Endokrina mekanismers betydelse för det växande barnet.
Endokrina mekanismers betydelse för det växande barnet.
Project number : 3440
Created by: Jovanna Dahlgren, 2008-02-08
Last revised by: Jovanna Dahlgren, 2017-05-19
Project created in: FoU i Västra Götalandsregionen

PublishedPublished

1. Översiktlig projektbeskrivning

Engelsk titel

The role of endocrine mechanisms in the growing child.

Populärvetenskaplig sammanfattning av projektet

Fetma hos barn är ett globalt problem. Många av dessa har redan i barnaåren tecken på det metabola syndromet (insulinresistens, högt blodtryck, höga blodfetter). Det är angeläget att identifiera vilka barn som har en ökad risk för att utveckla metabola syndromet. Detta kommer att bli besvarat i våra studier. Tre stora populationsbaserade studier pågår där vi följer prospektivt interaktion mellan genetik, perinatala händelser med hormonell programmering och livsstilens påverkan för utvecklingen av metabola syndromet och hur detta förebyggs. Multivariata modeller kommer att utvecklas för att identifiera högriskindivider.
Idag saknas det vedertagna effektiva behandlingsformer för att bekämpa barnfetma, men mycket talar för att en individualiserad strategi med flera olika alternativa behandlingar inkluderat kirurgisk åtgärd är en mer framgångsrik väg, vilket vi studerar. Nyligen har IGF-I gjorts möjlig som terapi för barn med tillväxthormonresistens resp. diabetes typ 2, då behandlingen har positiva metabola effekter. Vad gäller benohälsa är det av vikt att utveckla non-invasiva mätmetoder anpassade för barn. Vi har nu utvecklat unika pediatriska referenser och kan därför studera benkvalitet hos flera sjukdomsgrupper.

This application addresses major medical need and challenges in the growing child. The well-known increase in child obesity is of main concern as it has health, social and economical implications for the individual and the society. The risk of developing the metabolic syndrome and cardiovascular disease occurs already during adolescence. It is therefore of major importance to find the risk factors for obesity and the metabolic syndrome and identify children at risk. This will be answered in our studies. In three large population studies followed prospectively we will study interactions between genetics, perinatal events and life style for the development of metabolic syndrome. Multivariate models will be developed to identify high-risk groups for the metabolic syndrome.
Treatment of established obesity in children is an unexplored area. Until now lifestyle changes have been used, but we have ongoing studies evaluating the metabolic effect of new therapeutic tools. Recently insulin-like growth factor I (IGF-I) has been made available and is shown to be a potent growth factor in patients with growth hormone (GH) resistance or with diabetes, and could theoretically be a potent treatment against the metabolic syndrome in adolescents as it has metabolic effects.
It is of great importance to find new non-invasive clinical markers for bone diseases in children and to achieve new, fast and reliable bone measurement techniques. We have now created world unique paediatric references and will study the bone quality and quantity in several different diseases or acquired low peak bone mass due to treatment with glucocorticoids. Finally, the impact of dysregulation of sex steroids during childhood and adolescence will be studied extensively.

Vetenskaplig sammanfattning av projektet

BACKGROUND
The risk of developing the metabolic syndrome occurs already during childhood with insulin resistance and cardiovascular disease (1). We have shown that the diastolic 24-hour blood pressure is increased in obese adolescences (2) and in addition these children face cardiac hypertrophy (3). It is of major importance to find the risk factors for obesity and the metabolic syndrome and identify children at risk. We know some risk factors such as parental obesity, heredity for type 2 diabetes, central adiposity, hypothalamic dysregulation, born growth retarded (called small for gestational age, (SGA)), rapid early growth and the timing of the adiposity rebound. These factors may be studied in detail to assess the genetic or environmental contribution to the interaction. Moreover, preliminary data show that some syndromes have increased risk (4,5) whereas other syndromes are protected.

Not only obesity per se but the magnitude of weight gain will have an implication on the risk to develop the metabolic syndrome (6). Many children born SGA with subsequent weight gain (7) and obese children have an earlier onset of adrenarche (the awakening of the adrenal function at an age of 5-7 years), suggesting a common pathology. Moreover, obese children become obese adults (8) and treatment may be more efficient if started in childhood. Treatment of established obesity in children is an unexplored area. Until now lifestyle changes have been used, but we have ongoing studies evaluating the metabolic effect of group therapy, very low calory diet, pharmaceutical therapy and at last but not at least gastric by-pas surgery (9).

