Skip to main content

Treatment of Insulin Resistance in Youth: The Role of Metformin

  • Chapter
Energy Metabolism and Obesity

Part of the book series: Contemporary Endocrinology ((COE))

  • 1149 Accesses

Abstract

The authors review the pathogenesis and diagnostic evaluation of insulin resistance in obesity and the polycystic ovary syndrome. They discuss the benefits and risks of lifestyle intervention and pharmacotherapy and present a tailored approach to pharmacotherapy in high risk adolescents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

Abstract

  1. Preeyasombat C, Bacchetti P, Lazar AA, Lustig RH. Racial and etiopathologic dichotomies in insulin hypersecretion and resistance in obese children. J Pediatr 2005;146:474–481.

    Article  PubMed  CAS  Google Scholar 

  2. Kratzsch J, Dehmel B, Pulzer F, et al. Increased serum GHBP levels in obese pubertal children and adolescents: relationship to body composition, leptin and indicators of metabolic disturbances. Int J Obes Relat Metab Disord 1997;21:1130–1136.

    Article  PubMed  CAS  Google Scholar 

  3. Freemark M. Metabolic consequences of obesity and their management. In: Brook CGD, Clayton PE, Brown RS, ed. Brook’s clinical pediatric endocrinology. Fifth ed. Malden: Blackwell Publishing Ltd; 2005:419–435.

    Google Scholar 

  4. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–2374.

    Article  PubMed  CAS  Google Scholar 

  5. Bonora E, Kiechl S, Willeit J, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care 2003;26:1251–1257.

    Article  PubMed  Google Scholar 

  6. Baron AD. Impaired glucose tolerance as a disease. Am J Cardiol 2001;88:16H–19H.

    Article  PubMed  CAS  Google Scholar 

  7. Shinozaki K, Kashiwagi A, Masada M, Okamura T. Molecular mechanisms of impaired endothelial function associated with insulin resistance. Curr Drug Targets Cardiovasc Haematol Disord 2004;4:1–11.

    Article  PubMed  CAS  Google Scholar 

  8. Rashid S, Uffelman KD, Lewis GF. The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states. J Diabetes Complications 2002;16:24–28.

    Article  PubMed  Google Scholar 

  9. Brands MW, Hall JE, Keen HL. Is insulin resistance linked to hypertension? Clin Exp Pharmacol Physiol 1998;25:70–76.

    Article  PubMed  CAS  Google Scholar 

  10. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002;137:25–33.

    PubMed  CAS  Google Scholar 

  11. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006;144:21–28.

    PubMed  Google Scholar 

  12. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–1638.

    Article  PubMed  Google Scholar 

  13. Lindsay RS, Hanson RL, Bennett PH, Knowler WC. Secular trends in birth weight, BMI, and diabetes in the offspring of diabetic mothers. Diabetes Care 2000;23:1249–1254.

    Article  PubMed  CAS  Google Scholar 

  14. Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005;353:1802–1809.

    Article  PubMed  CAS  Google Scholar 

  15. Ball GD, Weigensberg MJ, Cruz ML, Shaibi GQ, Kobaissi HA, Goran MI. Insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic children with a family history of type 2 diabetes. Int J Obes (Lond) 2005;29:1471–1477.

    Article  CAS  Google Scholar 

  16. Bacha F, Saad R, Gungor N, Janosky J, Arslanian SA. Obesity, regional fat distribution, and syndrome X in obese black versus white adolescents: race differential in diabetogenic and atherogenic risk factors. J Clin Endocrinol Metab 2003;88:2534–2540.

    Article  PubMed  CAS  Google Scholar 

  17. Arslanian SA. Metabolic differences between Caucasian and African-American children and the relationship to type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2002;15(Suppl 1):509–517.

    Google Scholar 

  18. Cisneros-Tapia R, Navarrete FA, Gallegos AC, Robles-Sardin AE, Mendez RO, Valencia ME. Insulin sensitivity and associated risk factors in Mexican children and adolescents. Diabetes Care 2005;28:2546–2547.

    Article  PubMed  Google Scholar 

  19. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802–810.

    Article  PubMed  CAS  Google Scholar 

  20. Freemark M. Pharmacologic approaches to the prevention of type 2 diabetes in high risk pediatric patients. J Clin Endocrinol Metab 2003;88:3–13.

