Prevention of diabetes in overweight/obese children through a family based intervention program including supervised exercise (PREDIKID project): study protocol for a randomized controlled trial

Lide Arenaza, María Medrano, María Amasene, Beatriz Rodríguez-Vigil, Ignacio Díez, Manuel Graña, Ignacio Tobalina, Edurne Maiz, Edurne Arteche, Eider Larrarte, Inge Huybrechts, Catherine L Davis, Jonatan R Ruiz, Francisco B Ortega, Javier Margareto, Idoia Labayen, Lide Arenaza, María Medrano, María Amasene, Beatriz Rodríguez-Vigil, Ignacio Díez, Manuel Graña, Ignacio Tobalina, Edurne Maiz, Edurne Arteche, Eider Larrarte, Inge Huybrechts, Catherine L Davis, Jonatan R Ruiz, Francisco B Ortega, Javier Margareto, Idoia Labayen

Abstract

Background: The global pandemic of obesity has led to an increased risk for prediabetes and type-2 diabetes (T2D). The aims of the current project are: (1) to evaluate the effect of a 22-week family based intervention program, including supervised exercise, on insulin resistance syndrome (IRS) risk in children with a high risk of developing T2D and (2) to identify the profile of microRNA in circulating exosomes and in peripheral blood mononuclear cells in children with a high risk of developing T2D and its response to a multidisciplinary intervention program including exercise.

Methods: A total of 84 children, aged 8-12 years, with a high risk of T2D will be included and randomly assigned to control (N = 42) or intervention (N = 42) groups. The control group will receive a family based lifestyle education and psycho-educational program (2 days/month), while the intervention group will attend the same lifestyle education and psycho-educational program plus the exercise program (3 days/week, 90 min per session including warm-up, moderate to vigorous aerobic activities, and strength exercises). The following measurements will be evaluated at baseline prior to randomization and after the intervention: fasting insulin, glucose and hemoglobin A1c; body composition (dual-energy X-ray absorptiometry); ectopic fat (magnetic resonance imaging); microRNA expression in circulating exosomes and in peripheral blood mononuclear cells (MiSeq; Illumina); cardiorespiratory fitness (cardiopulmonary exercise testing); dietary habits and physical activity (accelerometry).

Discussion: Prevention and identification of children with a high risk of developing T2D could help to improve their cardiovascular health and to reduce the comorbidities associated with obesity.

Trial registration: ClinicalTrials.gov, ID: NCT03027726 . Registered on 16 January 2017.

Keywords: Children; Ectopic fat; Exercise; Family based lifestyle intervention program; Type-2 diabetes; miRNA.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

This study was reviewed and approved by the Ethic Committee of Clinical Investigation of Euskadi (PI2014045). All parents or legal guardians will sign an informed written consent and all the children will give their assent before being enrolled in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Standard Protocol Items: Recommendations for Interventional Trials SPIRIT Figure. cIMT carotid intima media thickness; CRF cardiorespiratory fitness; HDL high-density lipoprotein; SAAT subcutaneous abdominal fat; TG triglycerides; VAT visceral abdominal fat
Fig. 2
Fig. 2
Planned study design

