Associations among osteocalcin, leptin and metabolic health in children ages 9-13 years in the United States

Kelly Virecoulon Giudici, Joseph M Kindler, Berdine R Martin, Emma M Laing, George P McCabe, Linda D McCabe, Dorothy B Hausman, Lígia Araújo Martini, Richard D Lewis, Connie M Weaver, Munro Peacock, Kathleen M Hill Gallant, Kelly Virecoulon Giudici, Joseph M Kindler, Berdine R Martin, Emma M Laing, George P McCabe, Linda D McCabe, Dorothy B Hausman, Lígia Araújo Martini, Richard D Lewis, Connie M Weaver, Munro Peacock, Kathleen M Hill Gallant

Abstract

Background: This study aimed to investigate the relationships among osteocalcin, leptin and metabolic health outcomes in children ages 9-13 years.

Methods: This was a cross-sectional analysis of baseline data from 161 boys and 157 girls (ages 9-13 years) who previously participated in a double-blinded randomized placebo controlled trial of vitamin D supplementation. Relationships among fasting serum total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC), leptin, and metabolic health outcomes were analyzed.

Results: Approximately 52% of study participants were obese based on percent body fat cutoffs (>25% for boys and >32% for girls) and about 5% had fasting serum glucose within the prediabetic range (i.e. 100 to 125 mg/dL). Serum tOC was not correlated with leptin, glucose, insulin, HOMA-IR, or HOMA-β after adjusting for percent body fat. However, serum ucOC negatively correlated with leptin (partial r = -0.16; p = 0.04) and glucose (partial r = -0.16; p = 0.04) after adjustment for percent body fat. Leptin was a positive predictor of insulin, glucose, HOMA-IR, and HOMA-β after adjusting for age, sex and percent body fat (all p < 0.001).

Conclusions: These data depict an inverse relationship between leptin and various metabolic health outcomes in children. However, the notion that tOC or ucOC link fat with energy metabolism in healthy children was not supported.

Clinical trial registration number: NCT00931580.

Keywords: Children; Glucose; Insulin; Leptin; Obesity; Osteocalcin.

Figures

Fig. 1
Fig. 1
Partial regression plots between ucOC and (a) glucose and (b) leptin adjusted for age, sex and percent body fat in children living in the United States
Fig. 2
Fig. 2
Partial regression plots between leptin and (a) serum insulin, (b) HOMA-IR, (c) HOMA-β, and (d) serum glucose adjusted for age, sex and percent body fat among children living in the United States

