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Figure 1.
Mean Percent Change in Body Mass Index (BMI) Over Time
Mean Percent Change in Body Mass Index (BMI) Over Time

BMI was calculated as weight in kilograms divided by height in meters squared. Error bars indicate 95% CIs. Teen-LABS indicates Teen–Longitudinal Assessment of Bariatric Surgery; TODAY, Treatment Options of Type 2 Diabetes in Adolescents and Youth.

Figure 2.
Changes in the Proportion of Participants With Hemoglobin A1c (HbA1c) Concentrations
Changes in the Proportion of Participants With Hemoglobin A1c (HbA1c) Concentrations

Teen-LABS indicates Teen–Longitudinal Assessment of Bariatric Surgery; TODAY, Treatment Options of Type 2 Diabetes in Adolescents and Youth.

Figure 3.
Mean Proportion of Participants by Secondary Outcome
Mean Proportion of Participants by Secondary Outcome

Mean proportion of participants with elevated blood pressure, dyslipidemia, low estimated glomerular filtration rate (eGFR), and elevated albumin-creatinine ratio (ACR). Error bars indicate 95% CIs. Teen-LABS indicates Teen–Longitudinal Assessment of Bariatric Surgery; TODAY, Treatment Options of Type 2 Diabetes in Adolescents and Youth.

Table 1.  
Baseline Characteristics by Study Groupa
Baseline Characteristics by Study Groupa
Table 2.  
Longitudinal Anthropometric and Laboratory Data
Longitudinal Anthropometric and Laboratory Data
1.
Fazeli Farsani  S, van der Aa  MP, van der Vorst  MM, Knibbe  CA, de Boer  A.  Global trends in the incidence and prevalence of type 2 diabetes in children and adolescents: a systematic review and evaluation of methodological approaches.  Diabetologia. 2013;56(7):1471-1488.PubMedGoogle ScholarCrossref
2.
Daniels  SR, Arnett  DK, Eckel  RH,  et al.  Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment.  Circulation. 2005;111(15):1999-2012.PubMedGoogle ScholarCrossref
3.
Dabelea  D, Bell  RA, D’Agostino  RB  Jr,  et al; Writing Group for the SEARCH for Diabetes in Youth Study Group.  Incidence of diabetes in youth in the United States.  JAMA. 2007;297(24):2716-2724.PubMedGoogle ScholarCrossref
4.
Zeitler  P, Hirst  K, Pyle  L,  et al; TODAY Study Group.  A clinical trial to maintain glycemic control in youth with type 2 diabetes.  N Engl J Med. 2012;366(24):2247-2256.PubMedGoogle ScholarCrossref
5.
Gottschalk  M, Danne  T, Vlajnic  A, Cara  JF.  Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study.  Diabetes Care. 2007;30(4):790-794.PubMedGoogle ScholarCrossref
6.
Rosenstock  J, Rood  J, Cobitz  A, Huang  C, Garber  A.  Improvement in glycaemic control with rosiglitazone/metformin fixed-dose combination therapy in patients with type 2 diabetes with very poor glycaemic control.  Diabetes Obes Metab. 2006;8(6):643-649.PubMedGoogle ScholarCrossref
7.
Narasimhan  S, Weinstock  RS.  Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study.  Mayo Clin Proc. 2014;89(6):806-816.PubMedGoogle ScholarCrossref
8.
Tryggestad  JB, Willi  SM.  Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial.  J Diabetes Complications. 2015;29(2):307-312.PubMedGoogle ScholarCrossref
9.
Linder  BL, Fradkin  JE, Rodgers  GP.  The TODAY study: an NIH perspective on its implications for research.  Diabetes Care. 2013;36(6):1775-1776.PubMedGoogle ScholarCrossref
10.
Nadeau  KJ, Anderson  BJ, Berg  EG,  et al.  Youth-onset type 2 diabetes consensus report: current status, challenges, and priorities.  Diabetes Care. 2016;39(9):1635-1642.PubMedGoogle ScholarCrossref
11.
Copeland  KC, Zeitler  P, Geffner  M,  et al; TODAY Study Group.  Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline.  J Clin Endocrinol Metab. 2011;96(1):159-167.PubMedGoogle ScholarCrossref
12.
Inge  TH, Courcoulas  AP, Jenkins  TM,  et al; Teen-LABS Consortium.  Weight loss and health status 3 years after bariatric surgery in adolescents.  N Engl J Med. 2016;374(2):113-123.PubMedGoogle ScholarCrossref
13.
American Diabetes Association.  2. Classification and diagnosis of diabetes.  Diabetes Care. 2017;40(suppl 1):S11-S24.PubMedGoogle ScholarCrossref
14.
Zeitler  P, Epstein  L, Grey  M,  et al; TODAY Study Group.  Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes.  Pediatr Diabetes. 2007;8(2):74-87.PubMedGoogle ScholarCrossref
15.
Buse  JB, Caprio  S, Cefalu  WT,  et al.  How do we define cure of diabetes?  Diabetes Care. 2009;32(11):2133-2135.PubMedGoogle ScholarCrossref
16.
Al-Saeed  AH, Constantino  MI, Molyneaux  L,  et al.  An inverse relationship between age of type 2 diabetes onset and complication risk and mortality: the impact of youth-onset type 2 diabetes.  Diabetes Care. 2016;39(5):823-829.PubMedGoogle ScholarCrossref
17.
Inge  TH, Krebs  NF, Garcia  VF,  et al.  Bariatric surgery for severely overweight adolescents: concerns and recommendations.  Pediatrics. 2004;114(1):217-223.PubMedGoogle ScholarCrossref
18.
Pratt  JS, Lenders  CM, Dionne  EA,  et al.  Best practice updates for pediatric/adolescent weight loss surgery.  Obesity (Silver Spring). 2009;17(5):901-910.PubMedGoogle ScholarCrossref
19.
Michalsky  M, Reichard  K, Inge  T, Pratt  J, Lenders  C; American Society for Metabolic and Bariatric Surgery.  ASMBS pediatric committee best practice guidelines.  Surg Obes Relat Dis. 2012;8(1):1-7.PubMedGoogle ScholarCrossref
20.
Aikenhead  A, Lobstein  T, Knai  C.  Review of current guidelines on adolescent bariatric surgery.  Clin Obes. 2011;1(1):3-11.PubMedGoogle ScholarCrossref
21.
Schauer  PR, Bhatt  DL, Kirwan  JP,  et al; STAMPEDE Investigators.  Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes.  N Engl J Med. 2014;370(21):2002-2013.PubMedGoogle ScholarCrossref
22.
Schauer  PR, Bhatt  DL, Kirwan  JP,  et al; STAMPEDE Investigators.  Bariatric surgery versus intensive medical therapy for diabetes: 5-year outcomes.  N Engl J Med. 2017;376(7):641-651.PubMedGoogle ScholarCrossref
23.
Sjöström  L, Peltonen  M, Jacobson  P,  et al.  Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications.  JAMA. 2014;311(22):2297-2304.PubMedGoogle ScholarCrossref
24.
Rubino  F, Nathan  DM, Eckel  RH,  et al; Delegates of the 2nd Diabetes Surgery Summit.  Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations.  Surg Obes Relat Dis. 2016;12(6):1144-1162.PubMedGoogle ScholarCrossref
25.
Manning  S, Pucci  A, Batterham  RL.  GLP-1: a mediator of the beneficial metabolic effects of bariatric surgery?  Physiology (Bethesda). 2015;30(1):50-62.PubMedGoogle Scholar
26.
Kelly  AS, Ryder  JR, Marlatt  KL, Rudser  KD, Jenkins  T, Inge  TH.  Changes in inflammation, oxidative stress and adipokines following bariatric surgery among adolescents with severe obesity.  Int J Obes (Lond). 2016;40(2):275-280.PubMedGoogle ScholarCrossref
27.
Ryan  KK, Tremaroli  V, Clemmensen  C,  et al.  FXR is a molecular target for the effects of vertical sleeve gastrectomy.  Nature. 2014;509(7499):183-188.PubMedGoogle ScholarCrossref
28.
Aron-Wisnewsky  J, Clement  K.  The effects of gastrointestinal surgery on gut microbiota: potential contribution to improved insulin sensitivity.  Curr Atheroscler Rep. 2014;16(11):454.PubMedGoogle ScholarCrossref
29.
Bout-Tabaku  S, Michalsky  MP, Jenkins  TM,  et al.  Musculoskeletal pain, self-reported physical function, and quality of life in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort.  JAMA Pediatr. 2015;169(6):552-559.PubMedGoogle ScholarCrossref
30.
Pi-Sunyer  X.  The Look AHEAD Trial: a review and discussion of its outcomes.  Curr Nutr Rep. 2014;3(4):387-391.PubMedGoogle ScholarCrossref
Original Investigation
May 2018

Comparison of Surgical and Medical Therapy for Type 2 Diabetes in Severely Obese Adolescents

Thomas H. Inge, MD, PhD1; Lori M. Laffel, MD2; Todd M. Jenkins, PhD3; et al Marsha D. Marcus, PhD4; Natasha I. Leibel, MD5; Mary L. Brandt, MD6,7; Morey Haymond, MD6,7; Elaine M. Urbina, MD3; Lawrence M. Dolan, MD3; Philip S. Zeitler, MD, PhD8; for the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) Consortia
Author Affiliations
  • 1Department of Pediatric Surgery, Children’s Hospital Colorado, University of Colorado, Denver, Aurora
  • 2Department of Pediatrics, Joslin Diabetes Center, Boston, Massachusetts
  • 3Department of Pediatrics and Surgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio
  • 4Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 5Department of Pediatrics, Columbia University, New York, New York
  • 6Michael E. Debakey Department of Surgery, Texas Children’s Hospital, Baylor College of Medicine, Houston
  • 7Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston
  • 8Department of Pediatrics, Children’s Hospital Colorado, University of Colorado, Denver, Aurora
JAMA Pediatr. 2018;172(5):452-460. doi:10.1001/jamapediatrics.2017.5763
Key Points

Question  How does bariatric surgery compare with medical therapy to treat type 2 diabetes in adolescents with severe obesity?

Findings  In this study of 93 severely obese adolescents with type 2 diabetes, hemoglobin A1c concentration and mean body mass index decreased in 30 patients who underwent surgical treatment and increased in 63 patients who received medical treatment at 2-year follow-up. Significant improvements in blood pressure, dyslipidemia, and abnormal kidney function were also observed in the patients treated surgically but not in those treated medically.

Meaning  Surgical treatment of severely obese adolescents with type 2 diabetes was associated with better glycemic control, reduced cardiovascular risk markers, and improved kidney function; these findings support the need for a well-designed, prospective controlled study to define the role of surgery for adolescents with type 2 diabetes.

Abstract

Importance  Because of the substantial increase in the occurrence of type 2 diabetes in the pediatric population and the medical complications of this condition, therapies are urgently needed that will achieve better glycemic control than standard medical management.

Objective  To compare glycemic control in cohorts of severely obese adolescents with type 2 diabetes undergoing medical and surgical interventions.

Design, Setting, and Participants  A secondary analysis of data collected by the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) consortia was performed. Teen-LABS enrolled 242 adolescents (≤19 years of age) from March 1, 2007, through December 31, 2011. TODAY randomized 699 participants (aged 10-17 years) from July 24, 2004, through February 25, 2009. Data analysis was performed from July 6, 2015, to June 24, 2017. Anthropometric, clinical, and laboratory data from adolescents with severe obesity and type 2 diabetes who underwent treatment with metabolic or bariatric surgery in the Teen-LABS study or medical therapy in the TODAY study were compared.

Interventions  Teen-LABS participants underwent a primary bariatric surgical procedure; TODAY participants were randomized to receive metformin therapy alone or in combination with rosiglitazone or an intensive lifestyle intervention; insulin therapy was given in cases of progression of disease.

Main Outcomes and Measures  Glycemic control, body mass index, prevalence of elevated blood pressure, dyslipidemia, abnormal kidney function, and clinical adverse events were measured.

Results  Data from 30 participants from Teen-LABS (mean [SD] age at baseline, 16.9 [1.3] years; 21 [70%] female; 18 [66%] white) and 63 from TODAY (mean [SD] age at baseline, 15.3 [1.3] years; 28 [44%] female; 45 [71%] white) were analyzed. During 2 years, mean hemoglobin A1c concentration decreased from 6.8% (95% CI, 6.4%-7.3%) to 5.5% (95% CI, 4.7% -6.3%) in Teen-LABS and increased from 6.4% (95% CI, 6.1%-6.7%) to 7.8% (95% CI, 7.2%-8.3%) in TODAY. Compared with baseline, the body mass index decreased by 29% (95% CI, 24%-34%) in Teen-LABS and increased by 3.7% (95% CI, 0.8%-6.7%) in TODAY. Twenty-three percent of Teen-LABS participants required a subsequent operation during the 2-year follow-up.

Conclusions and Relevance  Compared with medical therapy, surgical treatment of severely obese adolescents with type 2 diabetes was associated with better glycemic control, reduced weight, and improvement of other comorbidities. These data support the need for a well-designed, prospective controlled study to define the role of surgery for adolescents with type 2 diabetes, including health and surgical outcomes.

Introduction

During the past few decades, the occurrence of type 2 diabetes has substantially increased in the pediatric population, associated with a 2- to 4-fold increase in childhood overweight and obesity.1,2 Youth-onset type 2 diabetes now represents a substantial percentage of new cases of pediatric diabetes in the United States, ranging from 14% in non-Hispanic white individuals to 86% in American Indian individuals,3 with more than 5000 persons younger than 20 years diagnosed with type 2 diabetes annually in the United States.

The Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial was designed to investigate therapies directed at attaining durable glycemic control4 and found that nearly 50% of teens with type 2 diabetes progressed to needing insulin therapy after a median of 11 months.4 Thus, youth-onset type 2 diabetes appears to be a more aggressive disease with more rapid loss of β-cell function and a higher glycemic failure rate compared with adult-onset diabetes.5,6 In addition, the prevalence of hypertension and albuminuria tripled and elevated low-density lipoprotein cholesterol (LDL-C) concentrations increased 2.4-fold during 4 years of follow-up of TODAY participants. Collectively, these data suggest that youth with type 2 diabetes are at high risk for future cardiovascular and renal complications.7-10 Furthermore, neither metformin nor insulin, the only drugs approved by the US Food and Drug Administration to treat type 2 diabetes in youths, addresses the underlying pathophysiologic properties of obesity-related comorbidities. Thus, there is a need to identify management approaches, including metabolic surgery, that may yield clinically significant and durable glycemic control.

The Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study prospectively evaluated outcomes of adolescents who clinically qualified for bariatric surgery (eg, had a body mass index [BMI]≥35 [calculated as weight in kilograms divided by height in meters squared] and a major obesity-related comorbid condition or a BMI≥40) and underwent bariatric surgery at 5 US centers. Data from participants with type 2 diabetes enrolled in the Teen-LABS and TODAY studies were used to directly compare surgical and medical management of type 2 diabetes. This secondary analysis tested the hypothesis that for adolescents with type 2 diabetes, surgery would provide greater improvement in weight, diabetes, and other cardiovascular risk factors than would medical management during 2 years of follow-up.

Methods
Study Design and Participants

Teen-LABS enrolled 242 adolescents (≤19 years of age) from March 1, 2007, through December 31, 2011. TODAY enrollment started May 1, 2004, and ended December 31, 2009, with a total of 699 randomized participants (ages 10-17 years). Study details for both Teen-LABS and TODAY have been published elsewhere.4,11,12 The TODAY and Teen-LABS protocols were approved by the institutional review boards of each participating institution. Participants provided written informed parental consent and child assent. The participants provided consent for identifiers to be maintained at the data coordinating centers for each study. Deidentified data were used for the purposes of this current analysis.

Pertinent to this analysis, there were 30 Teen-LABS participants with type 2 diabetes at the time of surgery. Of these, 24 underwent Roux-en-Y gastric bypass and 6 underwent vertical sleeve gastrectomy procedures. Quiz Ref IDTODAY participants (irrespective of treatment group assignment) were frequency matched to the 30 Teen-LABS participants with type 2 diabetes using the following matching characteristics: baseline age (13-18 years), race, sex, ethnicity, and baseline BMI (>35). Through this process, a total of 63 TODAY participants were identified. This secondary analysis of these studies, performed from July 6, 2015, to June 24, 2017, includes data collected from the 30 surgically treated and 63 medically treated individuals at baseline, 6-month, 1-year, and 2-year study visits.

Comorbidity Definitions

Standard conventions were followed for the assessment and prevalence of conditions over time. In brief, presence of type 2 diabetes in Teen-LABS participants was defined as use of medications for diabetes, baseline hemoglobin A1c (HbA1c) concentration of 6.5% or higher (to convert to proportion of hemoglobin, multiply by 0.01), fasting glucose concentration of 126 mg/dL or higher (to convert to grams per liter, multiply by 10), or 2-hour glucose value greater than 200 mg/dL (to convert to millimoles per liter, multiply by 0.0555) during an oral glucose tolerance test in the 6 months before enrollment. Type 2 diabetes in TODAY was defined by standard American Diabetes Association glucose and HbA1c criteria13 except that asymptomatic patients with a normal fasting glucose concentration but elevated 2-hour glucose concentration during an oral glucose tolerance test were required to have an HbA1c concentration of 6% or greater.14 For both cohorts, complete remission of type 2 diabetes was defined as an HbA1c concentration less than 5.7% while taking no medications for type 2 diabetes, whereas partial remission was defined as an HbA1c concentration of 5.7% or greater but less than 6.5% while taking no medications for type 2 diabetes.15 Comparable definitions for dyslipidemia, elevated blood pressure, and abnormal kidney function were applied to both cohorts (eMethods in the Supplement). All laboratory assays for the Teen-LABS and TODAY cohorts were performed by the Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, Washington (see eMethods in the Supplement for assay details).

Assessment of Adverse Clinical Events

The procedure for assessment of adverse events in Teen-LABS12 and TODAY4 have been previously described, and details pertaining to this analysis are included in the eMethods in the Supplement.

Statistical Analysis

Categorical descriptive measures are presented using numbers and percentages. Continuous variables are summarized using means with SDs or medians with interquartile ranges. Quiz Ref IDThe primary outcome was glycemic control after 2 years, assessed as HbA1c concentrations for all included participants independent of TODAY treatment status. Generalized linear mixed effects models with group × visit interaction terms compared changes in HbA1c concentration, anthropometrics, comorbidities, and lipid outcomes between the study groups. The identity link function was used for the following outcomes: HbA1c level, height, weight, BMI, percentage of BMI change from baseline, waist circumference, systolic blood pressure, diastolic blood pressure, fasting glucose level, fasting insulin level (log transformed), total cholesterol level, LDL-C level, high-density lipoprotein cholesterol (HDL-C) level, triglyceride levels (log transformed), urine albumin-creatinine ratio (log transformed), and estimated glomerular filtration rate (eGFR); the logit link function was for the following outcomes: HbA1c level (<5.7%), elevated blood pressure, dyslipidemia, low eGFR, and elevated urinary albumin-creatinine ratio. An unstructured covariance was used in each model. The following variables were considered for inclusion in the final models: age, sex, race, BMI, lipid medication use, and blood pressure medication use. Overall, 251 of 279 (90.0%) of postbaseline and surgery HbA1c values across both cohorts were available for analysis. Multiple imputation by chained equations was performed to the patterns of missing data. A total of 30 imputed data sets were created for use in the multivariable models. SAS Proc MiAnalyze (SAS Institute Inc) was used to generate all estimates from the multiply imputed data sets. Sensitivity analyses using pattern-mixture models were performed to evaluate the missing at random assumption. Using this approach, we adjusted imputed HbA1c values from −5% through +5% of what they would be if the data were missing at random (eFigure 1 in the Supplement). On the basis of these analyses, the missing at random assumption was considered to be reasonable (eMethods in the Supplement). All statistical analyses were conducted using SAS, version 9.4 (SAS Institute Inc), and all reported P values were 2-sided. All comparisons except the primary outcome were considered to be exploratory, and no correction was made for multiple comparisons.

Results
Baseline Comparisons

Data from 30 participants from Teen-LABS (mean [SD] age at baseline, 16.9 [1.3] years; 21 [70%] female; 18 [66%] white) and 63 from TODAY (mean [SD] age at baseline, 15.3 [1.3] years; 28 [44%] female; 45 [71%] white) were analyzed (Table 1). The Teen-LABS cohort had a higher mean (SD) baseline BMI (54 [9.5] vs 41 [4.9], P < .001) and waist circumference (151.4 vs 121.2 cm, P < .001) than the TODAY cohort. At baseline, the cohorts did not differ with respect to mean HbA1c, fasting glucose, insulin, albumin, or serum creatinine levels or eGFR, based on cystatin C (Table 1). At baseline, 7 of 30 Teen-LABS participants (23%) were receiving injection therapy for type 2 diabetes (6 receiving insulin, 1 receiving exenatide). Of the remaining 23, all were taking oral medications (22 were taking metformin and 1 was taking glipizide). By protocol, all TODAY participants were taking metformin only at baseline. Teen-LABS participants also had a significantly greater cardiovascular risk factor burden than TODAY participants, with higher systolic and diastolic blood pressure, LDL-C concentration, and triglyceride concentrations at baseline (Table 1).

BMI Change Over Time

During 2 years of follow-up, BMI in the Teen-LABS cohort decreased by 29.0% (95% CI, −34.0% to −24.0%) from baseline compared with a 3.7% (95% CI, 0.8%-6.7%) increase in TODAY participants (Figure 1 and Table 2). This finding corresponded to a loss of 44.2 kg (95% CI, 37.8-50.6 kg) of body weight in the Teen-LABS cohort and a gain of 5.8 kg (95% CI, 1.4-10.2 kg) in the TODAY cohort. Mean height increased by 1.3 cm in the younger TODAY cohort but did not change over time in the Teen-LABS participants. Waist circumference decreased by 29.0 cm (95% CI, 24.6-33.6 cm) in the Teen-LABS cohort but increased by 4.3 cm (95% CI, 1.0-7.6 cm) in the TODAY cohort (Table 2).

Diabetes and Metabolic Status Over Time

Quiz Ref IDMean HbA1c concentration decreased from 6.8% (95% CI, 6.4%- 7.3%) to 5.5% (95% CI, 4.7%-6.3%) in Teen-LABS participants and increased from 6.4% (95% CI, 6.1%-6.7%) to 7.8% (95% CI, 7.2%-8.3%) in TODAY participants (Table 2).

The HbA1c concentration was next analyzed categorically using clinically meaningful ranges. The number of Teen-LABS participants with HbA1c concentrations less than 5.7% increased from 10 (34%) at baseline to 15 (74%) at 2 years but decreased from 17 (28%) at baseline to 7 (13%) in TODAY participants (Figure 2). At 2 years, 19 (94%) (95% CI, 68%-99%) of Teen-LABS participants and only 20 (38%) (95% CI, 26%-52%) of TODAY participants had HbA1c concentrations less than 6.5% (P = .003). The number of TODAY participants with HbA1c concentrations in the 6.5% or greater category increased from 23 (35%) at baseline to 34 (62%) at 2 years despite intensive medical management and emphasis on medication adherence.

Significant decreases in concentrations of fasting glucose and insulin were observed in Teen-LABS participants, whereas TODAY participants had an increase in fasting glucose and decrease in insulin concentrations (Table 2).

Other Outcomes

The number of participants with elevated blood pressure decreased from 20 (45%) (95% CI, 13%-34%) at baseline to 5 (20%) (95% CI, 8%-42%) at 2 years in the Teen-LABS group, whereas the number with elevated blood pressure in the TODAY cohort nearly doubled (13 [22%] to 23 [41%]) (Figure 3 and eTable 1 in the Supplement). The number of participants with dyslipidemia in the Teen-LABS cohort decreased from 21 (72%) (95% CI, 51%-86%) at baseline to 9 (24%) (95% CI, 10%-48%) at 2 years (Figure 3 and eTable 1 in the Supplement), associated with improvements in triglyceride and HDL-C concentrations (eFigures 2, 3, and 4 and eTable 1 in the Supplement). In the TODAY group, no appreciable change in dyslipidemia prevalence occurred, whereas a modest increase in triglyceride concentrations was seen. The number of Teen-LABS participants with low eGFR decreased from 7 (24%) at baseline to none at 2 years, and the number with elevated urinary albumin-creatinine ratio decreased from 8 (27%) at baseline to 1 (6%) at 2 years. The number of the subset of TODAY participants with low eGFR and elevated albumin-creatinine ratio did not change significantly over time (Figure 3 and eTable 1 in the Supplement).

Clinical Adverse Events

Quiz Ref IDDuring the 2-year period of follow-up, 7 of 30 individuals in the Teen-LABS cohort (23%) experienced complications that required subsequent operation and/or readmission that were related or possibly related (eg, cholecystectomy for gallstones) to their prior bariatric surgery (eTable 2 in the Supplement). Five other individuals (17%) required subsequent hospitalization for observation or other interventions (nonabdominal operations) that were unrelated to the prior bariatric operation (eTable 2 in the Supplement). No hypoglycemic events that required admission were observed in the surgical participants. In comparison, only 2 of the 63 TODAY participants (3%) required hospital admission during the 2-year follow-up period. The reasons for these admissions included calf swelling and ankle edema in one TODAY participant and knee pain and anemia in another.

Discussion

Adolescents with severe obesity and type 2 diabetes receiving medical treatment in the context of a rigorous and well-staffed multicenter clinical trial experienced modest weight gain, progression of type 2 diabetes, and no improvement in cardiovascular risk factors in 2 years of follow-up. In contrast, most of the adolescents undergoing surgical procedures experienced clinically significant weight reduction, remission of their diabetes, and improvement in cardiovascular risk factors and kidney dysfunction despite starting with a higher BMI. The striking differences in outcomes between these 2 treatments support consideration for surgical treatment for adolescents with severe obesity and type 2 diabetes. However, the surgical treatment benefits were also associated with surgical risks. Clinical events that required surgical management were observed in one-fifth of surgical participants. These types of events should be understood by physicians, teenagers, and families when considering the treatment options currently available for adolescents with type 2 diabetes.

Recently, Al-Saeed et al16 reported an inverse association between age at onset of type 2 diabetes and complication risk and mortality. Type 2 diabetes was more likely to be associated with metabolic syndrome features, albuminuria, and neuropathy when diagnosed in individuals aged 15 to 30 years compared with those aged 40 to 50 years. Moreover, mortality risk was found to be higher among those with type 2 diabetes diagnosed early in life, with peak mortality in early adulthood (eg, ages 30-40 years). These findings complement the recent report16 that elevated BMI at 17 years of age, even in the absence of diabetes, also portends premature mortality from the future development of diabetes.

Indications for use of bariatric surgery for adolescents have included type 2 diabetes in adolescents with a BMI of 35 or higher.2,17-19 Although this recommendation has been widely adopted internationally and incorporated into numerous clinical care guidelines summarized by Aikenhead et al,20 the evidence on which it is based is derived predominantly from adult bariatric outcome studies21,22 that have, in general, demonstrated rapid metabolic improvement in type 2 diabetes.

Numerous studies in adults with type 2 diabetes have demonstrated that bariatric procedures are well tolerated, with diabetes remission rates in the 38% to 60% range 1 to 3 years after surgery and durable remission in 30% of individuals at 15 years. A prospective randomized clinical trial in adults with type 2 diabetes and baseline BMIs of 27 to 43 confirmed the significant benefit of bariatric surgery compared with medical therapy on glycemic control (absolute HbA1c reduction of 2.1% after surgery vs 0.3% with medical therapy), lipid levels (triglycerides and HDL-C), insulin use, and quality of life.22 Other researchers have also found that surgery is associated with 50% reduction in the risk of developing microvascular complications and similar reduction in the risk of death from cardiovascular causes23 in individuals affected by type 2 diabetes, further justifying guidelines endorsed by 45 international professional organizations that support the use of metabolic surgery for treatment of type 2 diabetes.24

Of interest, adolescents in our study had greater than expected (95% with HbA1c<6.5%) improvement of type 2 diabetes after bariatric surgery during 2 years despite similar operations, similar weight loss, and identical definitions of disease response as those used in adult studies. The most plausible hypothesis for this response may be that the procedure occurs when there is more recoverable β-cell function because of a shorter duration of type 2 diabetes in adolescents compared with adults. Numerous investigators have established that greater odds of remission in adults are associated with shorter duration of disease, whereas lower odds are associated with the need for insulin preoperatively. However, after controlling for BMI change, there was greater metabolic improvement in the surgical cohort (absolute HbA1c decrease of 2.2%) attributable to surgery alone. This finding suggests that surgery in youths with type 2 diabetes provides an antidiabetic effect(s) greater than those expected with weight loss alone. Candidates for mediation of this weight loss–independent effect include modulation of endogenous enteroendocrine signaling (eg, glucagon-like peptide 1),25 enhanced production of healthy adipokines,26 down-regulation of inflammatory cytokines and mediators that contribute to hepatic and peripheral insulin resistance, changes in the bile acid pool27 associated with alterations in the microbiome,28 greater motivation to engage in active lifestyles,29 or a combination of these factors.

In the TODAY cohort, nearly 50% of youths were unable to maintain durable glycemic control (defined as HbA1c≥8% for 6 months or need for ongoing insulin therapy after metabolic decompensation) within 2 years despite consistent and closely monitored medical treatment, with a median time to failure of 11.5 months. These individuals experienced progressive worsening of glycemic control, hypertension, dyslipidemia, and abnormal renal function. Although there are no long-term studies of outcome in youth-onset type 2 diabetes to date, the assumption, based on adult studies,23,30 is that the worsening of these risk factors will result in increased rates of microvascular and macrovascular disease, such as myocardial infarction, congestive heart failure, blindness, and end-stage renal disease, possibly beginning in middle age.16 These data, combined with the effects of type 2 diabetes on mortality being greatest for those who received diagnoses at a young age,16 suggest that surgical therapy should be considered earlier rather than later for those who are diagnosed with youth-onset type 2 diabetes.

Limitations

This current analysis is limited by the design—a secondary analysis of previously collected data from 2 different cohorts enrolled in 2 different studies with different objectives. However, the similarities in methods and use of the same central laboratory for biochemical analyses provided a unique opportunity to make an important comparison between these 2 approaches to management of type 2 diabetes in adolescents. Relatively few adolescents with type 2 diabetes were enrolled in the Teen-LABS study. Thus, the power to detect changes in some outcomes of interest was limited. Similarly, relatively few underwent vertical sleeve gastrectomy, a procedure that is increasing in the United States and worldwide. Furthermore, 13% of postoperative visits in the surgery group and 8% of postbaseline visits in the medical cohort were not completed. However, statistical techniques were used to address these missing data, with associated sensitivity analyses demonstrating that missing data pattern assumptions were reasonable. Finally, these analyses are limited only to 2 years of follow-up. Long-term data are needed to assess the durability of the effect of bariatric surgery in young patients with type 2 diabetes.

Conclusion

For adolescents with severe obesity and type 2 diabetes, medical management, even within the context of a well-resourced clinical trial, resulted in increasing weight, failure to maintain glycemic control in half of the participants, and advancing cardiovascular risk burden. Bariatric surgery, however, was associated with remission of type 2 diabetes in most participants, along with improvements in weight and cardiovascular risk markers. Therefore, these data suggest that surgery provides superior treatment of adolescent type 2 diabetes and its comorbidities. However, this patient population is susceptible to major surgical complications, and there is still little known about the long-term effects of surgery compared with medical therapy, indicating a critical need for additional research. Despite the small number of participants, these findings provide estimates of outcomes that may be useful to those contemplating surgical treatment for youth-onset type 2 diabetes. Future work in this cohort should focus on longer-term assessments of health outcomes, including nutritional and other effects of surgery, recurrence of type 2 diabetes, cardiovascular end points, and mortality.

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Article Information

Accepted for Publication: December 21, 2017.

Corresponding Author: Thomas H. Inge, MD, PhD, Department of Pediatric Surgery, Children's Hospital Colorado, 13123 E 16th Ave, Box 323, Aurora, CO 80045-7106 (thomas.inge@childrenscolorado.org).

Published Online: March 12, 2018. doi:10.1001/jamapediatrics.2017.5763

Author Contributions: Dr Jenkins had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Inge, Jenkins, Brandt, Haymond, Dolan, Zeitler.

Acquisition, analysis, or interpretation of data: Laffel, Jenkins, Marcus, Leibel, Haymond, Urbina, Dolan, Zeitler.

Drafting of the manuscript: Laffel, Jenkins, Marcus, Urbina, Zeitler.

Critical revision of the manuscript for important intellectual content: Inge, Laffel, Jenkins, Leibel, Brandt, Haymond, Urbina, Dolan, Zeitler.

Statistical analysis: Jenkins, Zeitler.

Obtained funding: Inge, Zeitler.

Administrative, technical, or material support: Laffel, Marcus, Urbina.

Supervision: Laffel, Urbina, Dolan, Zeitler.

Conflict of Interest Disclosures: Dr Inge reported serving as a consultant for Standard Bariatrics, unrelated to this project. Dr Laffel reported receiving support from AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc, Dexcom Inc, Eli Lilly and Company, Insulet, Johnson & Johnson, MannKind Corporation, Menarini, Diagnostics, Novo Nordisk Inc, Roche Diagnostics, and Sanofi US, all unrelated to this project. Dr Marcus reported serving on the scientific advisory board of Weight Watchers International Inc. Dr Zeitler reported participating in research design consulting for Daichii-Sankyo, Merck, Janssen, Takeda, and Eli Lilly and Company. No other disclosures were reported.

Funding/Support: This work was completed with funding from grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, U01-DK61254, U01DK072493, UM1DK072493, and UM1DK095710 from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Office of the Director (University of Cincinnati); grants M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children’s Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children’s Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University), and M01-RR14467 (University of Oklahoma Health Sciences Center) from the National Center for Research Resources General Clinical Research Centers Program; and grants UL1-RR024134 (Children’s Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children’s Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St Louis), UL1-RR025758 (Massachusetts General Hospital), and UL1-RR025780 (University of Colorado Denver) from the National Centre for Advancing Translational Science Awards. The Teen-LABS study was also supported by grants UL1 TR000077-04 (Cincinnati Children’s Hospital Medical Center), UL1RR025755 (Nationwide Children’s Hospital), M01-RR00188 (Texas Children’s Hospital/Baylor College of Medicine), UL1 RR024153 and UL1TR000005 (University of Pittsburgh), and UL1 TR000165 (University of Alabama, Birmingham) from the National Center for Research Resources Clinical and Translational Science Awards.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Members: The following individuals and institutions constitute the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group (asterisk indicates principal investigator or director): Clinical Centers: Baylor College of Medicine: Siripoo McKay, MD,* Morey Haymond, MD,* Barbara Anderson, PhD, Cresendo Bush, Sheila Gunn, MD, Heather Holden, Mary Jones, George Jeha, MD, Sue McGirk, Sneha Thamotharan; Case Western Reserve University: Leona Cuttler, MD,* Ericka Abrams, Terri Casey, Bill Dahms, MD* (deceased), Carolyn Ievers-Landis, PhD, Beth Kaminski, Michaela Koontz, MD, Sarah MacLeish, Paul McGuigan, Sumana Narasimhan, MD*; Children’s Hospital Los Angeles: Mitchell Geffner, MD,* Veronica Barraza, Nancy Chang, Barry Conrad, Daina Dreimane, MD, Silvia Estrada, Lynda Fisher, MD, Evelyne Fleury-Milfort, Socorro Hernandez, Barbara Hollen, Francine Kaufman, MD, Emily Law, Vanessa Mansilla, Debra Miller, Cynthia Muñoz, Rosa Ortiz, Andriette Ward, MD, Keren Wexler, Y. K. Xu, Patrice Yasuda, PhD; Children's Hospital of Philadelphia: Lorraine Levitt Katz, MD,* Robert Berkowitz, MD, Sakeenah Boyd, Bonnie Johnson, Joan Kaplan, PhD, Catherine Keating, Chad Lassiter, Terri Lipman, PhD, Gerre McGinley, Heather McKnight-Menci, Beth Schwartzman, Steven Willi, MD; Children's Hospital of Pittsburgh: Silva Arslanian, MD,* Fida Bacha, MD, Sally Foster, Bryan Galvin, Tamara Hannon, Andrea Kriska, PhD, Ingrid Libman, MD, Marsha Marcus, PhD, Kristin Porter, Thomas Songer, PhD, Elizabeth Venditti, PhD; Columbia University Medical Center: Robin Goland, MD,* Dympna Gallagher, Patricia Kringas, Natasha Leibel, MD, Debbie Ng, Martin Ovalles, Daniel Seidman; Joslin Diabetes Center: Lori Laffel, MD,* Ann Goebel-Fabbri, Melanie Hall, Laurie Higgins, Joyce Keady, Maureen Malloy, Kerry Milaszewski, Lisa Rasbach; Massachusetts General Hospital: David Nathan, MDm* Amanda Angelescu, MD, Laurie Bissett, Carol Ciccarelli, Linda Delahanty, Valerie Goldman, Olga Hardy, MD, Mary Larkin, Lynne Levitsky, MD,* Rebecca McEachern, MD, Dennis Norman, PhD, Benjamin Nwosu, MD, Soja Park-Bennett, MD, Denise Richards, Nicole Sherry, MD, Barbara Steiner; Saint Louis University: Sherida Tollefsen, MD,* Silvia Carnes, David Dempsher, MD, David Flomo, Theresa Whelan, Bonita Wolff; State University of New York Upstate Medical University: Ruth Weinstock, MD, PhD,* Deborah Bowerman, Suzan Bristol, Jane Bulger, Jennifer Hartsig, Roberto Izquierdo, MD, Joanne Kearns, Ron Saletsky, PhD, Paula Trief, PhD; University of Colorado, Denver: Philip Zeitler, MD, PhD* (steering committee chair), Natalie Abramson, PhD, Amanda Bradhurst, Nicole Celona-Jacobs, Janine Higgins, PhD, Megan Kelsey, MD, Georgeanna Klingensmith, MD, Kristen Nadeau, MD, Teresa Witten; University of Oklahoma Health Sciences Center: Kenneth Copeland, MD* (steering committee vice-chair), Evynn Boss, Ryan Brown, MD, Jennifer Chadwick, Laura Chalmers, MD, Steven Chernausek, MD, Ashley Hebensperger, Chris Macha, Rebecca Newgent, Allison Nordyke, Donna Olson, Tawney Poulsen, Lauren Pratt, Jeff Preske, Jill Schanuel, Steve Sternlof, PhD; University of Texas Health Science Center at San Antonio: Jane Lynch, MD,* Nancy Amodei, Rose Ann Barajas, Catherine Cody, Dan Hale, MD, J. Hernandez, Cori Ibarra, Elisa Morales, Semilla Rivera, Guadalupe Rupert, Aimee Wauters; Washington University in St Louis: Neil White, MD,* Ana Arbeláez, MD, David Flomo, Jackie Jones, Tracy Jones, Michelle Sadler, Marilyn Tanner, Alexis Timpson, Robinson Welch; Yale University: Sonia Caprio, MD,* Margaret Grey, PhD, Cindy Guandalini, Sylvia Lavietes, PhD, Paulina Rose, Amy Syme, William Tamborlane, MD; Coordinating Center: George Washington University Biostatistics Center: Kathryn Hirst, PhD,* Sharon Edelstein, Preethy Feit, Nisha Grover, Christen Long, Laura Pyle; Project Office: National Institute of Diabetes and Digestive and Kidney Diseases: Barbara Linder,* MD, PhD; Central Units; Central Blood Laboratory (Northwest Lipid Research Laboratories, University of Washington): Santica Marcovina, PhD,* Jessica Harting; DEXA Reading Center (University of California at San Francisco): John Shepherd, PhD,* Bo Fan, Lorena Marquez, Mary Sherman, Jeff Wang; Diet Assessment Center (University of South Carolina): Michele Nichols,* Beth Mayer-Davis, PhD, Yuan Liu; Echocardiogram Reading Center (Johns Hopkins University): Joao Lima, MD,* Sam Gidding, MD, JoAnn Puccella, Erin Ricketts; Fundus Photography Reading Center (University of Wisconsin): Ronald Danis, PhD,* Amitha Domalpally, Anne Goulding, Sherri Neill, Pam Vargo; Lifestyle Program Core (Washington University): Denise Wilfley, PhD,* Deb Aldrich-Rasche, K. Franklin, Cherie Massmann, Dennis O’Brien, Jeremy Patterson, Tiffany Tibbs, PhD, Dorothy Van Buren, PhD; Other: Hospital for Sick Children, Toronto: Mark Palmert, MD, Medstar Research Institute, Washington, DC: Robert Ratner, MD, Texas Tech University Health Sciences Center: Daina Dremaine, MD, University of Florida: Janet Silverstein, MD; University of Cincinnati: Mark Simmons, PhDc; Texas Children’s Hospital, Baylor College of Medicine: Vadim Sherman, MD, Margaret Callie Lee, MPH, David Allen, BS, Natoya Caston, BSN, Keri Turybury, MS, RD, LD, Gia Washington, PhD, Karin Price, PhD; Children’s Hospital of Alabama, University of Alabama: Ronald Clements, MD, Richard Stahl, MD, Molly Bray, PhD, Beverly Haynes, BSN, Heather Austin, PhD, Constance Cushing, DPT; University of Pittsburgh Medical Center: Ramesh Ramanathan, MD, Carol A. McCloskey, MD, George M. Eid, MD, Jessie Eagleton, MPH, William Gourash, MSN, CRNP, Lindsay Lee, MS, RD, Sheila Pierson, BS, Catherine Gibbs, MS, Dana Farrell, BS, Christopher Coburn, PhD, Dana Rofey, PhD, Rebecca Search, MPH, Mark Shaw, MS, Eleanor Shirley, MA, Kevin Topolski, MEd; Nationwide Children’s Hospital: Steven Teich, MD, Allen Browne, MD, Karen Carter, CCRC, Melinda Helton, RN, Bonny Bowen, RN, Cynthia Yensel, RN, MS, Patsy Guittar, MSN, Deanna Lear, RN, MS, Robert David Murray, MD, Andrea Hedge, Kevin Smith, PhD, Amy Baughcum, PhD, Grace Wentzel, CCRP, Paula Davies, CCRC; National Institute of Diabetes and Digestive and Kidney Diseases: Mary Evans, PhD; Other Collaborators: Santica M. Marcovina, PhD, ScD, Northwest Lipid Research Laboratory, University of Washington, David E. Kleiner, MD, PhD, National Cancer Institute, National Institutes of Health, Stephen Daniels, MD, PhD, University of Colorado.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: Jane Khoury, PhD, and Changchun Xie, PhD, provided statistical expertise. The following individuals contributed to the successful planning and/or execution of the study: Cincinnati Children’s Hospital Medical Center: Michael Helmrath, MD, MS, Stavra Xanthakos, MD, MS; University of Cincinnati: Chanchung Xie, PhD; Texas Children’s Hospital, Baylor College of Medicine: Mary Brandt, MD; Children’s Hospital of Alabama, University of Alabama: Mike Chen, MD; University of Pittsburgh Medical Center: Anita Courcoulas, MD; Nationwide Children’s Hospital: Marc Michalsky, MD; National Institute of Diabetes and Digestive and Kidney Diseases: Mary Evans, PhD. Other Collaborators: Carroll M. Harmon, MD, PhD, Women and Children’s Hospital of Buffalo, Santica M. Marcovina, PhD, ScD, Director of Northwest Lipid Research Laboratory, University of Washington. We also thank the talented clinical staff at each site for their dedication to the patient population represented in this study and appreciate the important work done by the adjudication committee. The TODAY Study Group thanks the following companies for donations in support of the study’s efforts: Becton, Dickinson and Company, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, LifeScan Inc, Pfizer, and Sanofi Aventis. The TODAY Study Group acknowledges the participation and guidance of the American Indian partners associated with the clinical center located at the University of Oklahoma Health Sciences Center, including members of the Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, Choctaw Nation of Oklahoma, and Oklahoma City Area Indian Health Service (the opinions expressed in this article are those of the authors and do not necessarily reflect the views of the respective Tribal and Indian Health Service Institution Review Boards or their members). Materials developed and used for the TODAY standard diabetes education program and the intensive lifestyle intervention program are available to the public at https://today.bsc.gwu.edu/. The Teen-LABS Consortium thanks the central study coordinator, Rosie Miller, RN, CCRC, for her extraordinary dedication and resourcefulness in conduct of the study. These individuals were not personally compensated.

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