Main Article Content
Oral glucose tolerance test, glucose dysregulation, ADA recommendation, analytical variables, children, adolescents.
Background: Recently, the validity of the oral glucose tolerance test (OGTT) as a gold-standard test for the diagnosis of glucose dysregulation (GD) has been questioned due to the pre-analytical, analytical, and post-analytical variables which can potentially affect its reproducibility and accuracy.
Aims: In this short update, the many variables that affect the reproducibility and accuracy of the OGTT are described and discussed aiming to enhance its diagnostic value in clinical practice.
Search strategy: A systematic search was implemented in June 2022, using Scopus, PubMed, Embase and Google Scholar focusing on OGTT relevant papers published in the last 10 years. Moreover, the reference lists of these articles were checked for additional pertinent studies. The research and selection of articles was also supported by the long-term authors' experience in the use of OGTT for the diagnosis of GD in children and adolescents.
Conclusion: The complexity of diagnosing GD presupposes that clinicians have specific knowledge and experience to perform rigorous assessment of glucose metabolism. It is worth mentioning that during OGTT, subjects with glucose levels close to the cut-off values proposed by WHO (World Health Organization)/ADA (American Diabetes Association) require careful evaluation in order to avoid misclassification and unnecessary interventions. For this reason, ADA recommends a second test to confirm the diagnosis of diabetes.
2. Pettitt DJ, Talton J, Dabelea D, et al.; SEARCH for Diabetes in Youth Study Group. Prevalence of diabetes in U.S. youth in 2009: the SEARCH for Diabetes in Youth Study. Diabetes Care 2014;37:402–8.
3. Garvick S, Altenburg L, Dunlap B, Fisher A, Watson A, Gregory T. Diagnosis and management of type 2 diabetes in children. JAAPA 2022;35:16-22.
4. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes–2020. Diabetes Care. 2020; 43 (Suppl 1):S14–S31.
5. De Sanctis V, Daar S, Soliman AT, et al. Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience. Acta Biomed 2022;93(1):e2022158.
6. Jang T, Mo G, Stewart C, et al. Obesity and diabetes mellitus in patients with sickle cell disease. Ann Hematol 2021;100:2203-5.
7. Khare S, Desimone M, Kasim N, Chan CL. Cystic fibrosis-related diabetes: Prevalence, screening, and diagnosis. J Clin Transl Endocrinol 2021;27:100290.
8. Moran A, Pillay K, Becker D, Granados A, Hameed S, Acerini CL. ISPAD Clinical Practice Consensus Guidelines 2018: Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2018;19:64–74.
9. Guner Ozenen G, Aksoylar S, Goksen D, et al. Metabolic syndrome and risk factors after hematopoietic stem cell transplantation in children and adolescents. J Pediatr Endocrinol Metab 2021;34:485-93.
10. Campos C. Chronic hyperglycemia and glucose toxicity: pathology and clinical sequelae. Postgrad Med 2012;124:90-7.
11. Bogdanet D, O'Shea P, Lyons C, Shafat A, Dunne F. The Oral Glucose Tolerance Test-Is It Time for a Change?-A Literature Review with an Emphasis on Pregnancy. J Clin Med 2020;9 (11):3451.
12. Hovestadt I, Kiess W, Lewien C,et al. HbA1c percentiles and the association between BMI, age, gender, puberty, and HbA1c levels in healthy German children and adolescents. Pediatr Diabetes 2022;23194-202.
13. Nam HK, Cho WK, Kim JH, et al. HbA1c Cutoff for Prediabetes and Diabetes Based on Oral Glucose Tolerance Test in Obese Children and Adolescents. J Korean Med Sci 2018;33(12):e93.
14. Klein KR, Walker CP, McFerren AL, Huffman H, Frohlich F, Buse JB. Carbohydrate Intake Prior to Oral Glucose Tolerance Testing. J Endocr Soc 2021;5(5):bvab049.
15. Jagannathan R, Neves JS, Dorcely B, et al . The Oral Glucose Tolerance Test: 100 Years Later. Diabetes Metab Syndr Obes 2020;13:3787-805.