Recently insulin-like growth factor I (IGF-I) has been made available. IGF-I is a growth factor of critical importance for all organs during fetal life, but important also during childhood, adolescence and adult life. It has metabolic and anabolic effects and theoretically could be an efficient treatment in adolescents suffering of the metabolic syndrome, diabetes or growth disorders. IGF-I could be a candidate treatment in short stature not responding to GH treatment such as idiopatic short stature, short children born SGA, Turner-, Noonan- and Silver-Russells syndrome, all entities with low IGF-I.

Also bone health is established in young ages and bone disease is of major concern in adults, especially osteoporosis in women. The WHO has defined osteoporosis for adults. Today there is no consen¬sus of when a child should be regarded as having osteoporosis (10). It is of great interest to find accurate, fast and safe methods for determining bone quantity and quality in growing individuals. The skeleton is a supporting tissue but also a complex endocrine organ regulated by diet, loading, growth factors and hormone. High doses of glucocortioids have serious side effects like osteoporosis and they have been shown to affect the growth of children. Glucocorticoids are hormones and important drugs for the treatment of several diseases such as asthma, inflammatory diseases, rheumatic diseases, and in Duchenne muscular dystrophy to slow down the muscular weakness. Glucocorticoids are also used to treat severe premature children to slow down bronchopulmonar disease. The mechanism behind this is in part mediated through reduced IGF-I. IGF-I is produced locally in bone forming cells (11) and is anabolic for bone growth. In the future we may add IGF-I treatment in these diseases to prevent the glucocorticoid effects of low IGF-I levels.
The impact of sex steroids is more important for adult health than previously emphasized. Sexual differentiation starts in fetal life, continues during infancy, and is completed during puberty. We have shown that there is a dysregulation of sex steroids in adult males born SGA (12), with a “feminized” hormonal pattern whereas others have shown a “masculinised” pattern with hyperandrogenism in females born SGA (7). The metabolic disadvantages of this are just in the beginning to be elucidated.

STUDY DESIGN
1. HEALTHY INDIVIDUALS - GROWTH AND PREVENTION OF OBESITY
AIM
1. Identification
General aim in all studies: Study interactions between genetics, perinatal events and life style for the development of metabolic syndrome. Identify already in young age high-risk groups for the metabolic syndrome based on multivariate models (using above identified variables) to focus prevention.
“Tillväxtstudien Göteborg”: Study longitudinally the phenomenon adiposity rebound and its interaction with adrenarche (see “Background”). Could the timing of adrenarche influence body composition, visceral fat development and decreased insulin sensitivity?
2. Intervention
“Tillväxt Halland”: Study parental knowledge of nutrition during infancy and to develop parent-adapted information for the first year at BVC to counteract overweight.
2.2. “IDEFIX”: Study the relation of BMI, anthropometry, metabolic risk factors and bone density to nutritional status, physical activity level and genetic markers in an unselected population of 2-8 year old children. These baseline data are used to assess the effect of health promotion in a subsample of this population.

WORKING PLAN
Several population-based surveys are followed and analyzed.
Study 1 -“Tillväxtstudien Göteborg”: Growth is measured from pregnancy monthly during infancy with umbilical cord sample in children born 2002-2004, n=250. A more detailed examination is performed semi-annually from an age of 4 years to 7 years to determine the correlation with adrenal and sex steroid levels, to determine onset of adrenarche versus changes in body composition (DXA), visceral and subcutaneous fat tissue (MRI), insulin sensitivity (OGTT), C-peptide, HOMA index, serum leptin and adiponectin, androgen and sex steroids in urine (GCMS).
Study 2-“Tillväxt Halland”: Growth and parental view of nutrition is followed prospectively from birth to 7 years of age in children born 2007-2008 in Halland (n=3500). In a subset of 1.500 children umbilical cord sample is taken to analyse IGF-I.
Study 3 – IDEFICS study is VGR part of EU supported project. The design is population-based surveys linked to preventive obesity interventions. In the Göteborg area a total of 750 children aged 2-4 and 750 aged 6-8 are recruited. Half of the children will be surveyed in control schools, and the other half in intervention schools. Blood sampling (incl genetics), DXA, DXL at the beginning and at the end of the 18-month intervention is performed.
Study 4 - Children born 1990 All children born 1990 in Göteborg (n=3500) are offered to participate in the adult follow up to identify the appropriate age and gender cut-offs of BMI during childhood leading to increased metabolic risks. Besides growth (height, weight, waist-hip ratio) also evaluation of pubertal stage, body composition, endocrine and metabolic status are studied.

2. OBESITY, THE METABOLIC SYNDROME & TREATMENT OUTCOME
AIM
Fartvind: Evaluate different set-ups for delivering a one-year ‘lifestyle’ treatment, ie. psykoeducative enhancement of healthy nutrition and increae in physical acitivity.
Surgery study: Evaluate the metabolic outcome of gastric by-pas surgery and study if results are better if surgery is performed in adolescense compared to adult life.
Responders & non-responders study: Study pretreatment determinants of better outcome of lifestyle treament interventions in obese patients that will respond well with those without response.
Study in hypothalamic obesity: a. Study mechanisms behind hypotalamic obesity (endocrine dysregulation at hypothalamic level). b. Evaluate treatment with either Ocreotide or Concerta.

PATIENTS
Fartvind studies: includes obese children aged 9-12 years (Grind n=70, Fartvind n=54). Data is compared with 30 controls and 30 overweight children.
Surgery study: includes all those obese children treated with gastric by pas surgery at DSBUS.
Responders & non-responders: 120 children and adolescents in a cohort of 280 obese subjects registered in 2004 at DSBUS. The 120 had participated in baseline studies and completed follow-up evaluations. Out of all those 120 obese children, extremes are identified (30 as responders and 30 as non-responders).
Hypothalmic obesity: includes all children with hypotalamic obesity at DSBUS, estimated 10/year. Children with sequele after craniopharyngioma and Prader Willy syndrome are examples.

WORKING PLAN
Fartvind studies: Randomisation to extra physical activity (Fartvind) or to individual vs group-wise treatement (Grind) is done. The intervention method is studied using the outcome in BMI. Background data of heredity, anthropometry, metabolic markers, blood pressure, fitness tests baroreceptor sensitivity and questionnaires of psychological characterstics are assessed as additional determinants to the outcome.
Surgery study: Before surgery, one month after as well as one and two years after surgery body composition with DXA, insulin sensitivity (OGTT), intima media function, 24-hour blood pressure and microdialysis is performed. Gastric peptides, C-peptide, adiponectine, sex steroids and IGF-I are analysed.
Responders & non-responders: Heredity, age, gender, treatment regime and growth data, antropometry, endocrine blood status before and one year after treatment is correlated to weight loss.
Children with hypothalamic obesity: Investigation concerning endocrine status, gastric peptides, insulin sensitivity (OGTT and clamp), microdialysis and DXA are performed. DNA will be taken to study relevant genes for development of diabetes and obesity. These data are combined with protein expression data from microdialysis and blood serum.

3. IGF-I – NORMAL SECRETION AND TREATMENT IN CHILDREN
AIM
Study 1 – IGF-I changes during infancy and childhood. Study the IGF-I changes during infancy and childhood in healthy children, in children born SGA or in children developing obesity. Compare these changes with metabolic outcomes.
Study 2 – IGF-I treatment in short stature
a. Improve the growth response with IGF-I treatment compared to GH treatment.
b. Study the metabolic effects, body composition and bone health on IGF-I treatment.
Study 3 – IGF-I treatment and the metabolic syndrome Normalize the metabolic status in children with diabetes type 2 with IGF-I treatment compared to Metformine.

METHOD/MATERIAL & WORKING PLAN
Study IGF-I changes during infancy and childhood - 250 children are followed in the study “Tillväxtstudie Göteborg” since birth with frequent IGF-I sampling during infancy and semi- annually from 4 years of age comparing sex steroids and metabolic outcomes.
Study IGF-I treatment in short stature: children with idiopatic short stature, short SGA children or short children with syndromes will be randomised to either IGF-I or GH treatment during one year. IGF-I, insulin sensitivity and body composition (DXA) is followed at start of treatment, 10 days, 30 days and one year after start.
Study the role of IGF-I treatment in the metabolic syndrome: Children with type 2-diabetes will be randomised to either treatment with IGF-I or to Metformine during a period of 6 months. IGF-I, GH status, insulin sensitivity, body composition (DXA) is evaluated before and 6 months after start of treatment.

4. BONE HEALTH AND BONE DISEASES
AIM
Study 1. Calcaneous bone mineral density using DXL in children
a. Study if heel DXA and DXL is a reliable new, easier and faster method for measure areal bone mineral density in children compared to total DXA
b. Validate the correlation between regular whole body DXA and DXL in children and adolescent.
Study 2. Skeletal health in boys with Dushenne muscle dystrofy and disabled children
a. Increase bone mineral density, muscle strength and function after whole body vibration therapy by regular weekly 6 months of therapy.
b. Study if bone markers are affected by this therapy.
Study 3. Bone and IGF-I levels in premature born children
a. Study the correlation between IGF-I levels versus bone mineral density and bone markers in children born severe premature, now 4 years of age.
b. Study the involvment of IGF-I in skeletal development early in life.
c. Identify individuals at risk of low peak bone mass & decreased bone mineral density.