References

    1. Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: a consensus on Type 2 diabetes prevention. Diabet Med. 2007;24:451–63. doi: 10.1111/j.1464-5491.2007.02157.x.
    1. Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epidemiology and treatment. Curr Diab Rep. 2014;14:508. doi: 10.1007/s11892-014-0508-y.
    1. Skinner AC, Perrin EM, Moss LA, Skelton JA. Cardiometabolic risks and severity of obesity in children and young adults. N Engl J Med. 2015;373:1307–17. doi: 10.1056/NEJMoa1502821.
    1. Rhodes ET, Prosser LA, Hoerger TJ, Lieu T, Ludwig DS, Laffel LM. Estimated morbidity and mortality in adolescents and young adults diagnosed with Type 2 diabetes mellitus. Diabet Med. 2012;29:453–63. doi: 10.1111/j.1464-5491.2011.03542.x.
    1. Amutha A, Mohan V. Diabetes complications in childhood and adolescent onset type 2 diabetes—a review. J Diabetes Complicat. 2016;30:951–7. doi: 10.1016/j.jdiacomp.2016.02.009.
    1. American Diabetes Association. Prevention or delay of type 2 diabetes. Diabetes Care. 2016;39(Suppl):S36–8.
    1. Mechanick JI, Hurley DL, Garvey WT. Adiposity based chronic disease as a new diagnostic term: American Association of Clinical Endocrinologists and the American College of Endocrinology Position Statement. Endocr Pract. 2017;23:327–8.
    1. Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism) Circulation. 2003;107:1448–53. doi: 10.1161/01.CIR.0000060923.07573.F2.
    1. Di Bonito P, Pacifico L, Chiesa C, Valerio G, Miraglia Del Giudice E, Maffeis C, Morandi A, Invitti C, Licenziati MR, Loche S, et al. Impaired fasting glucose and impaired glucose tolerance in children and adolescents with overweight/obesity. J Endocrinol Invest. 2017;40:409–16. doi: 10.1007/s40618-016-0576-8.
    1. Molnar D. The prevalence of the metabolic syndrome and type 2 diabetes mellitus in children and adolescents. Int J Obes Relat Metab Disord. 2004;28(Suppl 3):S70–4. doi: 10.1038/sj.ijo.0802811.
    1. Onge ES, Miller SA, Motycka C, DeBerry A. A review of the treatment of type 2 diabetes in children. J Pediatr Pharmacol Ther. 2015;20:4–16.
    1. Verbestel V, De Henauw S, Barba G, Eiben G, Gallois K, Hadjigeorgiou C, Konstabel K, Maes L, Marild S, Molnar D, et al. Effectiveness of the IDEFICS intervention on objectively measured physical activity and sedentary time in European children. Obes Rev. 2015;16(Suppl 2):57–67. doi: 10.1111/obr.12348.
    1. Wang Y, Cai L, Wu Y, Wilson RF, Weston C, Fawole O, Bleich SN, Cheskin LJ, Showell NN, Lau BD, et al. What childhood obesity prevention programmes work? A systematic review and meta-analysis. Obes Rev. 2015;16:547–65. doi: 10.1111/obr.12277.
    1. Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2013;4:270–81. doi: 10.4239/wjd.v4.i6.270.
    1. Lobstein T, Baur L, Uauy R. Obesity in children and young people: a crisis in public health. Obes Rev. 2004;5(Suppl 1):4–104. doi: 10.1111/j.1467-789X.2004.00133.x.
    1. Malik VS, Hu FB. Fructose and cardiometabolic health: what the evidence from sugar-sweetened beverages tells us. J Am Coll Cardiol. 2015;66:1615–24. doi: 10.1016/j.jacc.2015.08.025.
    1. Rouhani MH, Haghighatdoost F, Surkan PJ, Azadbakht L. Associations between dietary energy density and obesity: a systematic review and meta-analysis of observational studies. Nutrition. 2016;32:1037–47. doi: 10.1016/j.nut.2016.03.017.
    1. Mollard RC, Senechal M, MacIntosh AC, Hay J, Wicklow BA, Wittmeier KD, Sellers EA, Dean HJ, Ryner L, Berard L, McGavock JM. Dietary determinants of hepatic steatosis and visceral adiposity in overweight and obese youth at risk of type 2 diabetes. Am J Clin Nutr. 2014;99:804–12. doi: 10.3945/ajcn.113.079277.
    1. Cook LT, O’Reilly GA, Goran MI, Weigensberg MJ, Spruijt-Metz D, Davis JN. Vegetable consumption is linked to decreased visceral and liver fat and improved insulin resistance in overweight Latino youth. J Acad Nutr Diet. 2014;114:1776–83. doi: 10.1016/j.jand.2014.01.017.