References

    1. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207. doi: 10.1016/S0092-8674(00)81558-5.
    1. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG, Jr, Chua SC, Jr, Kim JK, Kaestner KH, Karsenty G. The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol. 2008;183:1235–1242. doi: 10.1083/jcb.200809113.
    1. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confraveux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456–469. doi: 10.1016/j.cell.2007.05.047.
    1. Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A. 2008;105:5266–5270. doi: 10.1073/pnas.0711119105.
    1. Lecka-Czernik B, Rosen CJ. Energy excess, glucose utilization, and skeletal remodeling: New insights. J Bone Miner Res. 2015;30(8):1356–61. doi: 10.1002/jbmr.2574.
    1. Lecka-Czernik B, Rosen CJ. Skeletal integration of energy homeostasis: translational implications. Bone. 2016;82:35–41. doi: 10.1016/j.bone.2015.07.026.
    1. Lombardi G, Sanchis-Gomar F, Perego S, Sansoni V, Banfi G. Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine. 2016;54(2):284–305. doi: 10.1007/s12020-015-0834-0.
    1. Glass NA, Torner JC, Letuchy EM, Burns TL, Janz KF, Eichenberger Gilmore JM, Schlechte JA, Levy SM. The relationship between greater prepubertal adiposity, subsequent age of maturation, and bone strength during adolescence. J Bone Miner Res. 2016;31(7):1455–65.
    1. Pollock NK, Laing EM, Baile CA, Hamrick MW, Hall DB, Lewis RD. Is adiposity advantageous for bone strength? a peripheral quantitative computed tomography study in late adolescent females. Am J Clin Nutr. 2007;86(5):1530–8.
    1. Sayers A, Lawlor DA, Sattar N, Tobias JH. The association between insulin levels and cortical bone: findings from a cross-sectional analysis of pQCT parameters in adolescents. J Bone Miner Res. 2012;27(3):610–8. doi: 10.1002/jbmr.1467.
    1. Dimitri P, Bishop N, Walsh JS, Eastell R. Obesity is a risk factor for fracture in children but is protective against fracture in adults: a paradox. Bone. 2012;50(2):457–466. doi: 10.1016/j.bone.2011.05.011.
    1. Pollock NK, Bernard PJ, Gower BA, Gundberg CM, Wenger K, Misra S, Bassali RW, Davis CL. Lower uncarboxylated osteocalcin concentrations in children with prediabetes is associated with beta-cell function. J Clin Endocrinol Metab. 2011;96(7):E1092–1099. doi: 10.1210/jc.2010-2731.
    1. Motyl KJ, Rosen CJ. Understanding leptin-dependent regulation of skeletal homeostasis. Biochimie. 2012;94(10):2089–2096. doi: 10.1016/j.biochi.2012.04.015.
    1. Takeda S, Karsenty G. Molecular bases of the sympathetic regulation of bone mass. Bone. 2008;42:837–840. doi: 10.1016/j.bone.2008.01.005.
    1. Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 1999;140(4):1630–1638.
    1. Lombardi G, Perego S, Luzi L, Banfi G. A four-season molecule: osteocalcin. Updates in its physiological roles. Endocrine. 2015;48(2):394–404. doi: 10.1007/s12020-014-0401-0.
    1. Karsenty G, Olson EN. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell. 2016;164(6):1248–56. doi: 10.1016/j.cell.2016.02.043.
    1. Abseyi N, Siklar Z, Berberoglu M, Hacihamdioglu B, Savas Erdeve S, Oçal G. Relationships between osteocalcin, glucose metabolism, and adiponectin in obese children: is there crosstalk between bone tissue and glucose metabolism? J Clin Res Pediatr Endocrinol. 2012;4(4):182–188. doi: 10.4274/Jcrpe.831.
    1. Lu C, Ivaska KK, Alen M, Wang Q, Tormakangas T, Xu L, Wiklund P, Mikkola TM, Pekkala S, Tian H, Väänänen HK, Cheng S. Serum osteocalcin is not associated with glucose but is inversely associated with leptin across generations of nondiabetic women. J Clin Endocrinol Metab. 2012;97(11):4106–4114. doi: 10.1210/jc.2012-2045.
    1. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellström D. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly swedish men. J Bone Miner Res. 2009;24:785–791. doi: 10.1359/jbmr.081234.
    1. Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hunghes B. Association between serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab. 2009;94:827–832. doi: 10.1210/jc.2008-1422.
    1. Zhou M, Ma X, Li H, Pan X, Tang J, Gao Y, Hou X, Lu H, Bao Y, Jia W. Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals. Eur J Endocrinol. 2009;161:723–729. doi: 10.1530/EJE-09-0585.
    1. Reinehr T, Roth CL. A new link between skeleton, obesity and insulin resistance: relationships between osteocalcin, leptin and insulin resistance in obese children before and after weight loss. Int J Obes (Lond) 2010;34(5):852–858. doi: 10.1038/ijo.2009.282.
    1. Sansoni V, Vernillo G, Perego S, Barbuti A, Merati G, Schena F, La Torre A, Banfi G, Lombardi G. Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners. Endocrine. 2016. [Epub ahead of print]
    1. Lombardi G, Lanteri P, Graziani R, Colombini A, Banfi G, Corsetti R. Bone and energy metabolism parameters in professional cyclists during the giro d’Italia 3-weeks stage race. PLoS One. 2012;7(7):e42077. doi: 10.1371/journal.pone.0042077.
    1. Lewis RD, Laing EM, Hill Gallant KM, Hall DB, McCabe GP, Hausman DB, Martin BR, Warden SJ, Peacock M, Weaver CM. A randomized trial of vitamin D3 supplementation in children: dose–response effects on vitamin D metabolites and calcium absorption. J Clin Endocrinol Metab. 2013;98:4816–4825. doi: 10.1210/jc.2013-2728.
