Background/Aims: Intrauterine exposure to hyperglycemia might impact the risk for future metabolic deteriorations. The aim was to characterize the association between different adipokines and neuropeptides and insulin resistance and BMI-SDS in children affected by diabetes during pregnancy. Methods: 76 children (mean age: 6 years, male:female = 36:40) born to mothers with gestational or pregestational diabetes and nondiabetic women were consecutively included for clinical assessments comprising anthropometrics and metabolic characterization [2-hour glucose tolerance test, leptin, peptide YY (PYY), neuropeptide Y (NPY), ghrelin, growth differentiation factor 15 (GDF-15), and adiponectin]. Results: The level of insulin resistance was associated with BMI-SDS (p < 0.001), leptin (p < 0.001), ghrelin (p = 0.002), age (p < 0.002) and negatively with GDF-15 (p = 0.005). BMI-SDS, leptin and GDF-15 were shown to have independent effects on insulin resistance by using a multiple regression model (additionally including age, and maternal diabetes status), whereas ghrelin lost significance (p = 0.345). No differences were present in adipokines and insulin resistance when children were evaluated by maternal glucometabolic status. However, we observed more strengthened associations between insulin resistance and covariates BMI-SDS and leptin in offspring of diabetic pregnancies. Conclusions: Young children with elevated BMI or leptin are affected by higher indices of insulin resistance, particularly those who were born to mothers with diabetes during pregnancy. The impact of this special risk constellation should be considered in future studies.

Wang Y, Lobstein T: Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes 2006;1:11-25.
Daniels SR: Complications of obesity in children and adolescents. Int J Obes (Lond) 2009;33(suppl 1):S60-S65.
Baker JL, Olsen LW, Sorensen TIA: Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007;357:2329-2337.
Li S, Chen W, Srinivasan SR, Xu J, Berenson GS: Relation of childhood obesity/cardiometabolic phenotypes to adult cardiometabolic profile: the Bogalusa Heart Study. Am J Epidemiol 2012;176(suppl 7):S142-S149.
Battista MC, Hivert MF, Duval K, Baillargeon JP: Intergenerational cycle of obesity and diabetes: how can we reduce the burdens of these conditions on the health of future generations? Exp Diabetes Res 2011:596060.
Boney CM, Verma A, Tucker R, Vohr BR: Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 2005;115:e290-e296.
Gaillard R, Felix JF, Duijts L, Jaddoe VW: Childhood consequences of maternal obesity and excessive weight gain during pregnancy. Acta Obstet Gynecol Scand 2014;93:1085-1089.
Plagemann A: A matter of insulin: development programming of body weight regulation. J Matern Fetal Neonatal Med 2008;21:143-148.
Franke K, Harder T, Aerts L, Melchior K, Fahrenkrog S, Rodekamp E, Ziska T, Van Assche FA, Dudenhausen JW, Plagemann A: Programming of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats. Brain Res 2005;1031:276-283.
Steculorum SM, Bouret SG: Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring. Endocrinology 2011;152:4171-4179.
Breton C: The hypothalamus-adipose axis is a key target of developmental programming by maternal nutritional manipulation. J Endocrinol 2013;216:R19-R31.
Yessoufou A, Moutairou K: Maternal diabetes in pregnancy: early and long-term outcomes on the offspring and the concept of ‘metabolic memory'. Exp Diabetes Res 2011;2011:218598.
Gallagher EJ, Leroith D, Karnieli E: Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Mt Sinai J Med 2010;77:511-523.
Meier U, Gressner AM: Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004;50:1511-1525.
Lean ME, Malkova D: Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence? Int J Obes (Lond) 2016;40:622-632.
Kalra SP, Kalra PS: Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin. Endocrine 2003;22:49-56.
Adela R, Banerjee SK: GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015;2015:490842.
Metzger B, Coustan D: Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 1998;21(suppl 2B):161-167.
Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geiss HC, Hesse V, Von Hippel A, Jaeger U, Johnsen D, Korte W, Menner K, Müller G, Müller JM, Niemann-Pilatus A, Remer T, Schaefer F, Wittchen HU, Zabransky S, Zellner K, Ziegler A, Hebebrand J: Percentiles of body mass index in children and adolescents evaluated from different regional German studies. Monatsschr Kinderheilkd 2001;149:807-818.
Villar J, et al: International standards for newborn weight, length and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 2014;384:857-868.
Konietschke F, Placzek M, Schaarschmidt F, Hothorn LA: nparcomp: an R Software Package for nonparametric multiple comparisons and simultaneous confidence intervals. J Stat Softw 2015;64:1-17.
Brunner E, Munzel U: The nonparametric Behrens-Fisher Problem: asymptotic theory and a small-sample approximation. Biom J 2000;1:17-21.
R Development Core Team: R: A Language and Environment for Statistical Computing. Vienna, R Foundation for Statistical Computing, 2015. (accessed October 25, 2015).
Donovan LE, Cundy T: Does exposure to hyperglycemia in utero increases the risk of obesity and diabetes in the offspring? A critical reappraisal. Diabet Med 2015;32:295-304.
Yajnik CS: Fetal programming of diabetes: still so much to learn! Diabetes Care May 2010;33:1146-1148.
Dabelea D. Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC: Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes Dec 2000;49:2208-2211.
Knight B, Shields BM, Hill A, Powell RJ, Wright D, Hattersley AT: The impact of maternal glycemia and obesity on early postnatal growth in a nondiabetic Caucasian population. Diabetes Care 2007;30:777-783.
Borgono CA, Hamilton JK, Ye C, Hanley AJ, Connelly PW, Sermer M, Zinman B, Retnakaran R: Determinants of Insulin resistance in infants at age 1 year. Impact of gestational diabetes mellitus. Diabetes Care 2012;35:1795-1797.
Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, Richards GE, Metzger BE: Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 1991;40(suppl 2):121-125.
Krishnaveni GV, Hill JC, Leary SD, Veena SR, Saperia J, Saroja A, Karat SC, Fall CH: Anthropometry, glucose tolerance and insulin concentrations in Indian children: relationships to maternal glucose and insulin concentrations during pregnancy. Diabetes Care 2005;28:2919-2925.
Pettitt DJ, McKenna S, McLaughlin C, Patterson CC, Hadden DR, McCance DR: Maternal glucose at 28 weeks of gestation is not associated with obesity in 2-year-old offspring: the Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) family study. Diabetes Care 2010;33:1219-1223.
Deierlein AL, Siega-Riz, AM, Chantala K, Herring AH: The association between maternal glucose concentration and child BMI at age 3 years. Diabetes Care 2011;34:480-484.
Baptiste-Roberts K, Nicholson WK, Wang NY, Brancati FL: Gestational diabetes and subsequent growth patterns of offspring: the National Collaborative Perinatal Project. Matern Child Health J 2012;16:125-132.
Thaware PK, McKenna S, Patterson CC, Hadden DR, Pettitt DJ, McCance DR: Untreated mild hyperglycemia during pregnancy and anthropometric measures of obesity in offspring at age 5-7 years. Diabetes Care 2015;38:1701-1706.
Crume TL, Ogden L, Daniels S, Hamman RF, Norris JM, Dabelea D: The impact of in utero exposure to diabetes on childhood body mass index growth trajectories: the EPOCH study. J Pediatr 2011;158:941-946.
Dabelea D, Crume T: Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 2011;60:1849-1855.
Bouchard L, Thibault S, Guay SP, Santure M, Monpetit A, St-Pierre J, Perron P, Brisson D: Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care 2010;33:2436-2441.
Fleisch AF, Agarwal N, Roberts MD, Han JC, Theim KR, Vexler A, Troendle J, Yanovski SZ, Yanovski JA: Influence of serum leptin on weight and body fat growth in children at high risk for adult obesity. J Clin Endocrinol Metab 2007;92:948-954.
West NA, Crume TL, Maligie MA, Dabelea D: Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia 2011;54:504-507.
Rohatgi A, Patel P, Das SR, Ayers CR, Khera A, Martinez-Rumayor A, Berry JD, McGuire DK, de Lemos JA: Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem 2012;58:172-182.
Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, Wollert KC: Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol 2012;167:671-678.
Vila G, Riedl M, Anderwald C, Resl M, Handisurya A, Clodi M, Prager G, Ludvik B, Krebs M, Luger A: The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin Chem 2011;57:309-316.
Ikezaki A, Hosoda H, Ito K, Iwama S, Miura N, Matsuoka H, Kondo C, Kojima M, Kangawa K, Sugihara S: Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 2002;51:3408-3411.
Persaud SJ, Bewick GA: Peptide YY: more than just an appetite regulator. Diabetologia 2014;57:1762-1769.
Roth CL, Enriori PJ, Harz K, Woelfle J, Cowley MA, Reinehr T: Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J Clin Endocrinol Metab 2005;90:6386-6391.
Kalra SP, Kalra PS: NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides 2004;38:201-211.
Sainsbury A, Bergen HT, Boey D, Bamming D, Cooney GJ, Lin S, Couzens M, Stroth N, Lee NJ, Lindner D, Singewald N, Karl T, Duffy L, Enriquez R, Slack K, Sperk G, Herzog H: Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice. Diabetes 2006;55:19-26.
Wilkin TJ, Metcalf BS, Murphy MJ, Kirkby J, Jeffery AN, Voss LD: The relative contributions of birth weight, weight change, and current weight to insulin resistance in contemporary 5-year-olds: the EarlyBird Study. Diabetes 2002;51:3468-3472.
Dabelea D, Mayer-Davis EJ, Lamichhane AP, D'Agostino RB Jr, Liese AD, Vehik KS, Narayan KM, Zeitler P, Hamman RF: Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case-Control Study. Diabetes Care 2008; 31:1422-1426.
Kelstrup L, Damm P, Mathiesen ER, Hansen T, Vaag AA, Pedersen O, Clausen TD: Insulin resistance and impaired pancreatic beta-cell function in adult offspring of women with diabetes in pregnancy. J Clin Endocrinol Metab 2013;98:3793-3801.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.