    1. House BT, Cook LT, Gyllenhammer LE, Schraw JM, Goran MI, Spruijt-Metz D, Weigensberg MJ, Davis JN. Meal skipping linked to increased visceral adipose tissue and triglycerides in overweight minority youth. Obesity (Silver Spring). 2014;22:E77–84. doi: 10.1002/oby.20487.
    1. House BT, Shearrer GE, Miller SJ, Pasch KE, Goran MI, Davis JN. Increased eating frequency linked to decreased obesity and improved metabolic outcomes. Int J Obes (Lond) 2015;39:136–41. doi: 10.1038/ijo.2014.81.
    1. Henderson M, Benedetti A, Barnett TA, Mathieu ME, Deladoey J, Gray-Donald K. Influence of adiposity, physical activity, fitness, and screen time on insulin dynamics over 2 years in children. JAMA Pediatr. 2016;170:227–35. doi: 10.1001/jamapediatrics.2015.3909.
    1. Sayin FK, Buyukinan M. Sleep duration and media time have a major impact on insulin resistance and metabolic risk factors in obese children and adolescents. Child Obes. 2016;12:272–8. doi: 10.1089/chi.2015.0126.
    1. De Bernardi Rodrigues AM, da Silva CC, Vasques AC, Camilo DF, Barreiro F, Cassani RS, Zambon MP, Antonio MA, Geloneze B. Association of sleep deprivation with reduction in insulin sensitivity as assessed by the hyperglycemic clamp technique in adolescents. JAMA Pediatr. 2016;170:487–94. doi: 10.1001/jamapediatrics.2015.4365.
    1. Wilfley DE, Staiano AE, Altman M, Lindros J, Lima A, Hassink SG, Dietz WH, Cook S. Improving access and systems of care for evidence-based childhood obesity treatment: conference key findings and next steps. Obesity (Silver Spring) 2017;25:16–29. doi: 10.1002/oby.21712.
    1. Elovainio M, Pulkki-Raback L, Hakulinen C, Lehtimaki T, Jokinen E, Ronnemaa T, Mikkila V, Tossavainen P, Jula A, Hutri-Kahonen N, et al. Psychosocial environment in childhood and body mass index growth over 32 years. Prev Med. 2017;97:50–5. doi: 10.1016/j.ypmed.2016.12.023.
    1. Olive LS, Telford RM, Byrne DG, Abhayaratna WP, Telford RD. Psychological distress leads to reduced physical activity and fitness in children: the Australian longitudinal LOOK study. J Behav Med. 2016;39:587–98. doi: 10.1007/s10865-016-9723-0.
    1. Rankin J, Matthews L, Cobley S, Han A, Sanders R, Wiltshire HD, Baker JS. Psychological consequences of childhood obesity: psychiatric comorbidity and prevention. Adolesc Health Med Ther. 2016;7:125–46. doi: 10.2147/AHMT.S101631.
    1. Wilkie HJ, Standage M, Gillison FB, Cumming SP, Katzmarzyk PT. Multiple lifestyle behaviours and overweight and obesity among children aged 9–11 years: results from the UK site of the International Study of Childhood Obesity, Lifestyle and the Environment. BMJ Open. 2016;6:e010677. doi: 10.1136/bmjopen-2015-010677.
    1. Nemet D, Barkan S, Epstein Y, Friedland O, Kowen G, Eliakim A. Short- and long-term beneficial effects of a combined dietary-behavioral-physical activity intervention for the treatment of childhood obesity. Pediatrics. 2005;115:e443–9. doi: 10.1542/peds.2004-2172.
    1. Pivovarov JA, Taplin CE, Riddell MC. Current perspectives on physical activity and exercise for youth with diabetes. Pediatr Diabetes. 2015;16:242–55. doi: 10.1111/pedi.12272.
    1. Marson EC, Delevatti RS, Prado AK, Netto N, Kruel LF. Effects of aerobic, resistance, and combined exercise training on insulin resistance markers in overweight or obese children and adolescents: a systematic review and meta-analysis. Prev Med. 2016;93:211–8. doi: 10.1016/j.ypmed.2016.10.020.
    1. Davis CL, Pollock NK, Waller JL, Allison JD, Dennis BA, Bassali R, Melendez A, Boyle CA, Gower BA. Exercise dose and diabetes risk in overweight and obese children: a randomized controlled trial. JAMA. 2012;308:1103–12. doi: 10.1001/2012.jama.10762.
    1. Panera N, Gnani D, Crudele A, Ceccarelli S, Nobili V, Alisi A. MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:15079–86. doi: 10.3748/wjg.v20.i41.15079.
    1. Campion J, Milagro FI, Martinez JA. Individuality and epigenetics in obesity. Obes Rev. 2009;10:383–92. doi: 10.1111/j.1467-789X.2009.00595.x.
    1. Tang X, Tang G, Ozcan S. Role of microRNAs in diabetes. Biochim Biophys Acta. 2008;1779:697–701. doi: 10.1016/j.bbagrm.2008.06.010.
    1. Dehwah MA, Xu A, Huang Q. MicroRNAs and type 2 diabetes/obesity. J Genet Genomics. 2012;39:11–8. doi: 10.1016/j.jgg.2011.11.007.
    1. Ortega FJ, Mercader JM, Moreno-Navarrete JM, Rovira O, Guerra E, Esteve E, Xifra G, Martinez C, Ricart W, Rieusset J, et al. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care. 2014;37:1375–83. doi: 10.2337/dc13-1847.
    1. Abente EJ, Subramanian M, Ramachandran V, Najafi-Shoushtari SH. MicroRNAs in obesity-associated disorders. Arch Biochem Biophys. 2016;589:108–19. doi: 10.1016/j.abb.2015.09.018.
    1. Parrizas M, Brugnara L, Esteban Y, Gonzalez-Franquesa A, Canivell S, Murillo S, Gordillo-Bastidas E, Cusso R, Cadefau JA, Garcia-Roves PM, et al. Circulating miR-192 and miR-193b are markers of prediabetes and are modulated by an exercise intervention. J Clin Endocrinol Metab. 2015;100:E407–15. doi: 10.1210/jc.2014-2574.
    1. Khalyfa A, Kheirandish-Gozal L, Bhattacharjee R, Khalyfa AA, Gozal D. Circulating microRNAs as potential biomarkers of endothelial dysfunction in obese children. Chest. 2016;149:786–800. doi: 10.1378/chest.15-0799.
    1. American Diabetes Association. Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 2000;23:381–9.
    1. Ferguson MA, Gutin B, Le NA, Karp W, Litaker M, Humphries M, Okuyama T, Riggs S, Owens S. Effects of exercise training and its cessation on components of the insulin resistance syndrome in obese children. Int J Obes Relat Metab Disord. 1999;23:889–95. doi: 10.1038/sj.ijo.0800968.
    1. Owens S, Gutin B, Allison J, Riggs S, Ferguson M, Litaker M, Thompson W. Effect of physical training on total and visceral fat in obese children. Med Sci Sports Exerc. 1999;31:143–8. doi: 10.1097/00005768-199901000-00022.
    1. Medrano M, Maiz E, Maldonado-Martin S, Arenaza L, Rodriguez-Vigil B, Ortega FB, Ruiz JR, Larrarte E, Diez-Lopez I, Sarasua-Miranda A, et al. The effect of a multidisciplinary intervention program on hepatic adiposity in overweight-obese children: protocol of the EFIGRO study. Contemp Clin Trials. 2015;45:346–55. doi: 10.1016/j.cct.2015.09.017.
    1. Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C. Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics. 2005;115:e500–3. doi: 10.1542/peds.2004-1921.
    1. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–95. doi: 10.2337/diacare.27.6.1487.
    1. NHBPEP: National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–76. doi: 10.1542/peds.114.2.S2.555.
    1. Wittmeier KD, Wicklow BA, MacIntosh AC, Sellers EA, Ryner LN, Serrai H, Gardiner PF, Dean HJ, McGavock JM. Hepatic steatosis and low cardiorespiratory fitness in youth with type 2 diabetes. Obesity (Silver Spring) 2012;20:1034–40. doi: 10.1038/oby.2011.379.
    1. Alderete TL, Toledo-Corral CM, Goran MI. Metabolic basis of ethnic differences in diabetes risk in overweight and obese youth. Curr Diab Rep. 2014;14:455. doi: 10.1007/s11892-013-0455-z.
    1. Toledo-Corral CM, Alderete TL, Hu HH, Nayak K, Esplana S, Liu T, Goran MI, Weigensberg MJ. Ectopic fat deposition in prediabetic overweight and obese minority adolescents. J Clin Endocrinol Metab. 2013;98:1115–21. doi: 10.1210/jc.2012-3806.
    1. Le KA, Ventura EE, Fisher JQ, Davis JN, Weigensberg MJ, Punyanitya M, Hu HH, Nayak KS, Goran MI. Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. Diabetes Care. 2011;34:485–90. doi: 10.2337/dc10-0760.
    1. Wicklow BA, Griffith AT, Dumontet JN, Venugopal N, Ryner LN, McGavock JM. Pancreatic lipid content is not associated with beta cell dysfunction in youth-onset type 2 diabetes. Can J Diabetes. 2015;39:398–404. doi: 10.1016/j.jcjd.2015.04.001.