WORKING PLAN
Study 1: Dr Swolin-Eide leads an ongoing unique study with the new calcaneous DXL. Based on published references from a cross-sectional study in healthy 2-9 years of age (13), we have recently fulfilled a 3-year-longitudinal study with 40 children, where the correlation to fractures and auxological data is made. Birth weight, actual weight, height, BMI and bone mineral density with DXL is recorded, as well as milk and AD-vitamin intake, fractures and physical activity.
Study 2.1: In western Sweden there are approx 40 boys with Dushenne muscle dystrofy. The 3-year longitudinal study will start fall 2007 in collaboration with Dr M Tulinius. We will also initiate a prospective study on the effect of whole body vibration therapy (Galileo) during 6 months in these boys and study total body, spine, heel BMD, bone markers, muscular function and hormonal levels. They will be measured at 3 months before start of treatment, at start and at 3, 6 and 12 months and the same parameter will be examined.
Study 2.2: In collaboration with Dr B Westerberg a similar study as 2.1 will be performed with whole body vibration therapy on 25 disabled children.
Study 3: Children born severe premature (week 24-32) in Göteborg have been included and extensively followed since birth regarding growth, nutrition and IGF-I. Now at an age of 4 years bone markers, body composition (DXA), bone mass (DXL) and skeletal development are compared with age- and gender mached controls.

5. SEX STEROIDS AND DISORDERS OF SEXUAL REGULATION

AIM
Study 1: To evaluate if prepubertal boys born SGA have increased estradiol levels, as shown in adult males. To study the metabolic disadvantages of dysregulation of sex steroids in this group of patients.
Study 2: To study the prevalens of premature thelarche (breast development) and to evaluate genetical background to this ovarian simulation (for ex McAlbright).

PATIENTS AND WORKING PLAN
Study 1: 5 year old boys from a population-based cohort (n=250, se obesity chapter) will be evaluated regarding sex steroids and bone maturity (indirect measure of effect).
Study 2: All females aged 3 years during 2008 in Trollhättan area will be evaluated to identify premature thelarche. Blood samples will be taken to analyse sex steroids, gonadotropins and gene expression of G-protein mutations (McAlbright).

PRELIMINARY RESULTS
Increased prevalence of obesity is shown in the population of children born 1990 compared with previous cohorts (14). A follow-up study has been performed in those born 2004 and shows an off-leveling the last years (15). Analysis of long-term results of gastric by-pas surgery on weight loss in severe obese adolescences is promising (17), but the metabolic evaluations will start 2007. We found that timing of puberty is important for development of visceral adipose tissue (18, 19), but prospective studies are needed to understand mechanisms. A cross-sectional study has been performed concerning bone quality in healthy children in pre-school ages. The precision of the DXL method has now been evaluated and world unique paediatric references are created (13). Bone mineral density was shown to correlate to age, gender, weight and height. Moreover, bone mineral density correlated to foot length and calcaneous height. Data from the study of Duchenne boys is accepted for publication and reviled that these patients have a reduced bone mineral density and bone turnover. However, the fracture incidence is normal (20).
SIGNIFICANCE
Obesity in adolescents and adults is a health risk with large medical, psychosocial and economical implications. It merits all efforts to study the mechanisms leading to overweight and to find BMI cut-offs in childhood that will have metabolic implications. It is crucial to identify already in childhood those individuals with increased risk of developing the metabolic syndrome. Moreover, the discovery of efficient treatment options in this patient group is of major concern.
The use of IGF-I as treatment in children with short stature or with the metabolic syndrome is a brand new area. If our theories are true and children have a better outcome in height as well as in metabolic effects with IGF-I treatment, this will lead to a dramatic evolution of the area of paediatric endocrinology.
Finally, it is of great importance to find new non-invasive clinical markers for bone diseases and to achieve new, fast and reliable bone measurement techniques for children. Individuals at risk of receiving low peak bone mass could bee found and early intervention started.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva typ av studier

checked Longitudinella studier (Longitudinal Studies)
checked Prospektiva studier (Prospective Studies)
checked Kohortstudier (Cohort Studies)
checked Randomiserad klinisk prövning (Randomized Controlled Trial)


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MeSH-termer för att beskriva ämnesområdet

information Added MeSH terms
Academic Dissertations
Works consisting of formal presentations made usually to fulfill requirements for an academic degree.
Endocrine Glands
Ductless glands that secrete HORMONES directly into the BLOOD CIRCULATION. These hormones influence the METABOLISM and other functions of cells in the body.
Endocrine System
The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the ENDOCRINE GLANDS, included are the CHROMAFFIN SYSTEM and the NEUROSECRETORY SYSTEMS.
Hormones
Chemical substances having a specific regulatory effect on the activity of a certain organ or organs. The term was originally applied to substances secreted by various ENDOCRINE GLANDS and transported in the bloodstream to the target organs. It is sometimes extended to include those substances that are not produced by the endocrine glands but that have similar effects.
Growth Hormone
A polypeptide that is secreted by the adenohypophysis (PITUITARY GLAND, ANTERIOR). Growth hormone, also known as somatotropin, stimulates mitosis, cell differentiation and cell growth. Species-specific growth hormones have been synthesized.
Child
A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL.
Obesity
A status with BODY WEIGHT that is grossly above the acceptable or desirable weight, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).

Projektets delaktighet i utbildning

checked Avhandling


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2. Projektorganisation och finansiering

Arbetsplatser involverade i projektet

information Added workplaces
Landsting - Västra Götalandsregionen - Specialiserad vård - Sahlgrenska Universitetssjukhuset - Område 1 - Övrigt

3. Processen och projektets redovisning

Hur långt har projektet framskridit?

Projektet pågår, rekrytering/datainsamling stängd

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2008-01-01

Datum då projektet är slutrapporterat

2010-12-31

Publikationer från detta projekt

  1. Aring E, Dahlgren J, Alvin K, Nilsson J, Andersson Grönlund M.
    Fort Lauderdale, USA, May 2-6, 2010: ARVO (The Association for Research in Vision and Ophthalmology); 2010.
  2. Fort Lauderdale, USA, May 2-6, 2010: ARVO (The Association for Research in Vision and Ophthalmology); 2010.
  3. Mårild S, Flodmark CE, Serling M, Friberg P, Dahlgren J, Lönroth H, Gronowitz E, Marcus C.
    Obesity Rev 2010:(Suppl 1):47.
  4. Allvin K, Dahlgren J, Hellström A, Andersson Grönlund M.
    Gothenburg: Medicinska Riksstämma; 2010.
  5. Dahlgren J, Mårild S.
    Stockholm, Sweden: International Congress On Obesity; 2010.
  6. Gronowitz E, Dahlgren J, Friberg P, Elmberg K, Mårild S.
    Stockholm, Sweden: International Congress On Obesity; 2010.
  7. Gronowitz E, Olbers T, Mårild S, Dahlgren J, Flodmark CE, Werling M, Friberg P, Lönnroth H, Marcus C.
    Obesity Rev 2010:11(Suppl 1):70.
  8. Dahlgren J, Decker R, Albertsson-Wikland K, Kriström B, Gustafsson J, Hochberg Z.
    San Diego, California, USA: ENDO 2010; 2010.
  9. Gronowitz E, Olbers T, Marild S, Flodmark C, Dahlgren J, Marcus C.
    Horm Res. 2009:72:56.
  10. Friberg P, Marcus C, Gronowitz E, Flodmark C, Werling M, Dahlgren J, Lonroth H, Olbers T.
    Circulation 2009:120(18):S402-S402.
  11. Allvin K, Ankarberg-Lindgren C, Niklasson A, Dahlgren J.
    Hormone research in paediatrics 2009:72(Suppl. 3):417.
  12. Gronowitz E, Olbers T, Mårild S, Flodmark C, Dahlgren J, Marcus C.
    Hormone research in paediatrics 2009:72(suppl 3):56.
  13. Lidwall B, Tengskog M, Dahlgren J.
    Hormone research in paediatrics 2009:72(suppl 3):267.
  14. Hellgren G, Andersson B, Nierop D, Dahlgren J, Hochberg Z, Albertsson-Wikland K.
    Gothenburg, Sweden: The 9th International Conference on Systems Biology; 2008.
  15. Decker R, Albertsson-Wikland K, Nierop AFM, Kriström B, Hochberg Z, Dahlgren J.
    Istanbul, Turky: 47th ESPE Meeting; 2008.
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Endokrina mekanismers betydelse för det växande barnet., from FoU i Sverige
http://www.researchweb.org/is/en/sverige/project/3440