Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Diabetes Reports
Published in: Current Diabetes Reports 1/2013

01-02-2013 | Pediatric Type 2 Diabetes (PS Zeitler, Section Editor)

Progression of β-Cell Dysfunction in Obese Youth

Authors: Cosimo Giannini, Sonia Caprio

Published in: Current Diabetes Reports | Issue 1/2013

Login to get access

Abstract

The epidemic of childhood obesity has led to a remarkable increase in the prevalence of type 2 diabetes (T2D) among youth worldwide. The decreasing age at onset of T2D has alarming public health implications. In particular, the longer duration of the disease, as well as the faster onset and progression of T2D related complications, will present a considerable burden for young adults and a strain on public health. Therefore, it is important to understand the pathophysiology of early phases of disruption of glucose tolerance and identify those critical points in which diabetes may be prevented. β-Cell dysfunction has been shown to represent one of the key pathogenetic defects underlying the progression to diabetes in obese youth. In the present review, we describe longitudinal and cross-sectional studies of changes in insulin sensitivity and secretion across the spectrum of glucose tolerance in obese adolescents. Further, the role of ectopic fat accumulation is discussed in relation to its association with both β-cell dysfunction and insulin resistance.
Literature
1.
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA. 2012;307(5):483–90
2.
Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2011;363(23):2211–9.
3.
Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet. 2010;375:1737–48.
4.
Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr. 2005;146:693–700.PubMedCrossRef
5.
• Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96:159–67. This paper is important because the large sample size (a prospective cross-sectional study of 704 adolescents with recent-onset T2D) and ethnic/racial diversity of the TODAY study participants represents the largest and best characterized sample of American youth with recent-onset T2D. Results from this study provide the most current data on the prevalence of autoimmunity in phenotypic T2D youth in the United States and particularly show youth with type 2 diabetes are: high percentage of women; Hispanics and non-Hispanic Blacks; and present relevant baseline abnormalities including high blood pressure, low HDL, elevated triglycerides, and microalbuminuria.PubMedCrossRef
6.
Dabelea D, Bell RA, D'Agostino Jr RB, Imperatore G, Johansen JM, Linder B, et al. Incidence of diabetes in youth in the United States. JAMA. 2007;297:2716–24.PubMedCrossRef
7.
Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 2000;23:381–9.
8.
Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care. 2004;27:1798–811.PubMedCrossRef
9.
Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003–2006. JAMA. 2008;299:2401–5.PubMedCrossRef
10.
Goran MI, Ball GD, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab. 2003;88:1417–27.PubMedCrossRef
11.
Elder DA, Herbers PM, Weis T, Standiford D, Woo JG, D’Alessio DA. beta-cell dysfunction in adolescents and adults with newly diagnosed type 2 diabetes mellitus. J Pediatr. 2012;160:904–10.PubMedCrossRef
12.
• Pinhas-Hamiel O, Zeitler P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet. 2007;369:1823–31. In this review authors described the main complications associated with type 2 diabetes in youth.PubMedCrossRef
13.
•• Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–56. This paper is important because using a well characterized large population it clearly highlights the difficulty in treating this disease in the pediatric population.PubMedCrossRef
14.
Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346:802–10.PubMedCrossRef
15.
Baranowski T, Cooper DM, Harrell J, Hirst K, Kaufman FR, Goran M, et al. Presence of diabetes risk factors in a large U.S. eighth-grade cohort. Diabetes Care. 2006;29:212–7.PubMedCrossRef
16.
Goran MI, Bergman RN, Avila Q, Watkins M, Ball GD, Shaibi GQ, et al. Impaired glucose tolerance and reduced beta-cell function in overweight Latino children with a positive family history for type 2 diabetes. J Clin Endocrinol Metab. 2004;89:207–12.PubMedCrossRef
17.
Csabi G, Torok K, Jeges S, Molnar D. Presence of metabolic cardiovascular syndrome in obese children. Eur J Pediatr. 2000;159:91–4.PubMedCrossRef
18.
19.
D'Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care. 2011;34 Suppl 2:S161–5.PubMedCrossRef
20.
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;46:701–10.PubMedCrossRef
21.
Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28:902–9.PubMedCrossRef
22.
Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ. Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care. 2003;26:2871–5.PubMedCrossRef
23.
Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.PubMedCrossRef
24.
Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia. 2002;45:85–96.PubMedCrossRef
25.
Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003;88:2300–8.PubMedCrossRef
26.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.PubMedCrossRef
27.
Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, et al. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008;57:1584–94.PubMedCrossRef
28.
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;54:1735–43.PubMedCrossRef
29.
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;32:456–61.PubMedCrossRef
30.
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.PubMedCrossRef
31.
•• 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;61:606–14. In this prospective longitudinal cohort study, authors evaluated insulin secretion by applying mathematical modeling during the hyperglycemic clamp and insulin sensitivity by hyperinsulinemic-euglycemic clamp in a group of obese NGT and IGT adolescents. In addition, glucose tolerance was reevaluated after 2 years. Data at baseline indicates that even within NGT individuals, oDI worsens as 2 h glucose tolerance test values increase. Longitudinal data shows progressors from NGT gained weight and had beta-cell defects predicting the risk of developing glucose alteration at follow up.PubMedCrossRef