    1. Jae SY, Franklin BA, Choo J, Yoon ES, Choi YH, Park WH. Fitness, body habitus, and the risk of incident type 2 diabetes mellitus in Korean men. Am J Cardiol. 2016;117:585–9. doi: 10.1016/j.amjcard.2015.11.046.
    1. Ruiz JR, Ortega FB, Rizzo NS, Villa I, Hurtig-Wennlof A, Oja L, Sjostrom M. High cardiovascular fitness is associated with low metabolic risk score in children: the European Youth Heart Study. Pediatr Res. 2007;61:350–5. doi: 10.1203/pdr.0b013e318030d1bd.
    1. Senechal M, Wicklow B, Wittmeier K, Hay J, MacIntosh AC, Eskicioglu P, Venugopal N, McGavock JM. Cardiorespiratory fitness and adiposity in metabolically healthy overweight and obese youth. Pediatrics. 2013;132:e85–92. doi: 10.1542/peds.2013-0296.
    1. Leger LA, Mercier D, Gadoury C, Lambert J. The multistage 20 metre shuttle run test for aerobic fitness. J Sports Sci. 1988;6:93–101. doi: 10.1080/02640418808729800.
    1. Thompson PD, Arena R, Riebe D, Pescatello LS. ACSM’s new preparticipation health screening recommendations from ACSM’s guidelines for exercise testing and prescription, ninth edition. Curr Sports Med Rep. 2013;12:215–17.
    1. Shah AS, Dolan LM, Kimball TR, Gao Z, Khoury PR, Daniels SR, Urbina EM. Influence of duration of diabetes, glycemic control, and traditional cardiovascular risk factors on early atherosclerotic vascular changes in adolescents and young adults with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:3740–5. doi: 10.1210/jc.2008-2039.
    1. Shah AS, Gao Z, Urbina EM, Kimball TR, Dolan LM. Prediabetes: the effects on arterial thickness and stiffness in obese youth. J Clin Endocrinol Metab. 2014;99:1037–43. doi: 10.1210/jc.2013-3519.
    1. Donath MY. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia. 2016;59:679–82. doi: 10.1007/s00125-016-3873-z.
    1. Syrenicz A, Garanty-Bogacka B, Syrenicz M, Gebala A, Walczak M. Low-grade systemic inflammation and the risk of type 2 diabetes in obese children and adolescents. Neuro Endocrinol Lett. 2006;27:453–8.
    1. Reinehr T, Karges B, Meissner T, Wiegand S, Fritsch M, Holl RW, Woelfle J. Fibroblast growth factor 21 and fetuin-A in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab. 2015;100:3004–10. doi: 10.1210/jc.2015-2192.
    1. Reinehr T, Woelfle J, Wiegand S, Karges B, Meissner T, Nagl K, Holl RW. Leptin but not adiponectin is related to type 2 diabetes mellitus in obese adolescents. Pediatr Diabetes. 2016;17(4):281–8.
    1. Reinehr T, Karges B, Meissner T, Wiegand S, Stoffel-Wagner B, Holl RW, Woelfle J. Inflammatory markers in obese adolescents with type 2 diabetes and their relationship to hepatokines and adipokines. J Pediatr. 2016.
    1. Rey-Lopez JP, Vicente-Rodriguez G, Ortega FB, Ruiz JR, Martinez-Gomez D, De Henauw S, Manios Y, Molnar D, Polito A, Verloigne M, et al. Sedentary patterns and media availability in European adolescents: The HELENA study. Prev Med. 2010;51:50–5. doi: 10.1016/j.ypmed.2010.03.013.
    1. Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol. 2013;9:513–21. doi: 10.1038/nrendo.2013.86.
    1. Guay C, Regazzi R. New emerging tasks for microRNAs in the control of beta-cell activities. Biochim Biophys Acta. 2016;1861:2121–9. doi: 10.1016/j.bbalip.2016.05.003.
    1. Currie CE, Elton RA, Todd J, Platt S. Indicators of socioeconomic status for adolescents: the WHO Health Behaviour in School-aged Children Survey. Health Educ Res. 1997;12:385–97. doi: 10.1093/her/12.3.385.
    1. Ortega FB, Lavie CJ, Blair SN. Obesity and cardiovascular disease. Circ Res. 2016;118:1752–70. doi: 10.1161/CIRCRESAHA.115.306883.
    1. Deiuliis JA. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. Int J Obes (Lond) 2016;40:88–101. doi: 10.1038/ijo.2015.170.
    1. Khalyfa A, Gozal D. Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J Transl Med. 2014;12:162. doi: 10.1186/1479-5876-12-162.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe