Skip to content
Accessible Unlicensed Requires Authentication Published by De Gruyter July 24, 2013

Effects of metformin in children and adolescents with Prader-Willi syndrome and early-onset morbid obesity: a pilot study

Jennifer L. Miller, Tiffany D. Linville and Elisabeth M. Dykens


Prader-Willi syndrome (PWS) is one of the most commonly recognized causes of early-onset childhood obesity. Individuals with PWS have significant hyperphagia and decreased recognition of satiety. The exact etiology of the hyperphagia remains unknown and, therefore, untreatable. We conducted a pilot, open-label study of response to metformin in 21 children with PWS and six with early morbid obesity (EMO). Participants had significant insulin resistance and glucose intolerance on oral glucose tolerance testing (OGTT) and were started on metformin for these biochemical findings. We administered the Hyperphagia Questionnaire to parents of patients before and after starting metformin treatment. Both the PWS and EMO groups showed significant improvements in food-related distress, anxiety, and ability to be redirected away from food on the Hyperphagia Questionnaire. In the PWS group, improvements were predominantly seen in females. Within the PWS group, responders to metformin had higher 2-h glucose levels on OGTT (7.48 mmol/L vs. 4.235 mmol/L; p=0.003) and higher fasting insulin levels (116 pmol/L vs. 53.5 pmol/L; p=0.04). Additionally, parents of 5/13 individuals with PWS and 5/6 with EMO reported that their child was able to feel full while on metformin (for many this was the first time they had ever described a feeling of fullness). Metformin may improve sense of satiety and decrease anxiety about food in some individuals with PWS and EMO. Positive response to metformin may depend on the degree of hyperinsulinism and glucose intolerance. Nonetheless, the results of this pilot study bear further investigation.

Corresponding author: Jennifer L. Miller, MD, Assistant Professor, Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL, USA, Phone: +1 352-334-1390, E-mail:


1. Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet 2009;17:3–13.Search in Google Scholar

2. Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome. Am J Med Genet A 2008;146:854–60.Search in Google Scholar

3. Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cassidy SB, Schrander JJ, et al. Prader-Willi syndrome: causes of death in an international series of 27 cases. Am J Med Genet A 2004;124A:333–8.Search in Google Scholar

4. Davies W, Lynn PM, Relkovic D, Wilkinson LS. Imprinted genes and neuroendocrine function. Front Neuroendocrinol 2008;29:413–27.Search in Google Scholar

5. Goldstone AP. The hypothalamus, hormones, and hunger: alterations in human obesity and illness. Prog Brain Res 2006;153:57–73.Search in Google Scholar

6. Holsen LM, Zarcone JR, Brooks WM, Butler MG, Thompson TI, et al. Neural mechanisms underlying hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring) 2006;14:1028–37.Search in Google Scholar

7. Miller JL, James GA, Goldstone AP, Couch JA, He G, et al. Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome. J Neurol Neurosurg Psychiatry 2007;78:615–9.Search in Google Scholar

8. Holsen LM, Zarcone JR, Chambers R, Butler MG, Bittel DC, et al. Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome. Int J Obes (Lond) 2009;33:273–83.Search in Google Scholar

9. Holsen LM, Savage CR, Martin LE, Bruce AS, Lepping RJ, et al. Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity. Int J Obes (Lond) 2012;36:638–47.Search in Google Scholar

10. Bizzarri C, Rigamonti AE, Luce A, Cappa M, Cella SG, et al. Children with Prader-Willi syndrome exhibit more evident meal-induced responses in plasma ghrelin and peptide YY levels than obese and lean children. Eur J Endocrinol 2010;162:499–505.Search in Google Scholar

11. Haqq AM, Grambow SC, Muehlbauer M, Newgard CB, Svetkey LP, et al. Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development. Clin Endocrinol (Oxf) 2008;69:911–20.Search in Google Scholar

12. Kennedy L, Bittel DC, Kibiryeva N, Kalra SP, Torto R, et al. Circulating adiponectin levels, body composition and obesity-related variables in Prader-Willi syndrome: comparison with obese subjects. Int J Obes (Lond) 2006;30:382–7.Search in Google Scholar

13. Proto C, Romualdi D, Cento RM, Romano C, Campagna G, et al. Free and total leptin serum levels and soluble leptin receptors levels in two models of genetic obesity: the Prader-Willi and the Down syndromes. Metabolism 2007;56:1076–80.Search in Google Scholar

14. Ring LE, Zeltser LM. Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels. J Clin Invest 2010;120:2931–41.Search in Google Scholar

15. Roth CL, Bongiovanni KD, Gohlke B, Woelfle J. Changes in dynamic insulin and gastrointestinal hormone secretion in obese children. J Pediatr Endocrinol Metab 2010;23: 1299–309.Search in Google Scholar

16. Thompson JA, Regnault TR. In utero origins of adult insulin resistance and vascular dysfunction. Semin Reprod Med 2011;29:211–24.Search in Google Scholar

17. Kim F, Pham M, Maloney E, Rizzo NO, Morton GJ, et al. Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol 2008;28:1982–8.Search in Google Scholar

18. Yau PL, Castro MG, Tagani A, Tsui WH, Convit A. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics 2012;130:e856–64.Search in Google Scholar

19. Miller J, Kranzler J, Liu Y, Schmalfuss I, Theriaque DW, et al. Neurocognitive findings in Prader-Willi syndrome and early-onset morbid obesity. J Pediatr 2006;149:192–8.Search in Google Scholar

20. McNeilly AD, Williamson R, Sutherland C, Balfour DJ, Stewart CA. High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task. Behav Brain Res 2011;217:134–41.Search in Google Scholar

21. Debette S, Beiser A, Hoffmann U, Decarli C, O’Donnell CJ, et al. Visceral fat is associated with lower brain volume in healthy middle-aged adults. Ann Neurol 2010;68:136–44.Search in Google Scholar

22. Yau PL, Javier DC, Ryan CM, Tsui WH, Ardekani BA, et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 2010;53:2298–306.Search in Google Scholar

23. Segura B, Jurado MA, Freixenet N, Bargalló N, Junqué C, et al. White matter fractional anisotropy is related to processing speed in metabolic syndrome patients: a case-control study. BMC Neurol 2010;10:64.Search in Google Scholar

24. Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, et al. Increased brain fatty acid uptake in metabolic syndrome. Diabetes 2010;59:2171–7.Search in Google Scholar

25. Luchsinger JA. Type 2 diabetes, related conditions, in relation and dementia: an opportunity for prevention? J Alzheimers Dis 2010;20:723–36.Search in Google Scholar

26. Chan NN, Feher MD, Bridges NA. Metformin therapy for diabetes in Prader-Willi syndrome J R Soc Med 1998;91:598.Search in Google Scholar

27. Hirsch HJ, Eldar-Geva T, Benarroch F, Rubinstein O, Gross-Tsur V. Primary testicular dysfunction is a major contributor to abnormal pubertal development in males with Prader-Willi syndrome. J Clin Endocrinol Metab 2009;94:2262–8.Search in Google Scholar

28. Schmidt F, Kapellen TM, Wiegand S, Herbst A, Wolf J, et al; DPV-Wiss Study Group; BMBF Competence Network Diabetes. Diabetes mellitus in children and adolescents with genetic syndromes. Exp Clin Endocrinol Diabetes 2012;120:579–85.Search in Google Scholar

29. Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav 2012;101:564–74.Search in Google Scholar

30. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107:E55.Search in Google Scholar

31. Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring) 2007;15:1816–26.Search in Google Scholar

32. Adler-Wailes DC, Periwal V, Ali AH, Brady SM, McDuffie JR, et al. Sex-associated differences in free fatty acid flux of obese adolescents. J Clin Endocrinol Metab 2013;98: 1676–8.Search in Google Scholar

33. Newal H, Myles N, Ward PB, Samaras C, Shiers D, et al. Efficacy of metformin for prevention of weight gain in psychiatric populations: a review. Int Clin Psychopharmacol 2012;27:69–75.Search in Google Scholar

34. Banks WA. Brain meets body: the blood-brain barrier as an endocrine interface. Endocrinology 2012;153:4111–9.Search in Google Scholar

35. Adam CL, Findlay PA. Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance. Int J Obes (Lond) 2010;34:980–8.Search in Google Scholar

36. Zhang Y, Wang Y, Bao C, Xu Y, Shen H, et al. Metformin interacts with AMPK through binding to γ subunit. Mol Cell Biochem 2012;368:69–76.Search in Google Scholar

37. Viollet B, Andreelli F. AMP-activated protein kinase and metabolic control. Handb Exp Pharmacol 2011;(203):303–30.Search in Google Scholar

38. Lv WS, Wen JP, Li L, Sun RX, Wang J, et al. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res 2012;1444:11–9.Search in Google Scholar

39. Aubert G, Mansuy V, Voirol MJ, Pellerin L, Pralong FP. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism 2011;60:327–34.Search in Google Scholar

40. Pimentel GD, Ropelle ER, Rocha GZ, Carvalheira JB. The role of neuronal AMPK as a mediator of nutritional regulation of food intake and energy homeostasis. Metabolism 2012;62:171–8.Search in Google Scholar

41. Stark R, Ashley SE, Andrews ZB. AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol Cell Endocrinol 2013;366:215–23.Search in Google Scholar

42. Garfield AS, Patterson C, Skora S, Gribble FM, Reimann F, et al. Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology 2012;153:4600–7.Search in Google Scholar

43. Haqq AM, Muehlbauer M, Svetkey LP, Newgard CB, Purnell JQ, et al. Altered distribution of adiponectin isoforms in children with Prader-Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones. Clin Endocrinol (Oxf) 2007;67:944–51.Search in Google Scholar

44. Haqq AM, Muehlbauer MJ, Newgard CB, Grambow S, Freemark M. The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index. J Clin Endocrinol Metab 2011;96:E225–32.Search in Google Scholar

Received: 2013-3-22
Accepted: 2013-6-3
Published Online: 2013-07-24
Published in Print: 2014-01-01

©2014 by Walter de Gruyter Berlin Boston