32.
•• Goran MI, Lane C, Toledo-Corral C, Weigensberg MJ. Persistence of pre-diabetes in overweight and obese Hispanic children: association with progressive insulin resistance, poor beta-cell function, and increasing visceral fat. Diabetes. 2008;57:3007–12. In this longitudinal study, Hispanic adolescents were longitudinally evaluated in order to characterize the risk of developing type 2 Diabetes. Results showed that the persistence of impaired glucose tolerance over time represents a relevant risk factor in predicting the risk of progression.PubMedCrossRef
33.
Tfayli H, Lee S, Arslanian S. Declining beta-cell function relative to insulin sensitivity with increasing fasting glucose levels in the nondiabetic range in children. Diabetes Care. 2010;33:2024–30.
34.
35.
Cossrow N, Falkner B. Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab. 2004;89:2590–4.PubMedCrossRef
36.
Arslanian S, Suprasongsin C. Insulin sensitivity, lipids, and body composition in childhood: is “syndrome X” present? J Clin Endocrinol Metab. 1996;81:1058–62.PubMedCrossRef
37.
Lee JM, Okumura MJ, Davis MM, Herman WH, Gurney JG. Prevalence and determinants of insulin resistance among U.S. adolescents: a population-based study. Diabetes Care. 2006;29:2427–32.PubMedCrossRef
38.
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;362:951–7.PubMedCrossRef
39.
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;49:1896–903.PubMedCrossRef
40.
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–89.PubMedCrossRef
41.
Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91:4287–94.PubMedCrossRef
42.
Nadeau KJ, Klingensmith G, Zeitler P. Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase. J Pediatr Gastroenterol Nutr. 2005;41:94–8.PubMedCrossRef
43.
• 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(8):1817–22. In this study authors well describe the role of hepatic fat accumulation in the pathogenesis of insulin resistance in obese youth.
44.
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.PubMedCrossRef
45.
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;57:367–71.PubMedCrossRef
46.
Tirosh A, Shai I, Afek A, Dubnov-Raz G, Ayalon N, Gordon B, et al. Adolescent BMI trajectory and risk of diabetes vs coronary disease. N Engl J Med. 2011;364:1315–25.PubMedCrossRef
47.
• Morrison JA, Glueck CJ, Horn PS, Wang P. Childhood predictors of adult type 2 diabetes at 9- and 26-year follow-ups. Arch Pediatr Adolesc Med. 2010;164:53–60. In this prospective longitudinal study authors attempted to determine whether pediatric office measures (waist circumference, body mass index [BMI], systolic [SBP], and diastolic [DBP] blood pressure, and parental diabetes) and laboratory measures (glucose, triglyceride, high-density lipoprotein cholesterol, and insulin) predict risk of type 2 diabetes mellitus (T2D) at ages 19 and 39 years. By using data from 9- and 26-year prospective follow-ups of schoolchildren, authors showed that office-based childhood measures predict the presence and absence of future T2D 9 and 26 years after baseline. In addition, they showed that childhood insulin measurement improves prediction, facilitating approaches to primary prevention of T2D.PubMedCrossRef
48.
Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115:e290–6.PubMedCrossRef
49.
Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav. 2006;88:234–43.PubMedCrossRef
50.
Mayer-Davis EJ. Type 2 diabetes in youth: epidemiology and current research toward prevention and treatment. J Am Diet Assoc. 2008;108(4 Suppl 1):S45–51.PubMedCrossRef
51.
Kempf K, Rathmann W, Herder C. Impaired glucose regulation and type 2 diabetes in children and adolescents. Diabetes Metab Res Rev. 2008;24:427–37.PubMedCrossRef
52.
Laitinen J, Pietilainen K, Wadsworth M, Sovio U, Jarvelin MR. Predictors of abdominal obesity among 31-y-old men and women born in Northern Finland in 1966. Eur J Clin Nutr. 2004;58:180–90.PubMedCrossRef
53.
Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–7.PubMedCrossRef
54.
Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36:62–7.PubMedCrossRef
55.
Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991;303:1019–22.PubMedCrossRef
56.
Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990;301:259–62.PubMedCrossRef
57.
Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med. 1976;295:349–53.PubMedCrossRef
58.
Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35:595–601.PubMedCrossRef
59.
Forsen T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med. 2000;133:176–82.PubMed
Metadata
Title
Progression of β-Cell Dysfunction in Obese Youth
Authors
Cosimo Giannini
Sonia Caprio
Publication date
01-02-2013
Publisher
Current Science Inc.
Published in
Current Diabetes Reports / Issue 1/2013
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-012-0347-7

Other articles of this Issue 1/2013

Current Diabetes Reports 1/2013 Go to the issue

Pediatric Type 2 Diabetes (PS Zeitler, Section Editor)

Metabolic Syndrome in Youth: Chimera or Useful Concept?

Hospital Management of Diabetes (G Umpierrez, Section Editor)

Management of Post-Transplant Diabetes

Diabetes and Pregnancy (CJ Homko, Section Editor)

Bariatric Surgery: Impact on Pregnancy Outcomes

Hospital Management of Diabetes (G Umpierrez, Section Editor)

Adult Hyperglycemic Crisis: A Review and Perspective

Pediatric Type 2 Diabetes (PS Zeitler, Section Editor)

Etiology of Insulin Resistance in Youth with Type 2 Diabetes

Hospital Management of Diabetes (G Umpierrez, Section Editor)

Management of Hyperglycemia During Enteral and Parenteral Nutrition Therapy
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits