Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) (TODAY)

• ClinicalTrials.gov Identifier: NCT00081328
• Recruitment Status: Completed
• First Posted: April 12, 2004
• Results First Posted: December 16, 2014
• Last Update Posted: July 30, 2021
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

Brief Summary:

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a consortium of investigators to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY).

The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to:

• compare and evaluate the safety of the three treatment arms;
• compare the effects of the three treatments on the pathophysiology of type 2 diabetes (T2D) with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes;
• evaluate the influence of individual and family behaviors on treatment response; and
• compare the relative cost effectiveness of the three treatment arms.

The three treatment regimens are: (1) metformin alone, (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP). The study recruits patients over a three-year period and follows patients for a minimum of two years. Patients are randomized within two years of the diagnosis of T2D.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type II	Drug: Metformin; Drug: Rosiglitazone; Behavioral: Lifestyle Program	Phase 3

Detailed Description:

T2DM has dramatically increased throughout the world in many ethnic groups and among people with diverse social and economic backgrounds. Over the last decade, the increase in the number of children and youth with T2DM has been labeled an "epidemic". Before the 1990s, it was rare for most pediatric centers to have patients with T2DM. By 1994, T2DM patients represented up to 16% of new cases of diabetes in children in urban areas, and by 1999, depending on geographic location, the range of percent of new cases due to T2DM was between 8-45% and disproportionately represented in minority populations.

T2DM in children and youth, as in adults, is due to the combination of insulin resistance and relative β-cell failure. It appears that there are a host of genetic and environmental risk factors for insulin resistance and limited β-cell reserve. The epidemic of pediatric T2DM is coincident with the rise in the number of children who are overweight or at risk for overweight and with a decrease in the physical activity pattern of youth. There has been a strong association between T2DM and the onset of puberty, a positive family history of T2DM, and elements of the metabolic syndrome such as acanthosis nigricans and polycystic ovarian syndrome (PCOS).

Preceding the development of frank diabetes, children and youth experience a period of prediabetes. Prediabetes is defined as either elevated fasting glucose or impaired glucose tolerance. Despite the dramatic increase in the number of cases of prediabetes and T2DM in pediatric populations, there have been no published large-scale studies investigating the pathophysiology, treatment, and complications of these disorders in children and youth. The long-term complications and costs associated with T2DM make such studies imperative. Between 1997 and 2002, the estimated cost of diabetes with regard to direct medical cost increased from $44 billion to $92 billion, and the total cost increased from $98 billion to $132 billion. The vast majority of monies are spent on the long-term complications of this disorder. Since the long-term microvascular and cardiovascular complications relate to duration of diabetes and to control of glycemia, it could be hypothesized that the increasing number of children and youth diagnosed with T2DM, if not effectively treated, could dramatically add to the economic burden of this disease over the ensuing decades.

Except in American Indian youth, there are no population-based data available with regard to prevalence of T2DM. Instead, only clinic-based reports indicate that there has been a tremendous increase in the number of children and adolescents with T2DM. T2DM occurs almost exclusively in children and youth who are overweight or at risk for overweight (BMI > 85th percentile for age). At the time of diagnosis, most pediatric patients are in the midst of Tanner Stage 2-4 puberty. Puberty contributes to insulin resistance due to augmentation of growth hormone secretion, and if these normal pubertal physiologic changes are not compensated for by increased insulin secretion, frank diabetes will develop. Half to three-quarters of patients have a parent and close to ninety percent have at least one first or second degree relative with T2DM. The clinical presentation of T2DM in youth ranges from mild asymptomatic hyperglycemia to severe ketoacidosis. In those who present with clinical symptoms due to hyperglycemia, glycosuria and weight loss are present in 20-40%, ketonuria is present in 33% and ketoacidosis is found in 5-10%. Patients without clinical symptoms are diagnosed as the result of routine blood or urine testing during a health care visit or by investigating a variety of complaints such as chronic infection, sleep apnea, hyperlipidemia, hypertension, and hirsutism or irregular periods associated with PCOS. It may be difficult to distinguish T1DM from T2DM at presentation. The absence of autoantibodies is a prerequisite for the diagnosis of T2DM. In addition, evidence of residual insulin secretion is suggestive of T2DM rather than T1DM.

Patients with T2DM have dual abnormalities of insulin resistance and insulin deficiency. It is hypothesized that to achieve the level of glycemic control required to optimize long-term outcome and decrease or prevent microvascular complications, treatment regimens should theoretically be designed to improve insulin resistance and preserve residual β-cell function. The available anti-diabetic agents have not been adequately evaluated in pediatric patients. This is particularly relevant with regard to using combination therapy to improve glycemic control or lifestyle interventions aimed at obesity and sedentary behavior.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 699 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Studies to Treat Or Prevent Pediatric Type 2 Diabetes (STOPP-T2D) Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Clinical Trial
• Study Start Date: May 2004
• Actual Primary Completion Date: February 2011
• Actual Study Completion Date: February 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Metformin alone	Drug: Metformin; capsule, 1000 mg bid
Experimental: 2; Metformin + Rosiglitazone	Drug: Metformin; capsule, 1000 mg bid; Drug: Rosiglitazone; capsule, 4 mg bid
Experimental: 3; Metformin + Lifestyle Program	Drug: Metformin; capsule, 1000 mg bid; Behavioral: Lifestyle Program; a lifestyle change (LC) phase of weekly sessions for months 1-6, followed by a bi-weekly lifestyle maintenance (LM) phase through months 7-12, and a continued contact (CC) phase from months 13 through the end of the study. The CC phase sessions are scheduled monthly for the initial 12 months (study months 13-24) and then quarterly or 4 times a year to the end of the study

Outcome Measures

Primary Outcome Measures :

1. Treatment Failure (Loss of Glycemic Control) [ Time Frame: Study duration - 2 years to 6.5 years of follow up from randomization ]
   Defined as A1c persistently >=8% over a 6-month period or persistent metabolic decompensation (inability to wean insulin within 3 months of initiation or the occurrence of a second episode within three months of discontinuing insulin)

Secondary Outcome Measures :

1. Insulin Sensitivity [ Time Frame: 24 months ]
   All participants were followed to 24 months. Insulin sensitivity is measured from OGTT as inverse of fasting insulin (mL/uU). The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
2. Number of Serious Adverse Events [ Time Frame: Reported as occurred during study follow-up - 2 years to 6.5 years from randomization. ]
   Number of serious adverse events reported during the trial. Participant could have multiple episodes reported.
3. Insulin Secretion [ Time Frame: 24 months ]
   Insulinogenic index determined from OGTT as difference in insulin at 30 minutes minus 0 minutes divided by difference in glucose at 30 minutes minus 0 minutes. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
4. Body Composition -- BMI [ Time Frame: 24 months ]
   Body mass index (BMI) measured in kg per meters squared. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
5. Body Composition -- Waist Circumference [ Time Frame: 24 months ]
   Waist circumference (cm) measured at the iliac crest at its outermost point with the measuring tape placed around the participant in a horizontal plane parallel to the floor at the mark and the measurement teken at the end of normal expiration without the tape compressing the skin. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
6. Body Composition -- Bone Density [ Time Frame: 24 months ]
   Measured by DXA, both whole body scan and AP-spine scan. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time. In addition, in about 1/3 of participants DXA scans could not be obtained on participants weighing more than 300 pounds (136 kg), the upper limit in size set by the machine manufacturers. Scans were considered invalid if a body part (e.g., arm, leg) was completely off or partially off the scanner, there was hand-hip overlap, or there was motion or movement during the scan.
7. Body Composition -- Fat Mass [ Time Frame: 24 months ]
   Determined by DXA whole body scan. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time. In addition, in about 1/3 of participants DXA scans could not be obtained on participants weighing more than 300 pounds (136 kg), the upper limit in size set by the machine manufacturers. Scans were considered invalid if a body part (e.g., arm, leg) was completely off or partially off the scanner, there was hand-hip overlap, or there was motion or movement during the scan.
8. Comorbidity -- Hypertension [ Time Frame: Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. ]
   A diagnosis was made by an out-of-range value >=95th percentile or systolic >=130 or diastolic >=80 sustained over 6 months or on an anti-hypertensive medication.
9. Comorbidity -- LDL Dyslipidemia [ Time Frame: Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. ]
   A diagnosis was made from out-of-range value >= 130 mg/dL sustained over 6 months or put on lipid lowering medication.
10. Comorbidity -- Triglycerides Dyslipidemia [ Time Frame: Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. ]
    A diagnosis was made by an out-of-range value >=150 mg/dL sustained over 6 months or on appropriate lipid lowering medication.

