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Diabetes and insulin injection modalities: Effects on hepatic expression and activity of 11b-hydroxysteroid dehydrogenase type 1 in juvenile diabetic rats


Academic year: 2021

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Page no Subject Categories Abstract No.

Plenary Lectures

1 PL1 Environmental chemicals, brain development and human intelligence 1

1 PL2 Recent stories on the genetics of adrenal hyperfunction and tumors 2

1 PL3 Calcium-sensing receptor signalling in physiology and diseases 3

2 PL4 Genomic imprinting and evolution 4

2 PL5 Genetics of common and uncommon obesity 5

2 PL6 Cell therapy in Type 1 diabetes - ISPAD 6


3 S1 Innovative therapies in bone and mineral metabolism 1.1–1.3

4 S2 Genetics and epigenetics of thyroid dysgenesis 2.1–2.3

5 S3 Optimizing nocturnal diabetes control 3.1–3.3

6 S4 New avenues in paediatric autoimmune disease 4.1–4.3

7 S5 Mitochondrial dysfunction and endoplasmic reticulum stress in endocrine diseases 5.1–5.3

7 S6 Prevention of childhood obesity 6.1–6.3

8 S7 Overgrowth disorders 7.1–7.3

9 S8 Stem cells in endocrine organs 8.1–8.3

10 S9 Recent advances in congenital adrenal hyperplasia 9.1–9.3

11 S10 Endocrine management of preterms 10.1–10.3

Novel Advances & Controversies in Paediatric Endocrinology

13 NA Non-invasive prenatal diagnosis 1.1–1.2

13 NA Non-coding RNA in paediatric endocrinology 2.1–2.2

13 CON Challenges in the Management of DSD 1.1–1.4

Henning Anderson Award

15 HA1 KCNQ1 Mutations Cause Both Neonatal Diabetes and Hyperinsulinemic

Hypoglycaemia of Infancy 1

15 HA2 BOREALIN Mutations in Thyroid Dysgenesis Reveal a New Function of this

Protein in Cell Adhesion and Migration 2

Working Groups

17 WG1 ESPE Disorders of Sex Development Working Group (DSD) 1.1–1.6

18 WG2 ESPE Obesity Working Group (OWG) 2.1–2.5

20 WG3 ESPE Turner Syndrome Working Group (TS) 3.1–3.5

21 WG4 ESPE Bone and Growth Plate Working Group (BGP) 4.1–4.5

23 WG5 ESPE Diabetes Technology and Therapeutics Working Group 5.1–5.7

25 WG6 ESPE Paediatric and Adolescent Gynaecology Working Group (PAG) 6.1–6.5

26 WG7 ESPE Paediatric Endocrine Nurse Specialists and Allied Health

Professionals Working Group (PENS) 7.1–7.5

Free Communications

28 FC1 Adrenals 1.1–1.6

30 FC2 Bone & Mineral Metabolism 2.1–2.6

33 FC3 Pituitary 3.1–3.6


39 FC5 Management of Disorders of Insulin Secretion 5.1–5.6

41 FC6 Syndromes: Mechanisms and Management 6.1–6.6

44 FC7 Gonads & DSD 7.1–7.6

46 FC8 Growth: Clinical 8.1–8.6

49 FC9 Pathophysiology of Disorders of Insulin Secretion 9.1–9.6

52 FC10 Perinatal Endocrinology 10.1–10.6 55 FC11 Thyroid 11.1–11.6 57 FC12 Neuroendocrinology 12.1–12.6 60 FC13 Management of Obesity 13.1–13.6 63 FC14 Growth : Mechanisms 14.1–14.6 65 FC15 Late Breaking 15.1–15.6

Rapid Free Communications

69 RFC1 Adrenals 1.1–1.8

72 RFC2 Bone & Mineral Metabolism 2.1–2.8

76 RFC3 Pituitary 3.1–3.8

80 RFC4 Pathophysiology of Obesity 4.2–4.7

83 RFC5 Management of Disorders of Insulin Secretion 5.1–5.8

87 RFC6 Syndromes: Mechanisms and Management 6.2–6.8

91 RFC7 Gonads & DSD 7.1–7.8

94 RFC8 Growth: Clinical 8.1–8.8

98 RFC9 Pathophysiology of Disorders of Insulin Secretion 9.1–9.8

101 RFC10 Perinatal Endocrinology 10.1–10.8 104 RFC11 Thyroid 11.1–11.7 108 RFC12 Neuroendocrinology 12.1–12.8 111 RFC13 Management of Obesity 13.1–13.8 114 RFC14 Growth : Mechanisms 14.1–14.8 118 RFC15 Late Breaking 15.1–15.8 Poster Presentations 122 Adrenal P1 P1-P1–P1-P48 143 Adrenal P2 P2-P49–P2-P97

162 Bone & Mineral Metabolism P1 P1-P98–P1-P145

181 Bone & Mineral Metabolism P2 P2-P146–P2-P189

198 Diabetes P1 P1-P190–P1-P261

228 Diabetes P2 P2-P262–P2-P334

255 Gonads & DSD P1 P1-P335–P1-P382

275 Gonads & DSD P2 P2-P383–P2-P441

298 Fat Metabolism and Obesity P1 P1-P442–P1-P489

319 Fat Metabolism and Obesity P2 P2-P490–P2-P545

342 Perinatal Endocrinology P1 P1-P546–P1-P569

352 Perinatal Endocrinology P2 P2-P570–P2-P592

362 Growth P1 P1-P593–P1-P640

382 Growth P2 P2-P641–P2-P687

399 Endocrinology and Multisystemic Diseases P1 P1-P688–P1-P699

405 Endocrinology and Multisystemic Diseases P2 P2-P700–P2-P721

414 Pituitary and Neuroendocrinology P1 P1-P722–P1-P757

429 Pituitary and Neuroendocrinology P2 P2-P758–P2-P797

444 Syndromes: Mechanisms and Management P1 P1-P798–P1-P833

461 Syndromes: Mechanisms and Management P2 P2-P834–P2-P883

481 Thyroid P1 P1-P884–P1-P931

501 Thyroid P2 P2-P932–P2-P980

521 Late Breaking P1 LBP1–LBP13



Plenary Lectures


Environmental Chemicals, Thyroid Hormone and Human Intelligence

Barbara Demeneix Paris, France

Thyroid hormone is the only hormone for which all babies are screened at birth. This is because it has been known for decades that the consequences of thyroid hormone insufficiency during postnatal development, cretinism, are severe and irreversible. However, the last 15 years have witnessed major, and unexpected, insights how thyroid hormone acts during prenatal brain development across vertebrates. For instance, even mild maternal hypothyroidism or hyperthyroidism during early pregnancy are associated with IQ loss and modified brain structure in their children. Other recent insights include the tight control of tissue thyroid hormone levels by deiodinases and the existence of membrane thyroid hormone transporters (THTs). Mutations in THTs are associated with Allen Dudley Hernon syndrome, a severe form of intellectual and physical disability. In parallel to this increased understanding, we are witnessing an unprecedented increase in autism spectrum disorders (ASD) incidence, often correlated with IQ loss. Although, changes in diagnosis and awareness contribute to the ASD increase, many authors consider that environmental factors are implicated. Four arguments support this hypothesis. First, numerous chemicals are found routinely in human amniotic fluid including, pesticides, plasticizers (such as phthalates, BPA), nitrates, perchlorate, antimicrobials (such as Triclosan), flame-retardants, surfactants and mercury. Second, many chemical categories are demonstrated thyroid hormone disruptors. Third, prenatal exposure to many chemicals is significantly associated with IQ loss and/or increased ASD risk. Fourth, chemical production has risen exponentially in the last few decades, continually increasing exposure. I shall present data on how we exploit the evolutionary conservation of thyroid signalling to use transgenic Xenopus as a screening tool for environmental chemicals affecting thyroid hormone signal-ling and brain development. I shall also consider the evidence that interference with thyroid hormone orchestration of human brain development could be implicated in the observed increase in neurodevelopmental disease as well as in significant IQ loss at a population level, engendering enormous socio-economic costs.


Recent Advances in the Genetics of Adrenal Hyperfunction and Tumours

Je´roˆme Bertherat Paris, France

There is a variety of unilateral adrenocortical tumors (ACT) and bilateral nodular adrenal hyperplasias that can be responsible for Cushing’ syndrome. Before puberty the most frequent are adrenocortical cancer (ACC) or micronodular adrenocortical hyperplasia (MiAH). The most classic form of MiAH is primary pigmented nodular adrenocortical dysplasia (PPNAD), diagnosed in more than two-third of Carney Complex patients. In adults adrenocortical adenomas (ACA) and primary bilateral macro-nodular adrenal hyperplasia (PBMAH) along with ACC can causes various level of cortisol dysregulation, ranging from non secreting tumors to overt-Cushing. Recently, genomics led to spectacular and fast progress in the identification of genetic and epigenetic alterations of all type of ACT. Exome sequencing identified somatic activating mutations of the catalytic subunit of PKA (PRKACA) in ACA responsible for overt-Cushing. Combining pangenomic snp analysis and whole genome sequencing led to the identification of inactivating germline mutations of a new tumor suppressor gene, ARMC5, in PBMAH. The identification of ARMC5 as a gene frequently altered in adults with PBMAH revealed the hereditary nature of this disease. The use of combined genomics in ACC has shown alterations of key driver genes like CTNNB1 (b-catenin), TP53, ZNRF3, and demonstrated frequent epigenetic changes at 11p15 (IGF2 locus). With these progress the alterations of the cAMP and the Wnt/b-catenin signaling pathways are now clearly described. Interestingly, activation of the cAMP pathway lead to benign and small unilateral or bilateral tumors with a very high steroid synthesis capacity causing overt-Cushing. On the other hand activation of the Wnt/b-catenin signaling pathways seems to be mostly observed in more aggressive tumors with a lower secretion capacity. These progress offer not only new molecular tools for genetic predisposition screening and molecular classification of adrenal causes of cortisol excess, but also open new perspectives for therapeutic development.




“Genomic Imprinting and Evolution” Robert Feil

Montpellier, France

Genomic imprinting in mammals is controlled by DNA methylation. This essential epigenetic phenomenon mediates the mono-allelic expression of about hundred autosomal protein-coding genes and hundreds of regulatory non-protein-coding RNAs, such that these become expressed from one of the two parental alleles only. Although the first imprinted genes were discovered less than thirty years ago, given their key roles in fetal development, homeostasis and brain functions, these exceptional genes have been studied in great detail. For many, dosage is critical and environmentally-induced or stochastic perturbations cause disease. Evolutionarily, imprinting is a young phenomenon which arose at the time that placentation became more important for development with a growing dependence on maternal resources postnatally. Amongst the youngest, most recently evolved, imprinted genes many are imprinted in the placenta only, and different studies have linked their expression to fetal growth. The recent discovery of polymorphic imprinting in humans suggests that the evolutionary process is still ongoing. The underlying reasons are debated and different evolutionary theories

have been proposed. Imprinting research evolves fast as well and has boosted our understanding of endocrine and other imprinting-related disorders. A challenge for the future will be to unravel the relative importance of genetic versus epigenetic alterations in the emergence of imprinted gene expression, and in its pathological perturbation in animals and humans.


Abstract unavailable.





Innovative Therapies in Bone and Mineral Metab-olism: Anti FGF23 in X-linked Hypophosphatemia Thomas Carpenter


Background: Hypophosphatemia due to excess urinary

phosphate losses and rachitic bone disease occur in several related disorders. The most common form of the heritable hypopho-sphatemic disorders, X-linked hypophosphatemia (XLH), is due to loss-of-function mutations of the osteocyte/osteoblast protein, PHEX. Reduced abundance of phosphate transporters on the luminal surface of renal tubular cells in the syngeneic animal model of XLH, and inappropriately normal (or frankly low) circulating levels of 1,25 dihydroxyvitamin D (1,25D) are characteristic of the disease. Thus currently available therapies for XLH employ supplementation with phosphate and 1,25D. Objective and hypotheses: Current replacement with phos-phate and 1,25D is cumbersome, and fraught with complications. As the excessive renal phosphate losses and reduced capacity to maintain normal circulating 1,25D levels appear to be direct effects of increased FGF23 activity, we hypothesized that inhibition of FGF23 would serve to ameliorate the primary renal abnormalities, and restore a milieu conducive to the restoration of mineralization. Method: This talk will review potential strategies to improve therapeutic outcomes for children and adults with XLH, focusing on several clinical studies using an anti-FGF23 inhibitory antibody (KRN23). Results: Administration of KRN23 every 2–4 weeks corrects serum phosphate and improved 1,25D in adults and children. Improved patient-reported outcomes have been docu-mented in adults and radiographic improvement in rickets scores is evident in growing children. Conclusion: Patients affected with XLH would benefit from a more effective and better-tolerated therapy than the currently available approaches. Inhibition of FGF23 activity using an anti-FGF23 inhibitory antibody appears to be a safe and effective strategy to improve biochemical status, rickets, and well-being for patients with this disorder.


“Denosumab as an Alternative to Bisphosphonates in Osteogenesis Imperfecta”

Eckhard Schoenau Cologne, Germany

Osteogenesis imperfecta (OI) is a hereditary disease charac-terized by skeletal findings like increased fracture rate, deformed long bones and vertebral compression fractures. Non-skeletal findings include hypermobility of joint, hearing and dental impairments and weakness of collagen involving structures like

vessels and valves. Therapy is based on an interdisciplinary approach including orthopaedic surgery to correct deformities, physiotherapy to increase musclefunction and pharmacological treatment. During the last two decades antiresorptive therapy with bisphosphonates are more and more frequently used to treat patients with moderate or severe types of OI. Bisphosphonates bind permanently to the bone and stay there for many years or decades. Bisphophonates are frequently used to treat osteoporosis in elderly but they are only approved for the treatment of OI in very few countries. When treating children special caution has to be given to long term side effects. In the treatment of osteoporosis concerns about impairments of bone remodelling after longtime bisphosphonate treatment have been raised regarding occurrence of pathological fractures (femur) and osteonecrosis of the jaw. Recently the RANKL-Antibody Denosumab has become available for the treatment of postmenopausal osteoporosis and is also approved in a few other oncological indications with increased bone resorption. A benefit of the antibody might be the direct interaction with the osteoclasts and a complete resorption after a few months. Denosumab has been used in very rare indications in children and has proven to be highly effective in reducing osteoclastic activity. In a growing skeleton it seems that the risk of a severe hypocalcemia after application is more prominent than in adults and calcium has to be monitored closely and substituted with high doses of oral calcium for a few weeks. A pilot trial of 1 year involving 10 severely affected OI children showed a higher increase of areal bone mineral density (aBMD) than it was achieved during the previous treatment with bisphosphonates. It has to be kept in mind that it is not clear which would be the best aBMD for OI patients. Special concerns have to be given to a rebound hyper-calcemia and -calciuria at the end of the treatment period which might cause nephrocalcinosis and calcification of vessels and has to be studied in detail in the future.


