Background: Pigment epithelium-derived factor (PEDF) is associated with obesity and diabetes complications in adults, yet little is known about PEDF in younger individuals. We investigated the relationship between PEDF and various metabolic biomarkers in young healthy volunteers (HV) and similar-aged patients with diabetes (type 1 and type 2). Methods: A fasting blood sample was collected in 48 HV, 11 patients with type 1 diabetes (T1D), and 11 patients with type 2 diabetes (T2D) 12–25 years of age. In 9 healthy subjects, PEDF was also serially measured during a frequently sampled oral glucose tolerance test (OGTT). Results: PEDF was positively correlated with BMI and systolic blood pressure and negatively correlated with vitamin D. Upon multivariable analysis, BMI and vitamin D were independent predictors of PEDF. Prior to adjustment, PEDF was highest in T2D patients (7,168.9 ± 4417.4 ng/mL) and lowest in individuals with T1D (2,967.7 ± 947.1 ng/mL) but did not differ by diagnosis when adjusted for BMI and vitamin D. Among volunteers who underwent an OGTT, PEDF declined by ∼20% in response to an oral glucose load. Conclusion: PEDF was acutely regulated by a glucose load and was correlated with BMI but not with diabetes. The negative correlation with vitamin D, independent of BMI, raises the question whether PEDF plays a compensatory role in bone matrix mineralization.

1.
Famulla S, Lamers D, Hartwig S, Passlack W, Horrighs A, Cramer A, Lehr S, Sell H, Eckel J: Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells. Int J Obes (Lond) 2011;35: 762–772.
2.
Wang P, Smit E, Brouwers MC, Goossens GH, van der Kallen CJ, van Greevenbroek MM, Mariman EC: Plasma pigment epithe-lium-derived factor is positively associated with obesity in Caucasian subjects, in particular with the visceral fat depot. Eur J Endocrinol 2008;159: 713–718.
3.
Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Inoue H: Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with visceral adiposity in Japanese patients with type 2 diabetes. Diabetes Metab Res Rev 2009;25: 52–56.
4.
Matsui T, Nishino Y, Ojima A, Maeda S, Tahara N, Yamagishi S: Pigment epithelium-derived factor improves metabolic derangements and ameliorates dysregulation of adipocytokines in obese type 2 diabetic rats. Am J Pathol 2014;184: 1094–1103.
5.
Sabater M, Moreno-Navarrete JM, Ortega FJ, Pardo G, Salvador J, Ricart W, Fruhbeck G, Fernandez-Real JM: Circulating pigment epithelium-derived factor levels are associated with insulin resistance and decrease after weight loss. J Clin Endocrinol Metab 2010;95: 4720–4728.
6.
Crowe S, Wu LE, Economou C, Turpin SM, Matzaris M, Hoehn KL, Hevener AL, James DE, Duh EJ, Watt MJ: Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab 2009;10: 40–47.
7.
Jenkins AJ, Zhang SX, Rowley KG, Karschimkus CS, Nelson CL, Chung JS, O’Neal DN, Januszewski AS, Croft KD, Mori TA, Dragice vic G, Harper CA, Best JD, Lyons TJ, Ma JX: Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in type 1 diabetes. Diabet Med 2007;24: 1345–1351.
8.
Katakami N, Kaneto H, Yamasaki Y, Matsuhisa M: Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy. Diabetes Res Clin Pract 2008;81:e4–e7.
9.
Chen HB, Jia WP, Lu JX, Bao YQ, Li Q, Lu FD, Lu W, Yu HY, Xiang KS: Change and significance of serum pigment epithelium-derived factor in type 2 diabetic nephropathy (in Chinese). Zhonghua Yi Xue Za Zhi 2007;87: 1230–1233.
10.
Jenkins A, Zhang SX, Gosmanova A, Aston C, Dashti A, Baker MZ, Lyons T, Ma JX: Increased serum pigment epithelium derived factor levels in type 2 diabetes patients. Diabetes Res Clin Pract 2008;82:e5–e7.
11.
Haribalaganesh R, Sheikpranbabu S, Elayappan B, Venkataraman D, Gurunathan S: Pigment epithelium–derived factor down regulates hyperglycemia-induced apoptosis via pi3k/akt activation in goat retinal pericytes. Angiogenesis 2009;12: 381–389.
12.
Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX: Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes 2006;55: 1678–1685.
13.
Awad AS, You H, Gao T, Gvritishvili A, Cooper TK, Tombran-Tink J: Delayed treatment with a small pigment epithelium derived factor (PEDF) peptide prevents the progres sion of diabetic renal injury. PLoS One 2015;10:e0133777.
14.
Zang J, Guan G: Study of pigment epithelium-derived factor in pathogenesis of diabetic retinopathy. Eye Sci 2015;30: 81–88.
15.
Elahy M, Baindur-Hudson S, Cruzat VF, Newsholme P, Dass CR: Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic reti nopathy and neuropathy. J Endocrinol 2014;222:R129–R139.
16.
Jenkins AJ, Fu D, Azar M, Stoner JA, Kaufman DG, Zhang S, Klein RL, Lopes-Virella MF, Ma JX, Lyons TJ; VADT Investigators: Clinical correlates of serum pigment epithelium-derived factor in type 2 diabetes patients. J Diabetes Complications 2014;28: 353–359.
17.
Tryggestad JB, Wang JJ, Zhang SX, Thompson DM, Short KR: Elevated plasma pigment epithelium-derived factor in children with type 2 diabetes mellitus is attributable to obesity. Pediatr Diabetes 2015;16: 600–605.
18.
Sunderland KL, Tryggestad JB, Wang JJ, Teague AM, Pratt LV, Zhang SX, Thompson DM, Short KR: Pigment epithelium-derived factor (PEDF) varies with body composition and insulin resistance in healthy young people. J Clin Endocrinol Metab 2012;97:E2114–E2118.
19.
Lee SI, Patel M, Jones CM, Narendran P: Cardiovascular disease and type 1 diabetes: Prevalence, prediction and management in an ageing population. Ther Adv Chronic Dis 2015;6: 347–374.
20.
Yamagishi S, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K, Hino A, Jinnouchi Y, Takenaka K, Matsui T, Nakamura K, Imaizumi T: Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab 2006;91: 2447–2450.
21.
Umei H, Yamagishi SI, Imaizumi T: Positive association of serum levels of pigment epithelium-derived factor with high-sensitivity C-reactive protein in apparently healthy unmedicated subjects. J Int Med Res 2010;38: 443–448.
22.
Redondo MJ, Rodriguez LM, Haymond MW, Hampe CS, Smith EO, Balasubramanyam A, Devaraj S: Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes. Pediatr Diabetes 2014;15: 543–549.
23.
Teague AM, Fields DA, Aston CE, Short KR, Lyons TJ, Chernausek SD: Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of hispanic and native American women with diabetes mellitus. Reprod Biol Endocrinol 2015;13: 68.
24.
Chiu KC, Chu A, Go VL, Saad MF: Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79: 820–825.
25.
Tzotzas T, Papadopoulou FG, Tziomalos K, Karras S, Gastaris K, Perros P, Krassas GE: Rising serum 25-hydroxy-vitamin D levels after weight loss in obese women correlate with improvement in insulin resistance. J Clin Endocrinol Metab 2010;95: 4251–4257.
26.
Broadhead ML, Akiyama T, Choong PF, Dass CR: The pathophysiological role of PEDF in bone diseases. Curr Mol Med 2010;10: 296–301.
27.
Gattu AK, Swenson ES, Iwakiri Y, Samuel VT, Troiano N, Berry R, Church CD, Rodeheffer MS, Carpenter TO, Chung C: Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content. FASEB J 2013;27: 4384–4394.
28.
Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, Bertin T, Napierala D, Morello R, Gibbs R, White L, Miki R, Cohn DH, Crawford S, Travers R, Glorieux FH, Lee B: Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res 2011;26: 2798–2803.
29.
Ziff JL, Crompton M, Powell HR, Lavy JA, Aldren CP, Steel KP, Saeed SR, Dawson SJ: Mutations and altered expression of SERPINF1 in patients with familial otosclerosis. Hum Mol Genet 2016;25: 2393–2403.
30.
Roemmich JN, Clark PA, Mantzoros CS, Gurgol CM, Weltman A, Rogol AD: Relationship of leptin to bone mineralization in children and adolescents. J Clin Endocrinol Metab 2003;88: 599–604.
31.
Vishnevskaya M, Solntsava A: Bone mineral density in obese children. Pediatr Res 2011;70: 402.
32.
Forrest KY, Stuhldreher WL: Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res 2011;31: 48–54.
33.
Chen H, Jia W, Xu X, Fan Y, Zhu D, Wu H, Xie Z, Zheng Z: Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs. Biochem Biophys Res Commun 2008;369: 718–724.
34.
Chen C, Tso AW, Law LS, Cheung BM, Ong KL, Wat NM, Janus ED, Xu A, Lam KS: Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study. J Clin Endocrinol Metab 2010;95: 5074–5081.
35.
Cakir M, Sari R, Tosun O, Karayalcin U: Leptin response to oral glucose tolerance test in obese and nonobese premenopausal women. Endocr Res 2005; 31: 1–8.
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.