title: Evaluation of differential effects of metformin treatment in obese children according to pubertal stage and genetic variations: study protocol for a randomized controlled trial.
abstract: Overweight and obesity are considered to be serious public health problems. In pediatric populations, insulin resistance, dyslipidemia, and hypertension associated with obesity occur with increased frequencies. Metformin is an oral anti-hyperglycemic agent that has been demonstrated to be efficacious in the treatment of diabetic and non-diabetic obese adults. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Additionally, potential microbiota-mediated mechanisms of metformin effect have been recently described. However, scant work has been conducted in children, with no attention being paid to the potential effects of pubertal development. Thus, the main objective of the present study is to evaluate the effect of metformin treatment together with lifestyle recommendations in a randomized control trial (RCT) of obese children according to pubertal stage, genetic variants and signature of gut microbiota.
  
  
  
  This is a randomized, prospective, double-blind, placebo-controlled, multicenter trial, which is stratified by puberty and sex. Eighty pre-pubertal (40 boys and 40 girls) and 80 pubertal non-diabetic obese children (40 boys and 40 girls) are being recruited in four Spanish Clinical Hospitals. The inclusion criteria to participate in the RCT include a Body Mass Index (BMI) above the 95th percentile and age 7-14 years. The pubertal stage is determined based on the Tanner criteria. Participants are assigned to two groups in accordance with a randomization schedule and receive 1 g of metformin or placebo for six months in combination with healthy lifestyle recommendations in both groups. The primary outcomes include changes in the BMI Z score and the biomarkers associated with the early appearance of insulin resistance syndrome, inflammation, cardiovascular risk according of the presence of genetic determinants of metformin response, as well as possible modifications in microbiota.
  
  
  
  This study will assess the differential response of metformin treatment at six months in pre-pubertal and pubertal obese children.
  
  
  
  Registered by European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.
authors.affiliation: Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Center of Biomedical Research Laboratory 123, University of Granada, Avenida del Conocimiento s/n. 18006 Armilla, Granada, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pastor-Villaescusa
authors.affiliation: Clinical Analysis Services. IMIBIC/Reina Sofía Hospital, Córdoba University, Córdoba, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Caballero-Villarraso
authors.affiliation: PAIDI CTS-329. Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Cañete
authors.affiliation: Pediatric Department, Virgen de las Nieves University Hospital, Andalusian Health Service, Granada, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Hoyos
authors.affiliation: Pediatric Gastroenterology and Nutrition Unit, Virgen de las Nieves University Hospital, Pediatric Department, University of Granada, Granada, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Maldonado
authors.affiliation: Pediatric Department, Lozano Blesa University Clinical Hospital, University of Zaragoza, Zaragoza, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bueno
authors.affiliation: Unit of Investigation in Nutrition, Growth and Human Development of Galicia, Pediatric Department, Clinic University Hospital of Santiago, University of Santiago de Compostela, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Leis
authors.affiliation: Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Center of Biomedical Research Laboratory 123, University of Granada, Avenida del Conocimiento s/n. 18006 Armilla, Granada, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain.|Instituto de Investigación Biosanitaria ibs, Granada, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Gil
authors.affiliation: Unit of Pediatric Endocrinology, Reina Sofia University Hospital, Córdoba, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Cañete
authors.affiliation: Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Center of Biomedical Research Laboratory 123, University of Granada, Avenida del Conocimiento s/n. 18006 Armilla, Granada, Spain. caguiler@ugr.es.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain. caguiler@ugr.es.|Instituto de Investigación Biosanitaria ibs, Granada, Spain. caguiler@ugr.es.
authors.forename: Concepción M
authors.initials: CM
authors.lastname: Aguilera
mesh_terms: D000293:Adolescent; D000367:Age Factors; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002648:Child; D002985:Clinical Protocols; D004311:Double-Blind Method; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000382:microbiology; D000070497:Healthy Lifestyle; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D063766:Pediatric Obesity / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011627:Puberty; D012107:Research Design; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Children; Lifestyle intervention; Metformin; Microbiota; Obesity; Polymorphisms; Puberty