Advances in Treatment of Achondroplasia Laurence Legeai-Mallet

Paris, France

Skeletal development is a temporally-regulated non-linear process orchestrated by a complex genetic network that proceeds via two distinct ossification mechanisms, namely membranous and endochondral ossification. Genetic disorders of the skeletal system affect both bone and cartilage formation from early fetal development up to post-natal growth. Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Achondroplasia is the most common form of dwarfism; it involved FGFR3 gene mutations, in which skull, appendicular and axial skeletons are affected. The understanding of disease mechanisms lead to targeted treatment. To date, the development of innovative therapies to treat achondroplasia is expanding. Several potential therapeutic strategies have emerged. Preclinical studies have been carried out: e.g. C-type natriuretic peptide analog (BMN111), intermittent PTH injections, soluble FGFR3 therapy, Meclozine, Statin and pan-FGFR tyrosine kinase inhibitor (NVP-BGJ398) treatments. Among the putative targets to antagonize FGFR3


signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by down-regulating the MAPK pathway, which is activated as a result of FGFR3 gain-of-function mutation. Today, BMN111 (vosoritide) is currently in clinical trial (phase 2) in pediatric patients with ACH. The first data show the improvement of the growth velocity in children with ACH and support the further development of vosoritide for the treatment of children with achondroplasia with open growth plates.


Determination of Autosomal Monoallelic Expression in Thyroid Tissue Assessed by Whole-Exome and Bulk RNA Sequencing: A Role in Thyroid Dysgenesis, Autoimmunity and Cancer

Johnny Deladoey Montre´al, Canada

Background and hypotheses: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a disorder with a prevalence of one in 4,000 live births, the cause of which remains unknown. The most common diagnostic category is thyroid ectopy, which occurs in up to 80% of CHTD cases. CHTD is predominantly not inherited and has a high discordance rate (O92%) between monozygotic (MZ) twins. The sporadic nature of CHTD might be explained by somatic events such as autosomal monoallelic expression (AME), given that genes expressed in a monoallelic way are more vulnerable to otherwise benign heterozygous genetic or epigenetic mutations. Objective: To search for complete (90%) AME in normal and dysgenetic thyroid tissues. Method: Aggregated analysis of whole-exome and bulk RNA sequencing performed on two ectopic thyroids, four normal thyroids and the human thyroid cell line Nthy-ori. Results: A median of 5,062 (range 2,081–5,270) genes per sample showed sufficient numbers of heterozygous SNPs to be informative. The median monoallelic expression represented 22 (range 16–32) of the informative genes for each thyroid sample. Examples of genes displaying AME are FCGBP, ZNF331, USP10, BCLAF1 and some HLA genes; these genes are involved in epithelial-mesenchymal transition, cell migration, cancer and immunity. Conclusion: AME may account for the high discordance rate observed between MZ twins and for the sporadic nature of CHTD. Our findings have also implications for other pathologies including cancers and autoimmune disorders of the thyroid.


Genetics of Thyroid Dysgenesis and Associated Malformations

Michel Polak Paris, France

Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine sufficient regions. TD includes a broad spectrum of developmental anomalies varying from absence of thyroid (athyreosis) to an abnormally located thyroid (ectopy), small (hypoplasia) or asymmetric thyroid. Thyroid dysgenesis is usually sporadic, but up to 2% of cases is familial. Genetics of TD is complex and advances in develop-mental biology over the past two decades revealed monogenetic forms of TD. But these monogenetic forms represent less than 10% in TD and to date the discordance between monozygotic twins remains unexplained. However, inheritance of TD is not based on a simple Mendelian pattern and additional genetic elements might contribute to the wide spectrum of observed phenotypes. Accumulating evidence supports the view that the genetics is complex, possibly on a polygenic/multifactorial or epigenetic basis. Developmental biology allowed the identification of candidate genes (thyroid transcription factors) and broadened the spectrum of associated malformations in Humans. Detailed phenotype of patients, up-to-date technologies (high-throughput sequencing), and relevant animal models are crucial to advance our knowledge of the mechanisms in normal and abnormal thyroid development. We will provide an update on known responsible genes, new genes discovered in our laboratory and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge and elucidate the enigma of TD. Our work on TD is partly financed, by the Fondation Je´roˆme Lejeune for the study of thyroid dysgenesis of Down syndrome in murine models, by Merck Serono France, Sandoz SAS France, Electricite´ de France, Princess Grace de Monaco Foundation, by Fondation Maladies Rares and by a national clinical research grant “PHRC”: ClinicalTrials.gov Identifier: NCT01916018.


New Insights in Thyroid Development Mikael Nilsson

Go¨teborg, Sweden

The mammalian thyroid gland stands out in comparison to other organs as it develops from no less than three independent anlagen that originate in anterior endoderm. The median or central anlage present in the pharyngeal floor gives rise to the thyroid bud or diverticulum that provides progenitors to the thyroxin-producing follicular cells. Bilaterally, the ultimobranchial bodies bud off from the inferior-most pharyngeal pouch. Until recently those structures were considered merely as vehicles that brought neuroendocrine C cells of neural crest origin to the embryonic thyroid; by genetic lineage tracing in mice this concept is now abandoned in favour of an endoderm origin of thyroid C cell precursors, thus indicting that both endocrine cell lineages of the thyroid are foregut derivatives. Defective development of the midline primordium produces a spectrum of anatomical malfor-mations collectively referred to thyroid dysgenesis, the most common cause of congenital hypothyroidism in humans. Only few of those patients have a mutation in today known thyroid


developmental genes. The presentation will summarize the roles of established and newly discovered genes in thyroid morphogenesis before the pituitary gets control of the embryonic thyroid. A new concept of thyroid growth reminiscent of branching in e.g. lung development will be introduced. Deficient C cell development has no clinical phenotype, but transcription factors implicated in embryonic growth and migration of C cell precursors from endoderm may shed new light on the pathogenesis of medullary thyroid carcinoma in children with MEN2B, which will be discussed. Finally, in view of the possibility that the first somatic mutation in childhood papillary thyroid cancer may arise already in the foetus or infant, recent progress in tracing oncogenically mutant cells with a fluorescent transgene, with the purpose to investigate directly in the microscope putative interactions with bystander normal follicular cells before tumorigenesis gets started, will be presented.


Sleep and Glycaemic Control in Children with Type 1 Diabetes

Karine Spiegel Lyon, France

Rapidly accumulating epidemiologic and experimental evi-dence has indicated that insufficient sleep, such as commonly experienced in modern societies by all age groups, reduces insulin sensitivity and impairs glucose metabolism in healthy adults, and increases the risk of incident type 2 diabetes. Studies in type 1 or type 2 diabetic adults show a link between reduced sleep quality or duration and poor glyceamic control. While poor diabetes control may impair sleep due to nocturia, nocturnal hypoglycemia disrupting sleep and the need for night-time diabetes care, the fact that prospective studies show a relationship between insufficient sleep and the development or aggravation of existing type 1 or type 2 diabetes suggests the existence of an opposite direction of causality. Studies that examined the link between sleep and glyceamic control/glucose metabolism in pediatric populations are scarce. Nevertheless, similarly to adult studies, experimental and cohort studies have reported an association between short sleep and insulin resistance in healthy children/adolescents. No study used objective assessment of sleep to examine the link between habitual short/poor sleep and glyceamic control in type 1 diabetic children/adolescents. In this presentation, we will show preliminary results from an ongoing longitudinal study that uses both subjective and objective measures of sleep to delineate which sleep characteristics (quality, duration, regularity) best predicts glyceamic control in type 1 diabetic children and adolescents. The magnitude of the associations between sleep disturbances and glyceamic control in our sample suggests that intervention studies aiming to pay a sleep debt and/or improve sleep regularity may be clinically relevant.


Optimising Nocturnal Glucose Control in Children with T1D: Therapeutic Implications

Thomas Danne Hannover, Germany

Background: Nocturnal hypoglycemia is not regularly predictable on the basis of a bedtime BG level and can only be confirmed by BG tests at regular intervals during the night or continuous glucose monitoring (CGM). Objective and hypotheses: A bedtime snack containing carbohydrate as well as fat and protein may be useful in preventing nocturnal hypoglycemia, but this should not be at the expense of high overnight BG levels. In many individuals, a lowering of the insulin dose after intense exercise should be considered to prevent nocturnal hypoglycemia. Short- and long-acting insulin analogues and continuous insulin infusion therapy may further decrease risk for nocturnal hypoglycemia. Method: Availability of CGM results in real-time (RT-CGM) to the patient with diabetes and immediate corrections to keep glucose levels in range have been shown to improve day and nighttime glycemic control more effectively than ‘blinded’ collection of data analyzed by a health provider retrospectively. Flash Glucose Monitoring (FGM) is the newest method of glucose testing that is seen as a hybrid between meters and CGMs. Results: FGM does not have hypo- or hyperglycemia alarms and will only provide a trend graph if it has been swiped in the past eight hours. However, the IMPACT trial in adults with type 1 diabetes has revealed significantly lower rates of nocturnal hypoglycemia also with FGM. While RT-CGM is beneficial in both patients using multiple daily injections and insulin pump users, the latter combination is more effective for nocturnal glucose control, particularly when combined with low glucose suspension algorithms or predictive low glucose management. Recently the success of conventional Real-Time CGM has led to the development of hybrid and full closed-loop insulin delivery systems, which have now reached the stage of clinical trials in patients’ homes. These trials repeatedly showed optimized nocturnal glucose control. A first commercial device may be available on the market as early as 2017. Conclusion: Diabetes technology offers novel opportunities to optimize nighttime glucose control and may eventually propel wide-spread adaptation and reimbursement of devices for insulin delivery and glucose monitoring.


Optimizing Nocturnal Diabetes Control: Optimising Insulin Delivery with New Technology: But Where is the Evidence?

Roman Hovorka Cambridge, UK

The use of insulin pumps is increasing particularly in the paediatric population with between 50% to 74% pump users below the age of 6 years. Real-time continuous glucose monitoring


enables greater understanding of glucose excursions, provides low and high glucose alarms, and facilitates more responsive insulin dose adjustments. An enhancement of the sensor-augmented insulin therapy pump is the low-glucose suspend (LGS) and predictive low glucose management (PLGM) features reducing the risk of hypoglycaemia in hypoglycaemia prone individuals. The LGS function allows insulin to be automatically suspended for up to two hours when sensor glucose falls below a present threshold. The hypoglycaemia-prediction algorithms and automatic pump suspension enable insulin delivery to be suspended when hypoglycaemia is predicted. The Artificial Pancreas (closed loop system) automatically delivers insulin according to real-time sensor glucose levels, below and above preset insulin amount, combining glucose sensor, insulin pump and a control algorithm, to achieve as much as possible functionality of a healthy pancreas. In youth, closed-loop prototypes have been tested extensively under controlled laboratory conditions demonstrating reduced risk nocturnal hypoglycaemia and increased time in target glucose range. The risk of hypoglycaemia may be further reduced with the use of bihormonal (also known as dual-hormone) closed-loop systems delivering subcutaneous glucagon when hypoglycaemia is observed or predicted. Pioneering home studies have been performed to demonstrate benefits during free living. Performance of closed-loop systems is damped by variable and relatively slow absorption of currently available rapid-acting insulin analogues, which delays onset and prolongs insulin action. This may attenuate daytime closed-loop performance due to rapid glycaemic fluctuations observed during meal-times and exercise, as reflected by relatively better closed-loop glycaemic performance overnight compared to daytime.


Activating Mutations in STAT3 Leading to Early-Onset Multi-organ Autoimmune Disease

Megan Cooper MO, USA

Background:Monogenic disorders of the immune system are increasingly recognized as a cause of early-onset immune dysregulation and autoimmunity. We recently identified 13 patients with a newly-described syndrome of early-onset polyautoimmunity, including endocrinopathies, and immune deficiency caused by gain-of-function (GOF) variants in the STAT3 gene. STAT3 is a highly conserved transcription factor that affects cytokine-induced changes in gene expression. Patients bearing germline, loss-of-function STAT3 variants suffer from recurrent infections. Somatic, gain-of-function (GOF) mutations in STAT3 are associated with cancers. The identification of early-onset autoimmunity caused by germline STAT3 GOF variants thus represents a third category of disease caused by alterations in STAT3. Objective and hypotheses: The objectives of this talk are to discuss this recently identified syndrome of STAT3 GOF including review of clinical and immunological features of this disorder, potential mechanisms of disease, and therapeutic

strategies. Method: There have been more than 20 patients reported with autoimmunity associated with GOF STAT3. I will review the clinical features of these patients and recent work from our laboratory investigating the mechanism of immune dysregula-tion due to STAT3 GOF. Results: Patients with STAT3 GOF present at a young age (average 4 years), usually with autoimmunity of two or more organ systems. Cytopenias are the most common autoimmune disease, and others include type I DM (including neonatal onset), enteropathy, lung disease, thyroid disease, and arthritis. The majority of STAT3 GOF patients have short stature, for unclear reasons but possibly due to impaired STAT5b signaling. Analysis of T cell populations shows decreased peripheral blood regulatory T cells (Tregs). Recent studies from our laboratory suggest impaired Treg differentiation and enhanced Th17 differentiation directly caused by STAT3 GOF variants. Therapies have included immune suppression, stem cell trans-plantation, and anti-IL-6R. Conclusion: STAT3 GOF is a cause of early-onset autoimmunity. While the cause of immune dysregula-tion has not been fully elucidated, there are indicadysregula-tions that dysregulation of T cell differentiation may contribute to disease.


Abstract unavailable


Type 1 Diabetes: Lessons from nPOD Pathology and Clinical Trials

Alberto Pugliese Miami, Florida, USA

Type 1 diabetes (T1D) is considered chronic autoimmune disease in which autoreactive T-cells and inflammation cause severe loss of pancreatic beta cells. Insulitis, the pathologic hallmark of T1D, is an inflammatory lesion consisting of immune cell infiltrates around and within the islets. New research initiatives and methodologies are advancing our understanding of pancreas pathology. A major impetus to the field has been given by the institution of the JDRF nPOD (Network for the Pancreatic Organ donor with Diabetes, www.JDRFnPOD.org); nPOD recovers and provides pancreata from organ donors with T1D to the scientific community and facilitates collaborative studies about the pathogenesis and pathology of T1D. Studies by several nPOD investigators have revealed the predominant cellular types that infiltrate the islets, novel molecular aspects associated with insulitis, and the coexistence of additional pathological abnorm-alities. While insulitis is a critical element of T1D pathogenesis, it is present only in a modest proportion of islets at any given time, even at diagnosis, with overall limited relation to disease duration. Thus, the relative importance of insulitis as a determining factor of diabetes symptoms at diagnosis may be overestimated; at the same


time, growing evidence shows that beta cell loss at diagnosis is more modest than previously thought, and co-existing beta cell dysfunction may be a key contributor to insulin deficiency at diagnosis. This recognition has relevance for the design of clinical trials, as targeting the immune system only may have limited therapeutic efficacy. Combination therapies that promote both immunoregulation and address beta cell dysfunction should be more effective in treating this chronic disease process. It remains a major goal to clarify the relation of insulitis with the dynamics of beta cell loss and coexisting mechanisms of dysfunction, according to clinical stage; such improved understanding is key to design therapeutic strategies that target multiple pathogenic mechanisms.


Wolfram Syndrome, a Prototype of ER Stress-Induced Beta Cell Death

Fumihiko Urano MO, USA

Background:Endoplasmic reticulum (ER) participates in so many cellular tasks that trouble can ensue when it stops working properly, including b cell death in type 1 and type 2 diabetes mellitus. Despite the underlying importance of ER dysfunction in bcell death during the progression of diabetes, there is no effective treatment targeting the ER due to the complex etiologies of type 1 and type 2 diabetes. Objective and hypotheses: Our strategy for overcoming this challenge is to focus on genetic forms of diabetes in which mutations in single genes are involved in ER dysfunction and disease manifestations. Method: Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by juvenile-onset diabetes, optic nerve atrophy, hearing loss, and neurode-generation. The prevalence is estimated at 1:200,000-1:700,000. Caused by mutations in the WFS1 gene, Wolfram syndrome is considered a prototype of human ER disease. Diabetes mellitus is typically the first manifestation, usually diagnosed around age 6. We have recently shown that ER calcium depletion, followed by subsequent increase in cytoplasmic calcium levels, is a common molecular pathway altered in b cell models of type 1 and type 2 diabetes, as well as Wolfram syndrome. Results: We have recently shown that ER calcium depletion, followed by subsequent increase in cytoplasmic calcium levels, is a common molecular pathway altered in b cell models of type 1 and type 2 diabetes, as well as Wolfram syndrome. Conclusion: In this lecture, I will articulate the role of ER stress in b cell dysfunction and death in Wolfram syndrome and its relevance to type 1 and type 2 diabetes, and discuss a therapeutic strategy targeting the ER for diabetes.


Abstract unavailable


Activation of HSP 72: A Therapeutic Target for Diseases Related to both ER Stress and Mitochondrial Dysfunction

Mark Febbraio NSW, Australia

Over the past decade, work from our research group has demonstrated that over-expression or activation of the chaperone protein heat shock protein 72 (HSP72; the inducible form of the 70kDa family of heat shock proteins) in skeletal muscle reduces obesity-induced insulin resistance (for review see). These findings led to the development of the small molecule activator of HSP72, namely BGP-15 which, in pre-clinical studies, has proven to be effective in the treatment of several diseases including type 2 diabetes, atrial fibrillation and Duchenne Muscular Dystrophy. While we originally ascribed the mechanism of action of HSP72 activation to preventing inflammation and endoplasmic reticulum (ER) stress, we have recently shown that HSP72 is both necessary and sufficient to maintain mitochondrial structure and function in the context of obesity and insulin resistance. These recent results are most significant as they suggest that HSP72 may be a therapeutic target for not only T2D, but for conditions in which mitochondrial function is impaired. Recent work on the role of activating this pathway on both ER stress and mitochondrial structure and function and its relationship to cellular function will be discussed in this presentation.


Long-term Consequences of Childhood Obesity: The Impact of Genes and Lifestyle

Paul Franks Malmo¨, Sweden

In most complex traits, susceptibility to certain risk exposures and response to clinical interventions in is under genetic control, a concept broadly termed “gene-environment interaction”. Although in animals and in plants there is evidence supporting this notion, in humans most evidence is confined to rare monogenic disorders. In complex diseases like type 2 diabetes and obesity, interactions between genetic and environmental risk factors are likely to begin very early in life, perhaps even pre-conception. Of the hundreds of published studies, several stand out as having been replicated across diverse settings, although most have not, and even those that are replicated often lack robust evidence of mechanisms or causality. My lecture will begin by overviewing the rationale and the approaches used to studies gene-lifestyle interactions. I will begin by focusing on early life risk factors and the likely mechanisms of interaction between genes and the early life environment. I will also overview some of the evidence for gene-lifestyle interactions in type 2 diabetes and obesity later in life. I will end by speculating on how research in this field might evolve in the next decade and how doing so might lead to better disease prevention and treatment.



Early Childhood Life Style Intervention and Obesity Outcome

Claude Marcus Stockholm, Sweden

Background:Treatment of childhood and adolescent obesity is rarely effective if “cure” i.e., BMI below the obesity range, is used as the definition of success. However, results of obesity treatment is much more effective if treatment is initiated in 6–7 years old children. It is therefore urgent to develop interventions for young children, both preventive and obesity treatment efforts. Results from such interventions as well as preliminary results from ongoing studies will be presented. Results: Population-based prevention studies for young children such as Idefics, Primrose and many others have shown limited results when weight has been the main outcome. Improved parental knowledge about eating habits has been reported and in some studies also short-term effects on weight development have been observed. Early STOPP (Stockholm Obesity Prevention Project) is an ongoing longitudinal randomized controlled study from 1–6 years of age where obese and overweight parents with 1 year old children are targeted. It is well known that their children have a 5–10 times higher risk to develop obesity early in life. Promising results from the first 2–3 years of the intervention based on MI delivered support regarding sleep, physical activity and eating habits provided by health coaches will be presented. It is also unclear if obesity treatment is effective in young children, 4–5 years old. Preliminary results from the More or Less study where parents to 4–5 years old children with obesity are randomized to either to a program focused on parental skills or to standard care will also be presented. Conclusion: Taken together, the effectiveness of published interventions is limited and we need to learn and accept from these studies what is ineffective so we don’t repeatedly carry through the same ineffective studies only because we hope it will work – next time. However there are some promising interven-tions indicating that it is possible to reduce overweight and obesity at an early age.


Childhood Obesity Prevention: What Do We Need and How Are We Doing? A European Perspective

Johannes Brug

Amsterdam, The Netherlands

The worldwide prevalence of overweight and obesity has been steadily increasing, also among children and adolescents, and has reached alarming pandemic proportions in Europe and elsewhere. Childhood overweight is a main predictor of adult overweight and obesity. Obesity treatment is largely ineffective, and a still stronger focus on primary prevention is needed. Such prevention should take a population and a life course approach and should focus on promoting healthy energy balance-related behaviors rather than weight management or weight loss. To encourage and facilitate

healthful energy balance behavior, we need insight in the ‘causes of the causes’, i.e. in why children and their parents eat too much and move too little. Energy balance-related behaviors (sufficient healthy physical activity, healthy eating, and less sedentary time) are a result of personal motivations and abilities, and contextual or environmental opportunities. It is not personal determinants or environmental opportunities that make a difference; it is mediation and interaction between and across these ‘causes of the causes’ that drive healthful behaviors. To effectively encourage and facilitate healthful energy balance beahviors, health promotion efforts (to improve motivation and abilities), as well as health protection efforts (to make the healthy choice the default choice) are needed. Such an integrated approach needs to be supported by participation of the main stakeholders in all phases of intervention and policy development, implementation and evaluation. Such integrated prevention approaches have and are being developed and tested across Europe. In this presentation the rationale, data, results, ongoing efforts for cross-European research will be presented - such as the European Commission funded ENERGY (EuropeaN Energy-balance Research to prevent excessive weight Gain among Youth), and SPOTLIGHT (Sustainable prevention of obesity through integrated strategies) projects, as well as results from the European DEDIPAC (Determinants of DIet and Physical ACtivity knowledge hub) joint action.


Abstract unavailable


Abstract unavailable


The Role of GPR101 in Human Growth Constantine Stratakis, Fabio Faucz, Giampaolo Trivellin Bethesda, USA

We recently showed that Xq26.3 microduplications are associated with early childhood-onset gigantism, a condition we named X-linked acrogigantism (X-LAG). Patients with X-LAG present with mixed GH/PRL secreting pituitary macroadenomas and/or hyperplasia. The original smallest region of overlap for the microduplications included 4 coding genes, of which only one, an orphan G protein-coupled receptor named GPR101, was highly expressed in tumors. A single patient with GPR101


microduplication only was recently reported: this proves that GPR101 overexpression alone may cause gigantism. GPR101 was found to be expressed at very low levels or was not expressed in almost all adult human tissues examined, with the exception of specific regions of the brain, including the nucleus accumbens. High expression of GPR101 was observed in the human fetal pituitary but not in adult pituitary tissue and in pituitary tumors other than those with Xq26.3 defect. In contrast to human tissues, adult pituitaries of both rhesus monkey and rat expressed GPR101. However, the pituitary cell type expressing this receptor differs: gonadotrophs in monkeys and somatotrophs in rats express GPR101. In the developing zebrafish embryo, GPR101 showed a bimodal expression pattern: expression levels progressively waning during the first cell divisions (presumably representing maternal transcripts) and then gradually rising with the appearance of the first somites. Beginning at 48 h post-fertilization a strong and brain-specific staining including part of the hypothalamus and pituitary was seen. These studies show that GPR101 is likely to be a significant regulator of growth; the brain is the major site of GPR101 expression across different species, although divergent species-specific expression patterns are evident, especially con-cerning the pituitary. Differences among species might reflect their different growth, development and maturation patterns. It is also interesting to note that the highest GPR101 expression levels in adult human tissues were observed in the nucleus accumbens, which plays an important role as the reward center, hinting that GPR101 might also be involved in the regulation of food seeking behaviors, in addition to growth and/or puberty.


Novel Function of Pituitary Stem Cells during Organ Homeostasis

Cynthia Lilian Andoniadou London, UK

Background: Using genetic lineage tracing in the mouse pituitary, we previously revealed that SOX2 positive cells can act as stem cells in vivo and contribute to all hormone-secreting cell types during postnatal life. However, SOX2-expressing stem cells are not the sole source of new endocrine cells, instead they complement contribution from more committed cell types during organ homeostasis. Objective and hypotheses: We seek to determine key signalling mechanisms required to regulate organ turnover, since their disruption can underlie disease states e.g. organ failure or the formation of tumours. The WNT signalling pathway plays critical roles in stem cell function of many organs and pathway elevation in pituitary stem cells leads to tumours. Our aim is to understand the function of the WNT pathway during normal pituitary physiology, specifically if it is required for proliferation and to identify sources of WNT signals. Method: By combining genetic and molecular approaches we are able to manipulate the WNT pathway in the pituitary and to label WNT-responsive cells and follow their fates. Results: We find that WNT-responsive cells contribute the major source of new cells to

organ turnover. Unexpectedly, we uncover that SOX2-expressing stem cells secrete WNT ligands, thus acting as critical regulators of homeostasis in a paracrine manner. Conclusion: Pituitary stem cells contribute to the organ both directly through the generation of new cells, as well as indirectly through acting as essential niche cells promoting proliferation of more committed cell types. This represents a key step towards understanding the mechanisms controlling stimulation of new cell generation in situ, with an impact on future regenerative medicine approaches.


Pluripotent Stem Cells in Endocrinology Rudolph L. Leibel


The ability to differentiate human embryonal stem cells (hESC) and induced pluripotent stem cells (hiPSC) into virtually any cell type has enabled the creation of cellular models of diseases for which human cells are not readily accessible. Using these strategies, we have examined the molecular pathogenesis of monogenic forms of diabetes such as Wolfram’s syndrome and various MODYs using stem cell-derived insulin producing cells created from fibroblasts of patients with these disorders. Our recent development of a protocol for the generation of arcuate-type hypothalamic neurons from somatic cells of human subjects has enabled us to study the neurobiology of disorders such as Bardet-Biedl and Prader Willi syndromes, as well as disorders of proconvertase 1 activity. Using Crispr/Cas, we have both corrected beta cell and neuronal mutations in affected cell lines, and introduced mutations into unaffected cell lines. Such experiments allow the analysis of gene-gene interactions, the screening of molecules that may mitigate specific cellular phenotypes, and could ultimately provide transplantable cells for treatment of disease.


Hubs in the Pancreas David Hodson

Birmingham, UK

Background: The arrangement of beta cells within islets of Langerhans produces a gain-of-function in insulin release through the generation of rhythmic activity patterns. A privileged role for individual beta cells in orchestrating these responses has long-been suspected, but not directly examined. Objective and hypotheses: Identify and characterize a rare subpopulation of beta cells tasked with pacemaking insulin release. Method: Optogenetics, photopharmacology and photopainting approaches


were used to functionally interrogate and label single beta cells in situ within islets. Results: Specialized cells, termed hubs, possess lowered expression of beta cell identity markers (Pdx1, Nkx6.1, insulin etc) and are metabolically adapted, as evidenced by increased expression of glucokinase and elevated mitochondrial potential. Importantly, hubs are specifically targeted by proin-flammatory and glucotoxic insults to induce widespread islet dysfunction. Conclusion: The islet is wired by hubs, whose failure may contribute to type 1 and type 2 diabetes. Importantly, the finding that the beta cell population is heterogeneous has clear repercussions for the de novo construction of islets from stem cells, as well as treatment of diabetes.


Long-term Health in Congenital Adrenal Hyperplasia: Lessons from a National Study

Anna Nordenstro¨m Stockholm, Sweden

Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the cardiovascular and metabolic morbidity. The long term outcome in CAH was studied using the Swedish national CAH registry, 588 patients 335 females and 253 males, O80% with known severity of CAH; were compared with 100 controls per patient matched for sex, and year and place of birth. Information on mortalty, cause of death, morbidity, and psykosocial factors were derived through linkage of national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt-wasting, simple virilising, non-classic), CYP21A2 genotype (null, I2 splice, I172N, P30L) and before and after the introduction of neonatal screening. Results: The mean age of death was lower (41.2G26.9 vs 47.7G27.7 years (P!0.001). The hazard ratio of death was 2.3 (1.2–4.3) in males and 3.5 (2.0–6.0) in females. The causes of death were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). Metabolic disorders (OR 3.9), and cardiovascular disease (OR 2.7) were increased. Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), this was not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) and SW women were more likely to have an income in the top 20 percentile (OR 2.0). Both males and females had an increased psychiatric morbidity. In particular, the risk of substance misuse was increased with OR 2.8 in females and 1.9 in males and appeared most common among the girls and women with the most severe null genotype (OR 5.5). The risk of stress and adjustment disorders was doubled (OR 2.1). Conclusions:CAH was associated with excess mortality due to

adrenal crisis despite diagnosis and treatment. The salt-wasting phenotype seemed to have a worse outcome not only before the introduction of neonatal screening. Our studies show important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care. Late diagnosis may explain some of the findings. Those born before the introduction of neonatal screening were more affected, which may be explained by the higher age.


Recent Advances in CAH: New Approaches to Glucocorticoid Replacement

Richard Ross Sheffield, UK

Adult CAH patients have poor health outcomes and these in part relate to the method of glucocorticoid replacement in children and adults. Life-saving glucocorticoid replacement was introduced in the 1950s and the majority of children are treated with immediate release hydrocortisone whereas adults are treated with a mixture of hydrocortisone, prednisolone, prednisone and dexamethasone from one to four times daily and in circadian and reverse circadian regimens. Despite these personalised glucocorticoid treatments adult patients remain shorter than the normal population, have an increase in obesity and osteoporosis and impaired fertility and QoL. There are two major challenges in glucocorticoid replacement for CAH patients; prescribing the correct dose and replicating the cortisol circadian rhythm. At the present time there are no paediatric dose specific formulations of glucocorticoids making it challenging to titrate therapy in neonates and infants. Cortisol has a distinct circadian rhythm with low levels at night, rising in the early hours of the morning, peaking on waking, and declining over the day to low levels in the evening. Loss of this diurnal rhythm in CAH results in an early morning rise in androgen levels which is not controlled with current therapy. New technologies are being developed that deliver more physiological glucocorticoid replacement including a paediatric dose specific formulation, Infacort, hydrocortisone by subcutaneous pump, and Chronocort a delayed and sustained absorption hydrocortisone formulation that replicates the over-night profile of cortisol. Infacort is a multi-particulate hydrocorti-sone formulation with taste masking provided in doses of 0.5, 1, 2 and 5 mg that is bioequivalent to currently available immediate release hydrocortisone. Subcutaneous hydrocortisone infusions using insulin technology have been demonstrated to improve control of CAH in small case series. Chronocort has been shown to improve androgen control of adult patients with CAH in a phase 2 clinical trial. Future work will focus on optimising glucocorticoid replacement in CAH patients from birth to old age and demonstrating these treatments improve health outcomes.



Recent Advances in CAH: Treatments Saving GC Exposure

Richard Auchus MI, USA

Background: Glucocorticoid therapy in 21-hydroxylase deficiency (congenital adrenal hyperplasia, CAH) both replaces the cortisol deficiency and reduces adrenal androgen production. Androgen control, however, often requires supraphysiologic and/or nocturnal glucocorticoid exposure. Chronic treatment in this manner contributes to long-term complications observed in CAH cohorts, including high rates of obesity, low bone density, glucose intolerance, skin fragility, and excess mortality. While cortisol replacement remains mandatory, alternative non-gluco-corticoid agents to control androgen excess are desirable. Objective and hypotheses:We have explored 2 conceptually distinct approaches to lower adrenal androgen production in phase I trials: blockade of androgen synthesis and antagonism of corticotropin-releasing factor (CRF) action. Method: The first study included 6 women with classic CAH and serum androstenedione (AD) O1.5x the upper limit of normal (O12 nmol/l). These participants received 100 mg and 250 mg of the CYP17A1 (17-hydroxylase/17,20-lyase; P450c17 or P450 17A1) inhibitor abiraterone acetate (AA) for 6 consecutive days in sequential cycles of 100 or 250 mg/d. The second study employed a fixed-sequence single dose of 0, 300, or 600 mg of the CRF type 1 receptor antagonist NBI-77860 in 8 women with classic CAH. Results:In the AA study, mean first-morning AD for days 6 and 7 normalized in 5 of 6 participants at 250 mg/d. First-morning AD normalized in all participants on day 7 at 250 mg/d, and AD remained normal 2 to 8 h on day 6 at both doses. Testosterone (T) and its metabolites fell in parallel; hypertension and/or hypokalemia were not observed. In the NBI-77860 study, reductions of adrenocorticotropin and 17-hydroxyprogesterone were conclusively demonstrated in half of participants. Responses strongly correlated with drug exposure, providing evidence of target engagement. Conclusion: These studies demonstrate proof-of-concept for combination therapies using physiologic glucocor-ticoid dosing plus an agent to attenuate androgen production. Long-term studies of these and related drugs in children and adults with CAH are necessary to determine if these strategies are superior to conventional glucocorticoid therapy alone.


Glucose Metabolism and Management in Premature Babies

Kathryn Beardsall Cambridge, UK

Increasing numbers of infants are being born very preterm. These infants require intensive care and have a high risk of

mortality and morbidity which has been associated with both hyperglycaemia and hypoglycaemia. In utero, glucose levels are normally maintained between 4–6 mmol/l, but infants born preterm are exposed to significant periods of both hyperglycaemia and hypoglycaemia. Early postnatal glucose control may be an important modifiable risk factor for clinical outcomes. However challenges remain in reducing hyperglycaemia without increasing hypoglycaemia. Many physiological parameters are monitored continuously to prevent wide fluctuations and the development of real time continuous glucose monitors provides the opportunity to monitor glucose levels in the same way. Managing glucose control in the preterm infant is also challenging due to the marked variability in insulin sensitivity between babies. The development of computer based algorithms, that can use the wealth of data obtained from the frequent glucose levels obtained by continuous glucose monitoring, could provide for individualized guidance on insulin treatment. We have used the combination of real time CGMs alongside a computer based algorithm to manage preterm infants: to reduce the prevalence of hyperglycaemia without increasing the risk of hypoglycaemia. This will help determine the impact of different strategies for nutritional management and glucose control, and what is ‘optimal’ glucose control. It will be important to address the potential impact not just on short term outcomes but on longer term health.


The gonadotropic axis in premature babies Leo Dunkel

London, UK

Background: The transient postnatal activation of the hypothalamic-pituitary-gonadal (HPG) axis, also called “mini-puberty,” is a phenomenon during which gonadal hormone levels increase up to adult levels. Results: In boys gonadotropin and testosterone levels peak at one moths of age and are significantly higher in preterm than in full-term boys. Simultaneously, there is penile growth and the levels of prostate specific antigen increase, indicating increase in androgen effects. In preterm girls, FSH levels are extremely high after birth, but they decrease to similar levels as in full-term girls around the term age. Interestingly, when gonadotropin levels are assessed against postmenstrual age (i.e., age from the last menstruation of the mother) rather than chronological age (i.e., time from birth) the gonadotropin levels in premature infants actually decline to similar levels as in full-term infants at the same developmental stage suggesting that the duration of “minipuberty” is developmentally regulated. In girls, the decrease in FSH from its peak is associated with the maturation of antral follicles and increase of the follicle-derived AMH levels. Estradiol levels are higher in girls than in boys, but in girls the levels vary and do not display a similar uniform peak at one month as male testosterone levels. The growth of estrogen responsive target tissues (i.e., mammary glands and uterus) are maximally stimulated in full-term girls at birth by the high intrauterine estrogen whereas in preterm girls, the growth of the mammary


glands and the uterus are positively correlated with estradiol levels. Conclusion:The possible long-term significance of the observed differences in minipuberty between full-term and preterm infants requires further studies. These should include effects on reproductive development, childhood growth, bone mineral-ization, childhood psychosexual development, timing of puberty, sexual behaviour, and reproductive capacity in adulthood.


The Mineralcorticoid System and its Implications for Neonatal Adaptation in Premature Babies

Laetitia Martinerie Paris, France

Background and hypothesis: The neonatal period is

characterized by high urinary sodium loss, most notably in

preterm infants that questions the ability of the mineralocorticoid pathway to maintain sodium homeostasis. Results: We have demonstrated that neonatal sodium wasting is associated with a physiological renal aldosterone resistance in relation to a low renal mineralocorticoid receptor (MR) expression at birth in full-term infants, both in humans and mice, along with a down regulation of other mineralocorticoid signaling key-players. Moreover, very preterm infants present with defective aldosterone secretion while the kidney remains sensitive to aldosterone action owing to transient MR expression in the distal tubule during this period. Conversely, high circulating cortisol/corticosterone levels along with detectable renal glucocorticoid receptor are present at birth, consistent with functional glucocorticoid-signaling pathway both in preterm and full-term newborns. Conclusion: Thus, the neonatal period is characterized by defective mineralocorticoid signaling from two different mechanisms in preterm and full-term newborns, whereas renal glucocorticoid signaling is functional and very likely implicated in fetal programming. These results open new therapeutic possibilities for preterm infants in order to prevent from sodium wasting.


Novel Advances & Controversies in

Paediatric Endocrinology


Abstract unavailable.


Intrauterine Imaging Strategies for Bone Disease Yasemin Alanay

Istanbul, Turkey

Background:Fetal skeleton develops early in the fetal period. The appendicular and the axial skeleton undergo a programmed pattern of endochondral ossification, whereas the calvarium and portions of the clavicle and pubic bone ossify via membranous ossification. Disruption of the molecular mechanisms fine-tuning this process leads to osteo-chondrodysplasias (skeletal dysplasias) or dysostoses, namely genetic skeletal disorders. The 2015 revision of the Nosology and Classification of Genetic Skeletal Disorders provides a list of 436 disorders in 42 groups, and 364 related genes. Objective and hypotheses:Diagnosis of prenatal-onset genetic bone diseases mandates radiographic, clinical and molecular assessment. The combined use of these methods is essential for appropriate counselling of the parents. Information regarding the severity and natural history of an individual disorder is critical for the families and medical care providers. Method: In general, prenatal ultrasound (US) is currently the accepted modality for fetal assessment. Lethality should be determined based on US parameters and/or by molecular diagnosis. Those with a non-lethal condition may further be described as mild or severe. First trimester US, usually used for aneuploidy screening can identify severe, usually lethal skeletal dysplasias. Others are detected in the late second trimester, the remaining diagnosed in the third trimester or at birth. Imaging strategies have evolved in the last decade. Three-dimentional (3D) US is helpful in depicting and characterisation of the specific entity. Fetal magnetic resonance imaging (MRI) has also been documented to be useful for analysis of fetal spine and concurrent malformations. The most recent method is using 3D reconstructions of low dose computerized tomography images for prenatal evaluation. Results: The diagnosis of a genetic skeletal disorder is ideally made in the prenatal period to ensure accurate genetic counselling and provide a management plan before and after delivery. Imaging strategies are discussed with respect to possible outcome.


De.Coding Obesity – Control of Metabolism by the Noncoding Transcriptome

Jan-Wilhelm Kornfeld Cologne, Germany

The pervasiveness of noncoding transcription has revolutio-nized our understanding of gene regulation. Although not yet fully catalogued in terms of numbers, mammalian genomes express a broad spectrum of, small and long, noncoding RNAs. Whereas small noncoding RNAs like microRNAs and their role in energy metabolism and glucose handling are rather well understood, we have little understanding concerning the metaboregulatory properties of those 10,000s of long noncoding RNAs (lncRNAs) encoded in mammalian genomes. To adress this, we applied deep next-generation sequencing to quantify the expression of lncRNAs in two mouse models of obesity and insulin resistance. Intruigingly, we observed the majority of hepatic lncRNAs being downregulated in obese animals, whereas fasting increased lncRNA expression. Using in silico motif enrichment and ChiP-Seq analyses in coding versus noncoding gene promoters, we observed that noncoding promoters are enriched for binding events of smallMafs, a repressive class of transcription factors. Crucially, hepatic overexpression of smallMafs mimicked the obesity-evoked downregulation of the noncoding transcriptome and caused disturbancies in hepatic lipid handling, whereas antisense-nucleotide-mediated depletion of small Mafs prevented diet-induced obesity. Collectively, we here identified a novel signaling circuit coupling obesity-evoked changes in signal

transduction to global regulation of the Noncoding



Abstract unavailable.




Surgical Management of DSD: New Insights Sarah Creighton

London, UK

Traditional medical management of children born with atypical genitals includes genital surgery during early childhood. Young children cannot give informed consent and surgery is usually undertaken after a decision made by the multidisciplinary team with parental input. Long-term outcomes are uncertain and there is scanty research supporting the benefits of surgery on physical or mental well-being. Adult patients clearly describe the distress of multiple genital operations during childhood and repeated genital examinations. In addition small but increasing numbers of adolescents are now seeking to reassign gender and previous childhood genital surgery compromises this flexibility. However the impact on a family of a child with unexpectedly atypical genital anatomy should not be underestimated. Families find adjustment to the birth of such a child challenging and genital surgery is often the only or at least the main treatment option discussed. Many multidisciplinary teams are led by surgeons committed to genital surgery. In addition complex invasive surgery may be reimbursed at high tariffs for health care providers. Psychological support – although less costly – is often patchy or unavailable. Whilst parents may prefer to defer genital surgery until their child is old enough to take part in the decision making process, they may also feel ill-equipped to negotiate the undoubted challenges of childhood until that time. Credible non-surgical pathways with ongoing psychological support for the family currently do not exist. Current debate about the role of genital surgery is moving from clinical outcomes into the arena of human rights. It is probable that future decisions about normalising genital surgery will not remain in the hands of clinicians. Regardless of when this may happen, action must be taken now to develop and introduce non-surgical pathways as a matter of urgency. Parents need on-going support to acquire the skills and confidence to understand complex medical information, to be able to talk about genital differences and to de-medicalise sex and gender diversity. Without such support and given a choice between surgery and nothing, parents are still likely to choose genital surgery as the best – indeed perhaps the only – possible treatment option for their child.


Psychological Challenges Franco D’Alberton

Bologna, Italy

The new care paradigm for DSD promoted by the Chicago Consensus of 2005 raised many psychological challenges, the most important being the way decisions regarding the sex of rearing and diagnosis communication are made. The traditional care

paradigm, sustained by a binary sex categorization, suggested that for newborns, the decision about the sex of rearing should be made as soon as possible and no later than 18 months of life and that little should be said to the involved person in order to limit the potential effects of psychic trauma. New trends in DSD care are based on a more open conceptualization of gender, like in a bimodal continuum, where the subjective experience of the person and their full acknowledgement of their condition plays a major role. Moreover, experience has shown us that gender changes may happen in any stage of life. The decision about the sex of rearing of a newborn with a DSD challenges our knowledge, our ethical and moral certainties, our beliefs and personal opinions. Effective team work is necessary in order for individuals not to be overwhelmed by such a difficult process, maintaining the capacity to think together, thus avoiding shortcuts such as returning to previous ways of thinking. It is very important that healthcare operators work together, sharing their doubts, uncertainties and discussing the pros and cons of the possible choices in order to be able to help parents to cope with the new and unexpected situation. The aim of this close collaboration between specialists, beginning from birth or time of diagnosis, is to provide people living with DDS with the opportunity to live in an environment which is able to support the development of their personal, social and sexual identity as far as possible.


An Ethicist’s Viewpoint Clsssaudia Wiesemann Go¨ttingen, Germany

Decisions for children not able to consent must aim at promoting the well-being of the child and future adult and minimize physical and psychosocial risks. In atypical sex development, well-being is a complex category comprising physical and psychosocial health (present as well as long-term). The child has a right to a gendered identity, bodily integrity, fertility, quality of life including sexual life, and mental health. However, patient well-being is a normative concept and, depending on how it is interpreted, conflicts of interests may arise. Parents need psychosocial support to cope with the stress caused by their child’s medical condition. The child should be encouraged to participate in decision-making as early as possible, dependent on the child’s level of maturity and age. Children acquire decision-making competency between the ages of 10 and 14 and, if competent, must be addressed as relevant moral actors because of the highly personal nature of the issues at stake. In general, irreversible treatments with no direct health benefit should be postponed in order to leave options open for the future until the individual has capacity to consent.


Figure 1 Zebrafish knockdown results in lymphatic developmental defects.
Table 1. PWS CNT P Age (yrs) 13.1G3.4 12.9G1.9 NS BMI SD 2.2G1.9 2.1G0.5 NS Pubertal stage (Tanner) 2.1 G 0.8 2.8 G 1.1 0.05 Calcium (mg/dl) 9.7 G 0.4 9.8 G 0.4 NS Phosphorus (mg/dl) 4.5G0.6 4.5G0.5 NS PTH (pg/ml) 42.3G26.6 44.7G16.2 NS 25OH vitD (ng/ml) 2
Figure 1 Serum 25(OH) D levels in study group were significantly lower than those of controls.


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Thus, in these countries with a high prevalence of H pylori infection, peptic ulcer disease (PUD) is still common in the pediatric age.. This study aimed to describe the prevalence,