    Article  PubMed  CAS  Google Scholar 

  21. Isganaitis E, Lustig RH. Fast food, central nervous system insulin resistance, and obesity. Arterioscler Thromb Vasc Biol 2005;25:2451–2462.

    Article  PubMed  CAS  Google Scholar 

  22. Erlanson-Albertsson C. How palatable food disrupts appetite regulation. Basic Clin Pharmacol Toxicol 2005;97:61–73.

    Article  PubMed  CAS  Google Scholar 

  23. Pereira MA, Kartashov AI, Ebbeling CB, et al. Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet 2005;365:36–42.

    Article  PubMed  Google Scholar 

  24. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004;27:1487–1495.

    Article  PubMed  Google Scholar 

  25. Hrebicek J, Janout V, Malincikova J, Horakova D, Cizek L. Detection of insulin resistance by simple quantitative insulin sensitivity check index QUICKI for epidemiological assessment and prevention. J Clin Endocrinol Metab 2002;87:144–147.

    Article  PubMed  CAS  Google Scholar 

  26. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462–1470.

    Article  PubMed  CAS  Google Scholar 

  27. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473–481.

    Article  PubMed  CAS  Google Scholar 

  28. Ibanez L, Dimartino-Nardi J, Potau N, Saenger P. Premature adrenarche–normal variant or forerunner of adult disease? Endocr Rev 2000;21:671–696.

    Article  PubMed  CAS  Google Scholar 

  29. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.

    Article  PubMed  CAS  Google Scholar 

  30. Sherwin RS, Anderson RM, Buse JB, et al. The prevention or delay of type 2 diabetes. Diabetes Care 2003;26(Suppl 1):S62–69.

    Google Scholar 

  31. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–1350.

    Article  PubMed  CAS  Google Scholar 

  32. 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:e443–449.

    Article  PubMed  Google Scholar 

  33. Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol 1994;13:373–383.

    Article  PubMed  CAS  Google Scholar 

  34. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550–554.

    Article  PubMed  CAS  Google Scholar 

  35. Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab 2003;88(3):1323–1332.

    Article  PubMed  CAS  Google Scholar 

  36. Holland W, Morrison T, Chang Y, Wiernsperger N, Stith BJ. Metformin (Glucophage) inhibits tyrosine phosphatase activity to stimulate the insulin receptor tyrosine kinase. Biochem Pharmacol 2004;67:2081–2091.

    Article  PubMed  CAS  Google Scholar 

  37. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–1174.

    Article  PubMed  CAS  Google Scholar 

  38. Zou MH, Kirkpatrick SS, Davis BJ, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 2004;279:43940–43951.

    Article  PubMed  CAS  Google Scholar 

  39. Lindsay JR, Duffy NA, McKillop AM, et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 2005;22:654–657.

    Article  PubMed  CAS  Google Scholar 

  40. UKPDS group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865.

    Article  Google Scholar 

  41. Mannucci E, Tesi F, Bardini G, et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr Metab 2004;17:336–342.

    PubMed  CAS  Google Scholar 

  42. Chau-Van C, Gamba M, Salvi R, Gaillard RC, Pralong FP. Metformin inhibits adenosine 5’-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology.2007;148:507–11.

    Google Scholar 

  43. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

    Article  PubMed  Google Scholar 

  44. Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care 2003;26:977.

    Article  Google Scholar 

  45. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. Indian Diabetes Prevention Program. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49:289–297.

    Google Scholar 

  46. 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.

    Article  PubMed  CAS  Google Scholar 

  47. Kay JP, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 2001;50:1457–1461.

    Article  PubMed  CAS  Google Scholar 

  48. Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, Yap F, Ward GM, Cowell CT. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab. 2006;91:2074–80.

    Article  PubMed  CAS  Google Scholar 

  49. Lustig RH, Mietus-Snyder ML, Bacchetti P, Lazar AA, Velasquez-Mieyer PA, Christensen ML. Insulin dynamics predict body mass index and z-score response to insulin suppression or sensitization pharmacotherapy in obese children. J Pediatr 2006;148:23–29.

    Article  PubMed  CAS  Google Scholar 

  50. Freemark M. Liver dysfunction in pediatric obesity and insulin resistance: a randomized, controlled trial of metformin. Acta Paediatrica, in press.

