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World Journal of Pediatrics

, Volume 9, Issue 4, pp 293–299 | Cite as

Type 2 diabetes mellitus in pediatrics: a new challenge

Review article

Abstract

Background

The increased prevalence of childhood obesity in the last few years has been accompanied by the increase in prevalence of type 2 diabetes in pediatrics. In this paper, we will review the risk factors and the pathogenic determinants leading to type 2 diabetes in youth.

Data sources

We searched on PubMed with the key words: obesity, type 2 diabetes, children, adolescents, youth, non-alcoholic fatty liver disease, genes and selected those publications written in English that we judged to be relevant to the topic of the review.

Results

Based on the data present in the literature, we reviewed the following three topics: 1) the role of ectopic fat deposition, in particular of fatty liver, in the pathogenesis of pediatric type 2 diabetes; 2) the progression to type 2 diabetes in pediatrics and how it differs from adults, and 3) current theraputic options.

Conclusion

Type 2 diabetes in youth is a complex disease, creating new challenges in treatment and prevention.

Key words

non-alcoholic fatty liver disease obesity type 2 diabetes mellitus 

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References

  1. 1.
    de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010;92:1257–1264.PubMedCrossRefGoogle Scholar
  2. 2.
    Imperatore G, Boyle JP, Thompson TJ, Case D, Dabelea D, Hamman RF, et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care 2012;35:2515–2520.PubMedCrossRefGoogle Scholar
  3. 3.
    American Diabetes A. Standards of medical care in diabetes—2013. Diabetes Care 2013;36Suppl 1:S11–66.CrossRefGoogle Scholar
  4. 4.
    Cali AM, Bonadonna RC, Trombetta M, Weiss R, Caprio S. Metabolic abnormalities underlying the different prediabetic phenotypes in obese adolescents. J Clin Endocrinol Metab 2008;93:1767–1773.PubMedCrossRefGoogle Scholar
  5. 5.
    Rohlfing CL, Little RR, Wiedmeyer HM, England JD, Madsen R, Harris MI, et al. Use of GHb (HbA1c) in screening for undiagnosed diabetes in the U.S. population. Diabetes Care 2000;23:187–191.PubMedCrossRefGoogle Scholar
  6. 6.
    Pradhan AD, Rifai N, Buring JE, Ridker PM. Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women. Am J Med 2007;120:720–727.PubMedCrossRefGoogle Scholar
  7. 7.
    Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800–811.PubMedCrossRefGoogle Scholar
  8. 8.
    Nowicka P, Santoro N, Liu H, Lartaud D, Shaw MM, Goldberg R, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–1311.PubMedCrossRefGoogle Scholar
  9. 9.
    Liska D, Dufour S, Zern TL, Taksali S, Cali AM, Dziura J, et al. Interethnic differences in muscle, liver and abdominal fat partitioning in obese adolescents. PLoS One 2007;2:e569.PubMedCrossRefGoogle Scholar
  10. 10.
    Taksali SE, Caprio S, Dziura J, Dufour S, Cali AM, Goodman TR, et al. High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype. Diabetes 2008;57:367–371.PubMedCrossRefGoogle Scholar
  11. 11.
    Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, et al. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003;362:951–957.PubMedCrossRefGoogle Scholar
  12. 12.
    Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012;148:852–871.PubMedCrossRefGoogle Scholar
  13. 13.
    Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology 2009;49:1896–1903.PubMedCrossRefGoogle Scholar
  14. 14.
    D’Adamo E, Cali AM, Weiss R, Santoro N, Pierpont B, Northrup V, et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care 2010;33:1817–1822.PubMedCrossRefGoogle Scholar
  15. 15.
    Kim G, Giannini C, Pierpont B, Feldstein AE, Santoro N, Kursawe R, et al. Longitudinal effects of MRI-measured hepatic steatosis on biomarkers of glucose homeostasis and hepatic apoptosis in obese youth. Diabetes Care 2013;36:130–136.PubMedCrossRefGoogle Scholar
  16. 16.
    Mencin AA, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Pediatr Clin North Am 2011;58:1375–1392, x.PubMedCrossRefGoogle Scholar
  17. 17.
    Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388–1393.PubMedCrossRefGoogle Scholar
  18. 18.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592–1609.PubMedCrossRefGoogle Scholar
  19. 19.
    Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T, Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 1984;3:408–414.PubMedCrossRefGoogle Scholar
  20. 20.
    Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of nonalcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009;58:1538–1544.PubMedCrossRefGoogle Scholar
  21. 21.
    Santoro N, Feldstein AE, Enoksson E, Pierpont B, Kursawe R, Kim G, et al. The association between hepatic fat content and liver injury in obese children and adolescents: effects of ethnicity, insulin resistance, and common gene variants. Diabetes Care 2013;36:1353–1360.PubMedCrossRefGoogle Scholar
  22. 22.
    Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 2009;49:791–801.PubMedCrossRefGoogle Scholar
  23. 23.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465.PubMedCrossRefGoogle Scholar
  24. 24.
    Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012;55:781–789.PubMedCrossRefGoogle Scholar
  25. 25.
    Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One 2012;7:e37827.PubMedCrossRefGoogle Scholar
  26. 26.
    Santoro N, Kursawe R, D’Adamo E, Dykas DJ, Zhang CK, Bale AE, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010;52:1281–1290.PubMedCrossRefGoogle Scholar
  27. 27.
    Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7:e1001324.PubMedCrossRefGoogle Scholar
  28. 28.
    Giannini C, Caprio S. Islet function in obese adolescents. Diabetes Obes Metab 2012;14Suppl 3:40–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Yeckel CW, Taksali SE, Dziura J, Weiss R, Burgert TS, Sherwin RS, et al. The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance. J Clin Endocrinol Metab 2005;90:747–754.PubMedCrossRefGoogle Scholar
  30. 30.
    Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R. Beta-cell function across the spectrum of glucose tolerance in obese youth. Diabetes 2005;54:1735–1743.PubMedCrossRefGoogle Scholar
  31. 31.
    Cali AM, Man CD, Cobelli C, Dziura J, Seyal A, Shaw M, et al. Primary defects in beta-cell function further exacerbated by worsening of insulin resistance mark the development of impaired glucose tolerance in obese adolescents. Diabetes Care 2009;32:456–461.PubMedCrossRefGoogle Scholar
  32. 32.
    Giannini C, Weiss R, Cali A, Bonadonna R, Santoro N, Pierpont B, et al. Evidence for early defects in insulin sensitivity and secretion before the onset of glucose dysregulation in obese youths: a longitudinal study. Diabetes 2012;61:606–614.PubMedCrossRefGoogle Scholar
  33. 33.
    Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, et al. Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 1997;46:701–710.PubMedCrossRefGoogle Scholar
  34. 34.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 1988;319:1500–1506.PubMedCrossRefGoogle Scholar
  35. 35.
    Gungor N, Arslanian S. Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr 2004;144:656–659.PubMedCrossRefGoogle Scholar
  36. 36.
    Ahlqvist E, Ahluwalia TS, Groop L. Genetics of type 2 diabetes. Clin Chem 2011;57:241–254.PubMedCrossRefGoogle Scholar
  37. 37.
    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci 2010;1212:59–77.PubMedCrossRefGoogle Scholar
  39. 39.
    Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, et al. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab 2012;16:122–134.PubMedCrossRefGoogle Scholar
  40. 40.
    Andersson SA, Olsson AH, Esguerra JL, Heimann E, Ladenvall C, Edlund A, et al. Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes. Mol Cell Endocrinol 2012;364:36–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Dabelea D, Dolan LM, D’Agostino R Jr, Hernandez AM, McAteer JB, Hamman RF, et al. Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth. Diabetologia 2011;54:535–539.PubMedCrossRefGoogle Scholar
  42. 42.
    Barker A, Sharp SJ, Timpson NJ, Bouatia-Naji N, Warrington NM, Kanoni S, et al. Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children. Diabetes 2011;60:1805–1812.PubMedCrossRefGoogle Scholar
  43. 43.
    Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 2008;359:2220–2232.PubMedCrossRefGoogle Scholar
  44. 44.
    Meigs JB, Shrader P, Sullivan LM, McAteer JB, Fox CS, Dupuis J, et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008;359:2208–2219.PubMedCrossRefGoogle Scholar
  45. 45.
    de Miguel-Yanes JM, Shrader P, Pencina MJ, Fox CS, Manning AK, Grant RW, et al. Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms. Diabetes Care 2011;34:121–125.PubMedCrossRefGoogle Scholar
  46. 46.
    Balkau B, Lange C, Fezeu L, Tichet J, de Lauzon-Guillain B, Czernichow S, et al. Predicting diabetes: clinical, biological, and genetic approaches: data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR). Diabetes Care 2008;31:2056–2061.PubMedCrossRefGoogle Scholar
  47. 47.
    van Hoek M, Dehghan A, Witteman JC, van Duijn CM, Uitterlinden AG, Oostra BA, et al. Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes 2008;57:3122–3128.PubMedCrossRefGoogle Scholar
  48. 48.
    Vaxillaire M, Veslot J, Dina C, Proenca C, Cauchi S, Charpentier G, et al. Impact of common type 2 diabetes risk polymorphisms in the DESIR prospective study. Diabetes 2008;57:244–254.PubMedCrossRefGoogle Scholar
  49. 49.
    Talmud PJ, Hingorani AD, Cooper JA, Marmot MG, Brunner EJ, Kumari M, et al. Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study. BMJ 2010;340:b4838.PubMedCrossRefGoogle Scholar
  50. 50.
    Vassy JL, Durant NH, Kabagambe EK, Carnethon MR, Rasmussen-Torvik LJ, Fornage M, et al. A genotype risk score predicts type 2 diabetes from young adulthood: the CARDIA study. Diabetologia 2012;55:2604–2612.PubMedCrossRefGoogle Scholar
  51. 51.
    Giannini C, Man CD, Groop L, Cobelli C, Zhao H, Shaw MM, et al. The co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes. Diabetes Care 2013. Sep 23.[Epub ahead of print]Google Scholar
  52. 52.
    Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010;42:579–589.PubMedCrossRefGoogle Scholar
  53. 53.
    Group TS, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247–2256.CrossRefGoogle Scholar
  54. 54.
    Allen DB. TODAY—a stark glimpse of tomorrow. N Engl J Med 2012;366:2315–2316.PubMedCrossRefGoogle Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of PediatricsYale University School of MedicineNew HavenUSA
  2. 2.Department of PediatricsYale University School of MedicineNew HavenUSA

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