16. Sacks DB. Carbohydrates. In: Burtis CA, Ash-wood ER, Bruns DE, eds. Tietz textbook of clinical chemistry and molecular diagnostics. 4th ed. St. Louis: Elsevier Saunders 2006, pp. 837– 902.
17. Bansal N. Prediabetes diagnosis and treatment: A review. World J Diabetes 2015;6:296-303.
18. World Health Organization. Classification of diabetes mellitus. Geneva: World Health Organization; 2019.
19. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021;44 (Suppl 1):S15-S33.
20. Chatterton H, Younger T, Fischer A, Khunti K; Programme Development Group. Risk identification and interventions to prevent type 2 diabetes in adults at high risk: summary of NICE guidance. BMJ 2012;345:
21. 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;93:1767–73.
22. Nathan D M, Davidson MB, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance: Implications for care. Diabetes Care 2007;30:753–9.
23. Qiao Q, Lindstrom J, Valle TT, Tuomilehto J. Progression to clinically diagnosed and treated diabetes from impaired glucose tolerance and impaired fasting glycaemia. Diabet Med 2003;20:1027–33.
24. Levitan EB, Song Y, Ford ES, Liu S. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med 2004;164:2147–55.
25. Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005;293:194–202.
26. Reinehr T, Kiess W, de Sousa G, Stoffel-Wagner B, Wunsch R. Intima media thickness in childhood obesity: relations to inflammatory marker, glucose metabolism, and blood pressure. Metabolism 2006; 55:113–8.
27. Hagman E, Reinehr T, Kowalski J, Ekbom A, Marcus C, Holl RW. Impaired fasting glucose prevalence in two nationwide cohorts of obese children and adolescents. Int J Obes (Lond) 2014;38:40-5.
28. Ehtisham S, Shaw N, Kirk J, Barrett T. Development of an assessment tool for screening children for glucose intolerance by oral glucose tolerance test. Diabetes Care 2004;27:280–1.
29. Libman IM, Barinas-Mitchell E, Bartucci A, Robertson R, Arslanian S. Reproducibility of the Oral Glucose Tolerance Test in Overweight Children. Clin Endocrinol Metab 2008;93:4231–7.
30. Kostopoulou E, Skiadopoulos S, Partsalaki I, Rojas Gil AP, Spiliotis BE. Repetitiveness of the oral glucose tolerance test in children and adolescents. World J Clin Pediatr 2021;10:29-39.
31. Scheuing N, Holl RW, Dockter G, et al. High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study. PLoS One 2014;9 (11):e 112578.
32. Selvin E, Crainiceanu CM, Brancati FL, Coresh J.Short-term variability in measures of glycemia and implications for the classification of diabetes. Arch Intern Med 2007;167: 1545–1551.
33. Lanng S, Hansen A, Thorsteinsson B, Koch C. Glucose tolerance in patients with cystic fibrosis: five year prospective study. BMJ 1995; 311:655–9.
34. De Sanctis V, Daar S, Soliman AT, Tzoulis P, Karimi M, Di Maio S, Kattamis C. Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience. Acta Biomed. 2022;93(1):e2022158.
35. Kramer CK, Ye C, Hanley AJ, et al. Delayed timing of post-challenge peak blood glucose predicts declining beta cell function and worsening glucose tolerance over time: insight from the first year postpartum. Diabetologia 2015;58:1354-62.
36. Chung ST, Ha J, Onuzuruike AU, et al . Time to glucose peak during an oral glucose tolerance test identifies prediabetes risk. Clin Endocrinol (Oxf) 2017;87:484–91.
37. Lin YC, Chen HS. Longer time to peak glucose during the oral glucose tolerance test increases cardiovascular risk score and diabetes prevalence. PLoS One 2017;12:e0189047.
38. Kim JY, Tfayli H, Bacha F, et al. β-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak. Pediatr Diabetes 2020;21:18-27.
39. Kramer CK, Vuksan V, Choi H, Zinman B, Retnakaran R. Emerging parameters of the insulin and glucose response on the oral glucose tolerance test: reproducibility and implications for glucose homeostasis in individuals with and without diabetes. Diabetes Res Clin Pract 2014;105:88-95.
40. Bergman M, Abdul-Ghani M, DeFronzo RA, et al.. Review of methods for detecting glycemic disorders. Diabetes Res Clin Pract. 2020;165:108233.
41. Tricò D, Galderisi A, Mari A, Santoro N, Caprio S. One-hour post-load plasma glucose predicts progression to prediabetes in a multi-ethnic cohort of obese youths. Diabetes Obes Metab. 2019;21:1191-8.
42. Kasturi K, Onuzuruike AU, Kunnam S, Shomaker LB, Yanovski JA, Chung ST. Two- vs one-hour glucose tolerance testing: Predicting prediabetes in adolescent girls with obesity. Pediatr Diabetes.2019; 20:154-9.
43. Kim JY, Coletta DK, Mandarino LJ, Shaibi GQ. Glucose response curve and type 2 diabetes risk
in Latino adolescents. Diabetes Care 2012;35: 1925–30.
44. Nolfe G, Spreghini MR, Sforza RW, Morino G, Manco M. Beyond the morphology of the glucose
curve following an oral glucose tolerance test in obese youth. Eur J Endocrinol 2012;166: 107–14.
45. Bervoets L, Mewis A, Massa G. The shape of the plasma glucose curve during an oral glucose
tolerance test as an indicator of beta cell function and insulin sensitivity in end-pubertal obese
girls. Horm Metab Res 2015;47:445–51.
46 Ismail HM, Xu P, Libman IM, et al. Type 1 Diabetes TrialNet Study Group. The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. Diabetologia. 2018;61:84-92.
47. Kim JY, Michaliszyn SF, Nasr A, et al. The shape of the glucose response curve during an oral glucose tolerance test heralds biomarkers of type 2 diabetes risk in obese youth. Diabetes Care 2016; 39:1431–9.
48. Bergman M, Manco M, Sesti G,et al. Petition to replace current OGTT criteria for diagnosing prediabetes with the 1-hour post-load plasma glucose ≥ 155 mg/dl (8.6 mmol/L) Diabetes Res Clin Pract 2018;146:18–33.
49. Cheng KC, Li Y, Cheng JT. Limitations of Oral Glucose Tolerance Test in Animal Studies. J Diabetes Treat 2018:JDBT–146.
50. Standards Australia . Australian standard glycemic index of food. Sydney: Standards Australia; 2007.
51. Terra SG, Somayaji V, Schwartz S, et al. A dose-ranging study of the DPP-IV inhibitor PF-734200 added to metformin in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 2011;119:401–7.
52. Sakaguchi K, Takeda K, Maeda M, et al. Glucose area under the curve during oral glucose tolerance test as an index of glucose intolerance. Diabetol Int 2015;7:53-8.
53. Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 2007; 30: 89–94.
54. Al-Beltagi M, Bediwy AS, Saeed NK. Insulin-resistance in paediatric age: Its magnitude and implications. World J Diabetes 2022;13:282-307.
55. Erdős B, van Sloun B, Adriaens ME, et al. Personalized computational model quantifies
heterogeneity in postprandial responses to oral glucose challenge. PLoS Comput Biol 2021;17(3):
56. Pasqualetti S, Braga F, Panteghini M. Pre-analytical and analytical aspects affecting clinical reliability of plasma glucose results. Clin Biochem 2017;50:587-94.
57. Troisi RJ, Cowie CC, Harris MI. Diurnal variation in fasting plasma glucose: implications for diagnosis of diabetes in patients examined in the afternoon. JAMA 2000;284:3157–9.
58.Almomin AMS, Odhaib SA, Altemimi MT, et al. Serum Glucose Measurement after Five to Six Hours is Comparable to Eight Hours Fasting in Ramadan. Sultan Qaboos Univ Med J 2022;22:123-8.
59. Moebus S, Göres L, Lösch C, Jöckel KH. Impact of time since last caloric intake on blood glucose levels. Eur J Epidemiol 2011;26: 719–28.
60. Heinemann L. Are all glucose solutions used for oGTT equal? Diabet Med 2022;39(5):e14798.
61. Palmu S, Kuneinen S, Kautiainen H, Eriksson JG, Korhonen PE. Body surface area may explain sex differences in findings from the oral glucose tolerance test among subjects with normal glucose tolerance. Nutr Metab Cardiovasc Dis 2021;31:2678-84.
62. Palmu S, Rehunen S, Kautiainen H, Eriksson JG, Korhonen PE. Body surface area and glucose tolerance - The smaller the person, the greater the 2-hour plasma glucose. Diabetes Res Clin Pract 2019;157:107877.
63 Sicree RA, Zimmet PZ, Dunstan DW, Cameron AJ, Welborn TA, Shaw JE. Differences in height explain gender differences in the response to the oral glucose tolerance test- the Aus Diab study. Diabet Med 2008; 25:296-302.
64. Higgins C. Measurement of circulating glucose: The problem of inconsistent sample and methodology. Acute care testing.org 2008;1-9.
65. D’Orazio P, Burnett R Fogh-Anderson N, et al. Approved IFCC recommendation on reporting results for blood glucose. Clin Chem Lab Med 2006; 44: 1486-89.
66. Sacks DB. Carbohydrates. In: Burtis CA, Ash-wood ER, Bruns DE, eds. Tietz textbook of clinical chemistry and molecular diagnostics. 4th ed. St. Louis: Elsevier Saunders; 2006. p 837– 902.
67. Chan AYW, Swaminanthan R, Cockram CS. Effectiveness of sodium fluoride as a preservative of
glucose in blood. Clin Chem 1989;35:315–7.
68. World Health Organization (WHO). Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF Consultation. Geneva: World Health Org. 2006.
69. Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011;57:e1-47
70. Lippi G, Nybo M, Cadamuro J, Guimaraes JT, van Dongen-Lases E, Simundic AM.Blood glucose
determination: effect of tube additives. Adv Clin Chem 2018;84:101–23.
71. Norman M, Jones I. The shift from fluoride/ oxalate to acid citrate/fluoride blood collection
tubes for glucose testing - the impact upon patient results. Clin Biochem 2014;47:683– 5.
72. van den Berg SA, Thelen MH, Salden LP, van Thiel SW, Boonen KJ. It takes acid, rather than ice, to freeze glucose. Sci Rep 2015;5:8875.
73. Bonetti G, Cancelli V, Coccoli G, et al. Which sample tube should be used for routine glucose determination? Prim Care Diabetes 2016;10: 227–32.
74. van Balveren JA, Huijskens MJ, Gemen EF, Pequeriaux NC, Kusters R. Effects of time and temperature on 48 routine chemistry, haematology and coagulation analytes in whole blood samples. Ann Clin Biochem 2017;54:448–62.
75. Hal-Hinai H, Al-Ghatreefy O, Al Jafari S, Al Hadabi S, Sadek H. Glucose Estimation: The most suitable blood collection tube for glucose estimation.J Med Sc Clin Res 2019;7:394-404.
76. Burtis CA, Ashwood ER, Bruns DE. Tietz textbook of clinical chemistry and molecular diagnostics-e-book. Amsterdam: Elsevier Health Sciences; 2012.
77. Walshaw M. Routine OGTT screening for CFRD - no thanks. J R Soc Med 2009;102 (Suppl 1):40-4.
78. Chan CL, Pyle L, Newnes L, Nadeau KJ, Zeitler PS, Kelsey MM. Continuous glucose monitoring and its relationship to hemoglobin A1c and oral glucose tolerance testing in obese and prediabetic youth. J Clin Endocrinol Metab 2015;100:902-10.
79. Færch K, Amadid H, Bruhn L, et al. Discordance Between Glucose Levels Measured in Interstitial Fluid vs in Venous Plasma After Oral Glucose Administration: A Post-Hoc Analysis From the Randomised Controlled PRE-D Trial. Front Endocrinol (Lausanne) 2021;12:753810.