Prediabetes and Adolescence—Trends, Causes, Effects, and Screening

US Endocrinology, 2016;12(2):94–8 DOI:


Intermediate hyperglycemia, or prediabetes, is increasing worldwide, affecting people of all ages, including adolescents. Hormonal, physiological, psychological, and lifestyle changes in adolescence have been associated with disruptions in glucose homeostasis, such as decreased insulin sensitivity, insulin resistance, or the combination of both. As a rule, glucose homeostasis is ameliorated, in normal subjects, when puberty is completed. However, in susceptible individuals, like obese adolescents, or adolescents with a strong genetic background, there is a progression to type 2 diabetes onset. Thus, susceptible adolescents should be screened for prediabetes, using fasting plasma glucose, and glycated hemoglobin (HbA1c), and oral glucose tolerance testing. Prediabetic adolescents should be counseled for a healthy lifestyle including healthy dietary habits, increased physical activity, and/or stress management. Other pathological conditions should be adequately treated. Early recognition of prediabetes in adolescence will prevent type 2 diabetes onset, decreasing the diabetes-associated health burden in adult life. This review aims to revise the associations and elucidate on the gaps between prediabetes and adolescence, via a comprehensive review of the current medical literature.
Keywords: Prediabetes, adolescence, obesity, youth, childhood, puberty
Disclosure: Charikleia Stefanaki, Flora Bacopoulou, and Melpomeni Peppa have nothing to declare in relation to this article. No funding was received in the publication of this article.
Compliance with Ethics Guidelines: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Received: November 01, 2016 Accepted December 10, 2016
Correspondence: Charikleia Stefanaki, First Department of Pediatrics, Choremeio Research Laboratory, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, 3 Thivon Street, Athens 11527, Greece. E:
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

ACCEPTED MANUSCRIPT -- This manuscript has been accepted for publication. The manuscript may undergo some minor revisions before it is published in its final form.

Diabetes is a worldwide health problem, and its prevalence is expected to rise in the coming years, not only in adults, but also in youth. The first stage is characterized by insulin resistance accompanied by a compensatory increase in insulin secretion; this stage can last several years, and it is called prediabetes. Patients with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have insulin resistance, but the site of their predominant insulin resistance differs.1,2 Prediabetes is defined by the American Diabetes Association (ADA) as a fasting glucose concentration of 100–124 mg/dl, or a HbA1c value of between 5.7% and 6.4%, or a two-hour post-glucose tolerance concentration of 140–199 mg/dl. Therefore, prediabetes includes subjects with elevated fasting plasma glucose concentrations—IFG, and normal response to a glucose load, normal glucose tolerance, subjects with abnormal postprandial glucose excursion—IGT, but normal fasting glucose concentration, or a combination of the aforementioned.3 Those with IFG have predominantly hepatic insulin resistance, whereas those with IGT have predominantly muscle insulin resistance. The increased prevalence of obesity and diabetes mellitus dictates increased awareness and early identification of diabetes.

In Saudi Arabia, the prevalence of prediabetes was equal to 5.4%, based on oral glucose tolerance test (OGTT), and 21.9% based on HbA1c.4 According to epidemiological data from the UK, the prevalence rate of prediabetes in the general population increased from 11.6% to 35.3% from 2003 to 2011.5 An increase in prediabetes prevalence has also been observed in China, where prediabetes has risen to 15.5% in the general population.6 In a national cohort study of a representative sample of adolescents, it was estimated that the national population-based prevalence rates of IFG, IGT, and prediabetes among US adolescents aged 12–19 years were 13.1%, 3.4%, and 16.1%, respectively.7 In a recent report from the US, the prevalence of prediabetes increased from 9% to 23%.8 Worldwide, epidemiological trends demonstrate increases in the prevalence of prediabetes in the general population; adolescents seem to follow these trends, irrespectively of race. One of the most important and difficult stages in life is the transition from childhood to adulthood. This stage in life is called adolescence. It is characterized by various physical, emotional, social, and sexual developments. It is well established that the first two kinds of changes are due to developmental hormonal changes occurring during adolescence. These hormonal changes have been shown to be responsible for various effects on glucose metabolism.9,10

One of the most important and difficult stages in life is the transition from childhood to adulthood. This stage in life is called adolescence. It is characterized by various physical, emotional, social, and sexual developments. It is well established that the first two kinds of changes are due to developmental hormonal changes occurring during adolescence. These hormonal changes have been shown to be responsible for various effects on glucose metabolism.9,10

Because of a disturbing increase in obesity in adolescence over the past two decades, prediabetes and metabolic syndrome in adolescents have become major public health problems.11 However, screening and prevention of prediabetes in adolescence is often overlooked, leading to an increased rate of young adults with type 2 diabetes mellitus and metabolic syndrome. Much debate has taken place concerning the cut-off values of the revised impaired fasting glucose concentration levels.12 There is still no clear consensus on the definition of prediabetes, or metabolic syndrome in adolescents. We use the criteria of prediabetes in adults. However, there are only a few observational studies about prediabetes in adolescence.

In this review, we intend to unravel the associations between the endocrine physiology of adolescence and prediabetes, summarizing all the findings, and aspiring to contribute to the awareness of prediabetes during adolescence. We performed systematic research using PubMed, EBSCO, Google Scholar databases and ResearchGate site, in relation to adolescence and prediabetes.

Glucose and insulin metabolism in adolescence
Adolescence is characterized by the domination of luteinizing hormone (LH) concentrations over those of the follicle-stimulating hormone (FSH) under the stimulating effect of the hypothalamic gonadotropin-releasing hormone (GnRH). These changes lead to the secretion of sex steroids, namely estradiol in females and testosterone in males; development of secondary sexual characteristics; growth acceleration; lean and fat mass accumulation; and observed growth spurt. During this phase, a well-described physiological decrease in insulin sensitivity occurs, which resolves after completion of puberty, possibly independently of changes in body mass index (BMI).

Onset of adolescence, Tanner staging, and glucose metabolism
GnRH resides under the control of kisspeptin, its permissive neurokinin B, and its opposing dynorphin signals.13 GnRH does not seem to be implicated in glucose homeostasis derangement. On the contrary, the hypothalamic system of kisspeptins is implicated in the secretion of insulin, as they are highly abundant in the pancreas.14 Moreover, kisspeptins seem to have a protective role in gestational diabetes onset.15 On the other hand, it has been shown that ablation of dynorphin causes increase of fatty acid oxidation in male mice, reduction in adiposity, and increased weight loss during fasting, probably due to decreases in intestinal nutrient absorption.16 There has been no study performed about neurokinin B in relation with insulin resistance, or glucose intolerance, and dynorphin does not seem to essentially affect glucose homeostasis.17 Dynorphin seems to be implicated in the pathogenesis of obesity,18 and thus it affects only indirectly the pathogenesis of prediabetes in susceptible subjects.

1. Barengolts E, Gut Microbiota, Prebiotics, Probiotics, and Synbiotics in Management of Obesity and Prediabetes: Review of Randomized Controlled Trials, Endocr Pract, 2016;22:1224–34.
2. Calanna S, Scicali R, Di Pino A, et al., Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes. Nutrition, metabolism, and cardiovascular diseases, NMCD, 2014;24:670–6.
3. Abdul-Ghani MA, Tripathy D, DeFronzo RA, Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose, Diabetes Care, 2006;29:1130–9.
4. Al Amiri E, Abdullatif M, Abdulle A, et al., The prevalence, risk factors, and screening measure for prediabetes and diabetes among Emirati overweight/obese children and adolescents, BMC Public Health, 2015;15:1298.
5. Mainous AG, 3rd, Tanner RJ, Baker R, et al., Prevalence of prediabetes in England from 2003 to 2011: population-based, cross-sectional study, BMJ Open, 2014;4:e005002.
6. Li S, Guo S, He F, et al., Prevalence of diabetes mellitus and impaired fasting glucose, associated with risk factors in rural Kazakh adults in Xinjiang, China, Int J Environ Res Public Health, 2015;12:554–65.
7. Li C, Ford ES, Zhao G, Mokdad AH, Prevalence of pre-diabetes and its association with clustering of cardiometabolic risk factors and hyperinsulinemia among U.S. adolescents: National Health and Nutrition Examination Survey 2005-2006, Diabetes Care, 2009;32:342–7.
8. May AL, Kuklina EV, Yoon PW, Prevalence of cardiovascular disease risk factors among US adolescents, 1999-2008, Pediatrics, 2012;129:1035–41.
9. Burt Solorzano CM, McCartney CR, Obesity and the pubertal transition in girls and boys, Reproduction, 2010;140:399–410.
10. Casazza K, Hanks LJ, Alvarez JA, Role of various cytokines and growth factors in pubertal development, Med Sport Sci, 2010;55:14–31.
11. Agirbasli M, Tanrikulu AM, Berenson GS, Metabolic Syndrome: Bridging the Gap from Childhood to Adulthood, Cardiovasc Ther, 2016;34:30–6.
12. Kim SH, Shim WS, Kim EA, et al., The effect of lowering the threshold for diagnosis of impaired fasting glucose, Yonsei Med J, 2008;49:217–23.
13. Livadas S, Chrousos GP, Control of the onset of puberty, Curr Opin Pediatr, 2016;28:551–8.
14. Chen J, Fu R, Cui Y, et al., LIM-homeodomain transcription factor Isl-1 mediates kisspeptin's effect on insulin secretion in mice, Mol Endocrinol, 2014;28:1276–90.
15. Cetkovic A, Miljic D, Ljubic A, Plasma kisspeptin levels in pregnancies with diabetes and hypertensive disease as a potential marker of placental dysfunction and adverse perinatal outcome, Endocr Res, 2012;37:78–88.
16. Sainsbury A, Lin S, McNamara K, et al., Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice, Mol Endocrinol, 2007;21:1722–35.
17. Szeto HH, Soong Y, Wu DL, Cheng PY, Opioid modulation of fetal glucose homeostasis: role of receptor subtypes, J Pharmacol Exp Ther, 1995;275:334–9.
18. Khawaja XZ, Chattopadhyay AK, Green IC, Increased beta-endorphin and dynorphin concentrations in discrete hypothalamic regions of genetically obese (ob/ob) mice, Brain Res, 1991;555:164–8.
19. Wang N, Kuang L, Han B, et al., Follicle-stimulating hormone associates with prediabetes and diabetes in postmenopausal women, Acta Diabetol, 2016;53:227–36.
20. Ben-Shlomo I, Homburg R, Shalev E, Hyperandrogenic anovulation (the polycystic ovary syndrome)--back to the ovary?, Hum Reprod Update, 1998;4:296–300.
21. Eriksen MB, Glintborg D, Nielsen MF, et al., Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance, Biochem Biophys Res Commun, 2014;451:622–6.
22. Moran A, Jacobs DR, Jr., Steinberger J, et al., Insulin resistance during puberty: results from clamp studies in 357 children, Diabetes, 1999;48:2039–44. 23. Kelsey MM, Zeitler PS, Insulin Resistance of Puberty, Curr Diab Rep, 2016;16:64.
24. Goran MI, Gower BA, Longitudinal study on pubertal insulin resistance, Diabetes, 2001;50:2444–50.
25. Ball GD, Huang TT, Gower BA, et al., Longitudinal changes in insulin sensitivity, insulin secretion, and beta-cell function during puberty, J Pediatr, 2006;148:16–22.
26. Hoffman RP, Vicini P, Sivitz WI, Cobelli C, Pubertal adolescent malefemale differences in insulin sensitivity and glucose effectiveness determined by the one compartment minimal model, Pediatr Res, 2000;48:384–8.
27. New perspectives in GH research. Proceedings of a symposium. Davos, Switzerland. March 7-10, 2002, Horm Res, 2002;58 (Suppl 3):1–61.
28. Moller N, Jorgensen JO, Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects, Endocr Rev, 2009;30:152–77.
29. Clark RG, Thomas GB, Mortensen DL, et al., Growth hormone secretagogues stimulate the hypothalamic-pituitary-adrenal axis and are diabetogenic in the Zucker diabetic fatty rat, Endocrinology, 1997;138:4316–23.
30. Friedrich N, Thuesen B, Jorgensen T, et al., The association between IGF-1 and insulin resistance: a general population study in Danish adults, Diabetes Care, 2012;35:768–73.
31. Dominici FP, Argentino DP, Munoz MC, et al., Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity, Growth Horm IGF Res, 2005;15:324–36.
32. Moran A, Jacobs DR, Jr., Steinberger J, et al., Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis, J Clin Endocrinol Metab, 2002;87:4817–20.
33. Lee JM, Appugliese D, Kaciroti N, et al., Weight status in young girls and the onset of puberty, Pediatrics, 2007;119:e624–30.
34. Tomova A, Robeva R, Kumanov P, Influence of the body weight on the onset and progression of puberty in boys, J Pediatr Endocrinol Metab, 2015;28:859–65.
35. Paltoglou G, Fatouros IG, Valsamakis G, et al., Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion, Pediatr Res, 2015;78:158–64.
36. Wang Y, Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls, Pediatrics, 2002;110:903–10.
37. Babaoglu K, Hatun S, Arslanoglu I, et al., Evaluation of glucose intolerance in adolescents relative to adults with type 2 diabetes mellitus, J Pediatr Endocrinol Metab, 2006;19:1319–26.
38. Bacha F, Lee S, Gungor N, Arslanian SA, From pre-diabetes to type 2 diabetes in obese youth: pathophysiological characteristics along the spectrum of glucose dysregulation, Diabetes Care, 2010;33:2225–31.
39. Bacha F, Edmundowicz D, Sutton-Tyrell K, et al., Coronary artery calcification in obese youth: what are the phenotypic and metabolic determinants?, Diabetes Care, 2014;37:2632–9.
40. DeFronzo RA, Abdul-Ghani M, Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose, Am J Cardiol, 2011;108:3B–24B.
41. Alisi A, Nobili V, Non-alcoholic fatty liver disease in children now: lifestyle changes and pharmacologic treatments, Nutrition, 2012;28:722–6.
42. Adams LA, Angulo P, Recent concepts in non-alcoholic fatty liver disease, Diabet Med, 2005;22:1129–33.
43. Huang RC, Beilin LJ, Ayonrinde O, et al., Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents, Hepatology, 2013;58:1306–14.
44. Sert A, Pirgon O, Aypar E, et al., Relationship between left ventricular mass and carotid intima media thickness in obese adolescents with non-alcoholic fatty liver disease, J Pediatr Endocrinol Metab, 2012;25:927–34.
45. Vajro P, Lenta S, Socha P, et al., Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr, 2012;54:700–13.
46. Spruijt-Metz D, O'Reilly GA, Cook L, et al., Behavioral contributions to the pathogenesis of type 2 diabetes, Curr Diab Rep, 2014;14:475.
47. Wagner KA, Armah SM, Smith LG, et al., Associations between Diet Behaviors and Measures of Glycemia, in Clinical Setting, in Obese Adolescents, Child Obes, 2016;12:341–7.
48. Joslowski G, Halim J, Goletzke J, et al., Dietary glycemic load, insulin load, and weight loss in obese, insulin resistant adolescents: RESIST study, Clin Nutr, 2015;34:89–94.
49. Gibb RD, McRorie JW, Jr., Russell DA, et al., Psyllium fiber improves glycemic control proportional to loss of glycemic control: a metaanalysis of data in euglycemic subjects, patients at risk of type 2 diabetes mellitus, and patients being treated for type 2 diabetes mellitus, Am J Clin Nutr, 2015;102:1604–14.
50. Ahluwalia N, Herrick K, Caffeine intake from food and beverage sources and trends among children and adolescents in the United States: review of national quantitative studies from 1999 to 2011, Adv Nutr, 2015;6:102–11.
51. Pan XR, Li GW, Hu YH, et al., Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study, Diabetes Care, 1997;20:537–44.
52. Seth A, Sharma R, Childhood obesity, Indian J Pediatr, 2013;80:309–17.
53. El Ansari W, Berg-Beckhoff G, Nutritional Correlates of Perceived Stress among University Students in Egypt, Int J Environ Res Public Health, 2015;12:14164–76.
54. Sirri L, Ricci Garotti MG, Grandi S, Tossani E, Adolescents' hypochondriacal fears and beliefs: Relationship with demographic features, psychological distress, well-being and health-related behaviors, J Psychosom Res, 2015;79:259–64.
55. Knoll LJ, Magis-Weinberg L, Speekenbrink M, Blakemore SJ, Social influence on risk perception during adolescence, Psychol Sci, 2015;26:583–92.
56. Charmandari E, Achermann JC, Carel JC, et al., Stress response and child health, Sci Signal, 2012;5(248):mr1 57. American Diabetes Association, Standards of medical care in diabetes-2015 abridged for primary care providers, Clin Diabetes, 2015;33(2):97–111.
58. Gomez-Ambrosi J, Silva C, Galofre JC, et al., Body adiposity and type 2 diabetes: increased risk with a high body fat percentage even having a normal BMI, Obesity, 2011;19:1439–44.
59. Gomez-Ambrosi J, Silva C, Galofre JC, et al., Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity, Int J Obes (Lond), 2012;36:286–94.
60. Caprio S, Development of type 2 diabetes mellitus in the obese adolescent: a growing challenge, Endocr Pract, 2012;18:791–5.
61. Cosson E, Hamo-Tchatchouang E, Banu I, et al., A large proportion of prediabetes and diabetes goes undiagnosed when only fasting plasma glucose and/or HbA1c are measured in overweight or obese patients, Diabetes Metab, 2010;36:312–8.
62. Incani M, Sentinelli F, Perra L, et al., Glycated hemoglobin for the diagnosis of diabetes and prediabetes: Diagnostic impact on obese and lean subjects, and phenotypic characterization, J Diabetes Investig, 2015;6:44–50.
Keywords: Prediabetes, adolescence, obesity, youth, childhood, puberty