    1. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. CDC growth charts: United States. Adv Data. 2000;314:1–27.
    1. Williams DP, Going SB, Lohman TG, Harsha DW, Srinivasan SR, Webber LS, Berenson GS. Body fatness and risk for elevated blood pressure, total cholesterol, and serum lipoprotein ratios in children and adolescents. Am J Public Health. 1992;82(3):358–63. doi: 10.2105/AJPH.82.3.358.
    1. Going SB, Lohman TG, Eisenmann JC. Body composition assessments. In: Plowman SA, Meredith MD, editors. Fitnessgram/activitygram reference guide. 4. Dallas: The Cooper Institute; 2013. pp. 7–9.
    1. Pramojanee SN, Phimphilai M, Chattipakorn N, Chattipakorn SC. Possible roles of insulin signaling in osteoblasts. Endocr Res. 2014;39(4):144–151. doi: 10.3109/07435800.2013.879168.
    1. Karsenty G, Ferron M. The contribution of bone to whole organism physiology. Nature. 2012;481:314–320. doi: 10.1038/nature10763.
    1. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142(2):296–308. doi: 10.1016/j.cell.2010.06.003.
    1. Takaya J, Tanabe Y, Kuroyanagi Y, Kaneko K. Decreased undercarboxylated osteocalcin in children with type 2 diabetes mellitus. J Pediatr Endocrinol Metab. 2016;29(8):879–84. doi: 10.1515/jpem-2015-0417.
    1. Tubic B, Magnusson P, Mårild S, Leu M, Schwetz V, Sioen I, Herrmann D, Obermayer-Pietsch B, Lissner L. Swolin-eide D; IDEFICS consortium. Different osteocalcin forms, markers of metabolic syndrome and anthropometric measures in children within the IDEFICS cohort. Bone. 2016;84:230–6. doi: 10.1016/j.bone.2016.01.008.
    1. Rosato MT, Schneider SH, Shapses SA. Bone turnover and insulin-like growth factor I levels increase after improved glycemic control in noninsulin-dependent diabetes mellitus. Calcif Tissue Int. 1998;63(2):107–111. doi: 10.1007/s002239900498.
    1. Okazaki R, Totsuka Y, Hamano K, Ajima M, Miura M, Hirota Y, Hata K, Fukumoto S, Matsumoto T. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–2920.
    1. Van Summeren M, Braam L, Noirt F, Kuis W, Vermeer C. Pronounced elevation of undercarboxylated osteocalcin in healthy children. Pediatr Res. 2007;61:366–370. doi: 10.1203/pdr.0b013e318030d0b1.
    1. Rochefort GY, Rocher E, Aveline PC, Garnero P, Bab I, Chappard C, Jaffré C, Benhamou CL. Osteocalcin-insulin relationship in obese children: a role for the skeleton in energy metabolism. Clin Endocrinol (Oxf) 2011;75(2):265–270. doi: 10.1111/j.1365-2265.2011.04031.x.
    1. Alfadda AA, Masood A, Shaik SA, Dekhil H, Goran M. Association between osteocalcin, metabolic syndrome, and cardiovascular risk factors: role of total and undercarboxylated osteocalcin in patients with type 2 diabetes. Int J Endocrinol. 2013;2013:197519.
    1. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes. 1997;46(6):1087–93. doi: 10.2337/diab.46.6.1087.
    1. Cali AM, Caprio S. Prediabetes and type 2 diabetes in youth: an emerging epidemic disease? Curr OpinEndocrinol Diabetes Obes. 2008;15(2):123–127. doi: 10.1097/MED.0b013e3282f57251.
    1. Steinberger J, Daniels SR, American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young); American Heart Association Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism) 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(10):1448–1453. doi: 10.1161/01.CIR.0000060923.07573.F2.
    1. Gower BA, Pollock NK, Casazza K, Clemens TL, Goree LL, Granger WM. Associations of total and undercarboxylated osteocalcin with peripheral and hepatic insulin sensitivity and β-cell function in overweight adults. J Clin Endocrinol Metab. 2013;98(7):E1173–80. doi: 10.1210/jc.2013-1203.
    1. Arslanian S, Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity of healthy black versus white adolescents. J Pediatr. 1996;129:440–443. doi: 10.1016/S0022-3476(96)70078-1.
    1. Lee JM, Okumura MJ, Davis MM, Herman WH, Gurney JG. Prevalence and determinants of insulin resistance among U.S. Adolescents: a population-based study. Diabetes Care. 2006;29(11):2427–2432. doi: 10.2337/dc06-0709.
    1. Murphy MJ, Metcalf BS, Voss LD, Jeffery AN, Kirkby J, Mallam KM, Wilkin TJ. EarlyBird study (EarlyBird 6). girls at five are intrinsically more insulin resistant than boys: the programming hypotheses revisited – the EarlyBird study (EarlyBird study 6) Pediatrics. 2004;113(1):82–86. doi: 10.1542/peds.113.1.82.
    1. Jeffery AN, Metcalf BS, Hosking J, Streeter AJ, Voss LD, Wilkin TJ. Age before stage: insulin resistance rises before the onset of puberty: a 9-year longitudinal study (EarlyBird 26) Diabetes Care. 2012;35(3):536–541. doi: 10.2337/dc11-1281.
    1. Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36(6):1789–1796. doi: 10.2337/dc12-1235.
    1. Centers for Disease Control and Prevention . National diabetes statistics report: estimates of diabetes and its burden in the united states, 2014. Atlanta: US Department of Health and Human Services; 2014.
    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(4):e500–503. doi: 10.1542/peds.2004-1921.
    1. Kindler JM, Pollock NK, Laing EM, Jenkins NT, Oshri A, Isales C, Hamrick M, Lewis RD. Insulin resistance negatively influences the muscle-dependent IGF-1-bone mass relationship in premenarcheal girls. J Clin Endocrinol Metab. 2016;101(1):199–205. doi: 10.1210/jc.2015-3451.

Source: PubMed

3
Iratkozz fel