    Google Scholar 

  51. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005;21:871–879.

    Article  PubMed  CAS  Google Scholar 

  52. Hookman P, Barkin JS. Current biochemical studies of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis suggest a new therapeutic approach. Am J Gastroenterol 2003;98:2093–2097.

    PubMed  Google Scholar 

  53. Levri KM, Slaymaker E, Last A, et al. Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med 2005;3:457–461.

    Article  PubMed  Google Scholar 

  54. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951–953.

    Article  PubMed  CAS  Google Scholar 

  55. De Leo V, la Marca A, Petraglia F. Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr Rev.2003;24:633–667.

    Article  PubMed  CAS  Google Scholar 

  56. Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:2767–2774.

    Article  PubMed  CAS  Google Scholar 

  57. Orio F Jr, Palomba S, Cascella T, et al. Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. J Clin Endocrinol Metab 2005;90:6072–6076.

    Article  PubMed  CAS  Google Scholar 

  58. Bridger T, MacDonald S, Baltzer F, Rodd C. Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome. Arch Pediatr Adolesc Med 2006;160:241–246.

    Article  PubMed  Google Scholar 

  59. Allen HF, Mazzoni C, Heptulla RA, Murray MA, Miller N, Koenigs L, Reiter EO. Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome. J Pediatr Endocrinol Metab 2005;18:761–768.

    PubMed  CAS  Google Scholar 

  60. Ibanez L, Valls C, Potau N, Marcos MV, de Zegher F. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab 2000;85:3526–3530.

    Article  PubMed  CAS  Google Scholar 

  61. Ibanez L, Valls C, Ferrer A, Ong K, Dunger DB, De Zegher F. Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. J Clin Endocrinol Metab 2002;87:2870–2874.

    Article  PubMed  CAS  Google Scholar 

  62. Ibanez L, Ferrer A, Ong K, Amin R, Dunger D, de Zegher F. Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome. J Pediatr 2004;144:23–29.

    Article  PubMed  Google Scholar 

  63. Ibanez L, Valls C, Marcos MV, Ong K, Dunger DB, De Zegher F. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. J Clin Endocrinol Metab 2004;89:4331–4337.

    Article  PubMed  CAS  Google Scholar 

  64. Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de Zegher F. Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. J Clin Endocrinol Metab 2003;88:2600–2606.

    Article  PubMed  CAS  Google Scholar 

  65. Ibanez L, De Zegher F. Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception. J Clin Endocrinol Metab 2003;88:4720–4724.

    Article  PubMed  CAS  Google Scholar 

  66. Ibanez L, de Zegher F. Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. J Clin Endocrinol Metab 2004;89:1592–1597.

    Article  PubMed  CAS  Google Scholar 

  67. Ibanez L, Valls C, Cabre S, De Zegher F. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. J Clin Endocrinol Metab 2004;89:4716–4720.

    Article  PubMed  CAS  Google Scholar 

  68. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry. 2006;163(12):2072–9.

    Article  PubMed  Google Scholar 

  69. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 2003;163:2594–2602.

    Article  PubMed  Google Scholar 

  70. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 2005;28:539–543.

    Article  PubMed  CAS  Google Scholar 

  71. Artz E, Freemark M. The pathogenesis of insulin resistance in children: metabolic complications and the roles of diet, exercise and pharmacotherapy in the prevention of type 2 diabetes. Pediatr Endocrinol Rev 2004;1:296–309.

    PubMed  Google Scholar 

  72. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796–2803.

    Article  PubMed  CAS  Google Scholar 

  73. DREAM Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368:1096–1105.

    Article  CAS  Google Scholar 

  74. Freemark M. Pharmacotherapy of childhood diabetes: an evidence-based, conceptual approach. Diabetes Care 2007; 30:395–402.

    Article  PubMed  CAS  Google Scholar 

  75. Freemark M. Pharmacotherapy of childhood diabetes: a tailored approach. Rev Endocrinology 2007; 1:38–41.

    Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this chapter

Cite this chapter

Emott, M., Freemark, M. (2007). Treatment of Insulin Resistance in Youth: The Role of Metformin. In: Donohoue, P.A. (eds) Energy Metabolism and Obesity. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60327-139-4_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-139-4_13

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-671-9

  • Online ISBN: 978-1-60327-139-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics