a history of diabetic ketoacidosis. The C peptide level was low in 56.6% and normal in 43.4%. Additionally, it was found that C peptide levels were higher and the requirement for insulin was lower in the idiopathic diabetic cohort. Thus, accurate diagnosis is essential for management and prognosis, as some reports also mention a higher cardiovascular risk in the long term in these patients
Thanks to great advances in treatment, the 5-year survival rate for all paediatric patients with cancer now exceeds 80%. Childhood cancer survivors, however, have an increased risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease, specifically in individuals who underwent total body irradiation (TBI) or abdominal radiotherapy (RT). The underlying molecular mechanisms for this association are not known. Huang et al. examined adult survivors of childhood cancer, who had previously been treated with abdominal RT or TBI, and compared them with individuals treated with chemotherapy only (CHM) or healthy controls. They included individuals with no prior T2DM or obesity to detect early changes in gene expression of adipose tissue by RNA sequencing. The biggest differences were observed between individuals with TBI compared with CHM or healthy controls, with upregulation of inflammatory markers and dysregulation of adipocytokine expression. This suggests adipose tissue dysfunction in individuals with a history of TBI, which negatively impacts their cardiometabolic health
This observational study by Perri et al. examined the cognitive function and white matter microstructure, observed by magnetic resonance imaging (MRI), in children with congenital hypothyroidism. They compared 39 affected children with 39 healthy children and found that 10% of those with permanent hypothyroidism had an IQ score<70 and 28.6% had an IQ score of 71–84. There were particular effects on processing speed, visual attention, reading speed, calculations and numerical knowledge, which were lower than the control group. Family history was also relevant, with a lower IQ value, working memory index and processing speed in children of mothers with Hashimoto’s and those with a family history of thyroid disorders. MRI demonstrated white matter microstructural abnormalities which correlated with the clinical and cognitive findings. Despite timely diagnosis and treatment, children with congenital hypothyroidism remain at risk of white matter abnormalities and neurocognitive impairment. Further work is needed to look into the association between maternal thyroid disease and cognitive outcomes.
A current lack of approved drugs There are many reasons why a limited number of new drugs are currently approved for use in adolescents with type 2 diabetes mellitus (T2DM). First of all, T2DM is a relatively ‘new’ disease in paediatrics, initially described in the 1990s. Metformin was the first and only drug approved by the US Food and Drug Administration (US FDA), in 1999, for use in T2DM in youth. This was on the basis of a small, randomised clinical trial. Insulin was also approved for use by young people with T2DM, but this was based on its effective use in adults with T2DM and in children with T1DM, not a randomised controlled study in adolescents. Rosiglitazone and glimepiride failed as initial monotherapies versus metformin in T2DM in youth. Prior to the recent approval of liraglutide,1 no new drugs had been approved for use in paediatric T2DM on the basis of a randomised study for more than 20 years. A major reason why many of the new drugs approved for adult use have not been approved in paediatrics is that adolescents with T2DM are difficult to recruit for trials. For example, low-income disadvantaged parents are less readily engaged with research and often can’t afford to miss work so that their children can be screened for these studies. Adolescents with T2DM often miss clinic visits and are lost to follow-up. Their compliance with taking meds and carrying out other diabetes-related tasks is poor. Many patients are also excluded due to behavioural problems, depression, other psychiatric disorders and use of atypical anti-psychotic drugs. Another recruitment problem includes the relatively small number of cases with T2DM who are 10–17 years New medications for type 2 diabetes mellitus in youth William Tamborlane explains the relative lack of drugs used to treat adolescent type 2 diabetes mellitus, and the steps that are being taken to remedy this situation. More recently, the Pediatric Diabetes Consortium’s primary aim has been to improve the care of adolescents with T2DM by making drugs with proven effectiveness in adults available to them” William Tamborlane Liraglutide: the first drug approved for use in paediatric T2DM on the basis of a randomised study for over two decades. StudioMolekuul/Shutterstock Trials with PDC participation AstraZeneca:
Only about 200 adolescents with T2DM are listed in the UK registry and there are fewer than 1000 with T2DM in the German/ Austrian T2DM Registry. In addition, many adolescents who are screened for participation in T2DM trials are excluded, due to a variety of modifiable and non-modifiable exclusions. Improving drug availability However, a major turning point has been reached by the formation of the Pediatric Diabetes Consortium (PDC) of the 60 leading US paediatric diabetes treatment centres. The initial aim of the PDC was to establish the first paediatric T2DM registry in the USA. More recently, its primary aim has been to improve the care of adolescents with T2DM by making drugs with proven effectiveness in adults available to them.2 This has been accomplished by the collaboration of a large number of US paediatric endocrine centres to evaluate the efficacy and safety of new drugs for adolescents (10–17 years of age) with T2DM. In addition, the PDC Executive Committee has negotiated template trial budgets with industry and contract research organisation sponsors, which have been offered to each PDC centre that enrols in a trial. The PDC has also established monthly Oversight Committee calls with investigators and study co-ordinators at all centres that are enrolled in each clinical trial. The PDC has already accomplished its primary goal by participation in the studies highlighted in the panel (left). We strongly believe that the results of these and future randomised clinical trials will transform the care of young people with T2DM in the future. William V Tamborlane Professor and Chief of Pediatric Endocrinology, Yale University School of Medicine, Connecticut, USA
Alexia Peña Vargas updates us on the Australasian Paediatric Endocrine Group guidelines on screening, assessment and management of type 2 diabetes mellitus in young people.
The first Australasian guidelines for children with type 2 diabetes mellitus (T2DM) were developed to support healthcare providers in relation to screening and care of children with T2DM.1 They were developed in the context of the increased incidence of T2DM in children, particularly in high risk ethnic groups, and the higher diabetes complication rate in paediatric T2DM compared with adult T2DM.2 The guidelines emphasise the challenges and details of screening and management of children from indigenous backgrounds in Australia and New Zealand, which were not included in previous international paediatric guidelines.3 Specific screening for indigenous children in comparison with non-indigenous individuals is shown in the Table. This took into account the need for early identification of these children, using feasible approaches, as they are at high risk of suboptimal control and early diabetes complications.1 Recommendations In addition to the guidance for screening (see Table), the guidelines include the following recommendations. 1. Diabetes antibodies testing should be undertaken at diagnosis, and consideration should be given to genetic testing, if diabetes is present in two or more consecutive generations and diabetes autoantibodies are negative. 2. Diabetes education should be delivered by a specialised multidisciplinary team with expertise in managing paediatric
3. Blood glucose monitoring should be individualised according to treatment and need to improve glucose levels. 4. Tighter diabetes targets (glycated haemoglobin (HbA1c) 48mmol/mol [≤6.5%]) should be set for all children. This is due to the accelerated rate of developing diabetes complications and the higher mortality rate compared with patients with T1DM and adult-onset T2DM.2,4 This target HbA1c should be achieved without hypoglycaemia and/or undue treatment burden. 5. Advice on lifestyle should include optimising weight, a healthy diet, 60 minutes of moderate to vigorous physical activity per day, limitation of recreational screen time to ≤2 hours/day and quality sleep of 8–11 hours’ duration, according to age. 6. Metformin up to 2g/day should be used as the first-line medication in children with mild presentation or in those who are diagnosed after screening. 7. Insulin should be the first-line treatment for patients who present with diabetes ketoacidosis, hyperglycaemic hyperosmolar state or ketosis. It should be added to metformin where glycaemic targets have not been achieved or maintained with metformin monotherapy. 8. Newer medications approved for adults with T2DM should be considered if target diabetes control is not achieved with reasonable adherence to treatment and under the guidance of a paediatric endocrinologist. Even though this recommendation had limited evidence to support it, there is emerging evidence of the effectiveness of glucagon peptide-like receptor agonists (liraglutide) in adolescents with T2DM.5 9. Complications and co-morbidities should be screened for at diagnosis and during follow up, including obesity, retinopathy, nephropathy, neuropathy, psychosocial issues, reproductive disorders, liver disease, obstructive sleep apnoea, hypertension and dyslipidaemia. 10. Transition of adolescents with T2DM to a diabetes multidisciplinary care team including an adult endocrinologist should be arranged for their ongoing care. This particularly applies to those who have co-morbidities and/or those who are taking insulin. This allows earlier use of newer oral or injectable medications and early intervention for diabetes complications. The guidelines also highlight the need for ongoing research into childhood T2DM, as the evidence used to provide recommendations was limited.1 Alexia S Peña Vargas Paediatric Endocrinologist, Endocrinology and Diabetes, Women’s and Children’s Hospital, and Associate Professor, University of Adelaide, Australia
Orit Pinhas-Hamiel draws together the latest data to illustrate the complexity and devastating, far-reaching effects of this condition in young people
In many parts of the world, increasing numbers of
transgender/gender diverse (TGD) youth are seeking
medical care to bring their physical sex characteristics
into alignment with their gender identity: their inner sense
of self as male, female, or somewhere on the gender
spectrum.
Now, nearly three decades since the first publications, type 2 diabetes (T2DM) in children and adolescents is well established as a global problem. Increased numbers of affected adolescents and longer diabetes duration have yielded prospective studies with appropriate control groups. Compelling data comprising mixed ethnic populations arise from multicentre studies in the USA (TODAY/TODAY2 and the SEARCH for Diabetes in Youth), and studies from Canada and Australia. The limited data from Europe and Asia suggest similar trends. Young people with T2DM experience a wide range of complications and co-morbidities (Table 1). Acute complications include diabetic ketoacidosis, which can lead to recurrent admissions,1 hyperosmolar hyperglycaemic non-ketotic syndrome, and severe hypoglycaemic events, which have been reported in 2.6% of cases. The Figure shows the prevalence of complications compared with adolescents with type 1 diabetes (T1DM). Table 2 (page 10) summarises data showing the prevalence of microvascular complications and co-morbidities at diagnosis and at follow-up from several registries. Macrovascular complications T2DM is a major risk factor for cardiovascular disease (CVD), including myocardial infarction and stroke. Markers for early CVD, including carotid intima-media thickness, peripheral arterial stiffness and vascular endothelium, were reportedly higher than in adolescents with obesity and normal weight, even after short disease duration. The event rate for all adjudicated heart, vascular and cerebrovascular events was 6.4/1000 patient-years, which is triple the cardiovascular event rate seen in adults in the Diabetes Control and Complications Trial.
Diverse co-morbidities Co-morbidities impair the global health and quality of life of adolescents with T2DM and include the following. • Cognition – Poorer scores have been reported in several neurocognitive domains, particularly in executive functioning and memory. Differences in brain grey matter volume, white matter volume and microstructural integrity were shown in imaging studies.2 • Decreased bone mineral density – An age-related decline in bone z scores suggests an adverse impact of diabetes on bone mass attainment during puberty.3 • Disordered eating behaviours – At a mean age of 14.0 years, 6% had clinical and 20% had subclinical levels of binge eating.4 • Depression – About one-fifth endorse elevated depressive symptoms and about one-fifth endorse thoughts of self-harm.5 • Pregnancy – T2DM during pregnancy poses a long term impact, including increased risk for T2DM in offspring, in addition to the known neonatal and maternal complications.6
Multiple complications Data are still limited on the prevalence of multiple complications in single adolescents with T2DM. Data from the TODAY study on 500 participants at a mean age of 26.4±2.8 years and mean duration since diagnosis of 13.3±1.8 years showed that at least one complication occurred in 60.1% of the participants, two complications occurred in 21.3%, and 7.1% had three.7 Major complications such as blindness, amputations and dialysis have been reported,8 as well as serious cardiovascular events
Mortality During a median follow-up of 5.3 years, the mortality rate for T2DM was higher than for T1DM: 185.6 versus 70.6 deaths/100 000 patient-years.9 It was 2.4-fold higher than expected in the general population. Females had higher mortality rates than males. The leading underlying causes of death were motor vehicle accidents, accidental poisoning and intentional self-harm. These devastating sequelae indicate that T2DM in adolescents affects almost all organs and is more aggressive than T1DM, T2DM in adults, and simple obesity. Integrated aggressive medical interventions are needed. Orit Pinhas-Hamiel Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center; Sackler School of Medicine, Tel Aviv University, Israel
Princess Máxima Center, Utrecht,
The Netherlands, 7–8 October 2022
This 2-day event will discuss the aetiology of genetic and acquired hypothalamic dysfunction in childhood, its consequences and new ways of management to improve outcome. We will also focus on building new networks and collaboration within ESPE and Europe, together with patient organisations and Endo-ERN. Keynote lectures include: • The hypothalamus from an evolutionary point of view Dick Swaab, The Netherlands • Appetite-regulating hormones in hypothalamic obesity Hoog-Wei Gan, UK • Congenital disorders of hypothalamic dysfunction associated with hypopituitarism Mehul Dattani, UK • Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction Maithe Tauber, France • Hypothalamic syndrome in craniopharyngioma Hermann Müller, Germany • Hypothalamic dysfunction and hypothalamitis: a novel autoimmune endocrine disease? Fahrettin Kelestimur, Turkey • Radiation therapy and preserving hypothalamic function Geert Janssens, The Netherlands • Neurosurgical challenges in children with hypothalamic tumours Eelco Hoving, The Netherlands • Hypothalamic dysfunction requires individualised treatment Hanneke van Santen, The Netherlands Registration information will be available soon. We look forward to welcoming you to the 2022 ESPE Science Symposium.
22–26 September 2021 ‘Lifelong endocrine care through collaboration, discovery and innovation Over 3000 delegates registered for this year’s online ESPE Annual Meeting. They enjoyed a mixture of interactive sessions with live Q&A, including: • 8 plenary lectures • 8 ESPE Working Group • 13 symposia sessions • 7 ‘Meet the Expert’ sessions • 2020/2021 Award sessions • 2 controversy sessions • 3 Yearbook sessions • 2 ‘How do I?’ sessions • Live poster tours We welcomed participants from around the world: Thanks are due to Mehul Dattani, Poonam Dharmaraj and all the other members of the Programme Organising Committee for arranging such an engaging and interesting programme. All presentations are available to view by registered delegates until May 2022.
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