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria (during Screening and Run-in period):

• Diabetes by ADA criteria (laboratory determinations of fasting glucose ≥ 126 mg/dL, random glucose ≥ 200 mg/dL, or two-hour OGTT glucose ≥ 200 mg/dL) documented and confirmed in medical record. For patients diagnosed with diabetes during screening who have a normal fasting glucose but an elevated two-hour glucose during an OGTT, the HbA1c must be ≥ 6%.
• Duration since diagnosis less than two years by date of randomization.
• BMI ≥ 85th percentile documented at time of diagnosis or at screening.
• Fasting C-peptide at screening (drawn at least one week after treatment for ketosis or acidosis, if applicable) > 0.6 ng/mL.
• Absence of pancreatic autoimmunity (both GAD and ICA512 negative).
• Age 10-17, with randomization prior to 18th birthday.
• Signed informed consent/assent forms for the pre-randomization period.
• A family member or adult closely involved in the daily activities of the child agrees to participate in the child's treatment.
• Fluency in English or Spanish for both child and family member.
• Patient and family able to fully participate in trial protocol in the opinion of the investigator.

Exclusion Criteria (during Screening and Run-in period):

• Participating in another interventional research study protocol in the past 30 days.
• Genetic syndrome or disorder known to affect glucose tolerance other than diabetes.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on oral steroids more than 20 days during the past year.
• Patient on medication(s) that are known to affect insulin sensitivity or secretion within the last 30 days.
• Patient on medication(s) that are known to cause weight gain within the last 30 days.
• Patient on any weight-loss medication(s) within the last 30 days.
• Patient on medication(s) known to affect the metabolism of study drug.
• Inability to comprehend the lowest grade level at which lifestyle intervention materials are prepared, for both child and participating family member.
• Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
• Calculated creatinine clearance < 70 mL/min.
• Any transaminase > 2.5 ULN. If any transaminase 1.5-2.5 times ULN, then patient must be appropriately evaluated by PCP (minimum evaluation includes ceruloplasmin level, alpha-1 antitrypsin phenotype, ANA, anti-smooth muscle antibody, anti-LKM antibody, anti-HCV, and anti-HBc total antibody not IgM, iron, and TIBC) and is eligible if all other causes for elevation are ruled out and it is presumed due only to non-alcoholic fatty liver disease (NAFLD).
• Diabetic ketoacidosis (DKA) at any time after diagnosis unless only a single episode of DKA related to a significant medical illness.
• Physical limitations preventing patient from being randomized to the lifestyle intervention.
• Patient plans to leave the geographic area within one calendar year.
• Abnormal reticulocyte count or HbA1c chromatogram at time of screening.
• Admitted use of anabolic steroids within the past 60 days.
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that would prevent participation in the opinion of the investigator.
• Patient participates in a formal weight-loss program.

Inclusion Criteria (post Run-in and Randomization):

• Duration since diagnosis less than 2 years at randomization.
• HbA1c < 8% on metformin alone.
• Age 10-17, with randomization before patient is 18 years old.
• Signed consent/assent forms for randomization and the post-randomization phase.
• A family member or adult closely involved in the daily activities of the child agrees to participate in the child's treatment.
• Fluency in English or Spanish for both child and family member.
• Patient and family able to fully participate in trial protocol in the opinion of the investigator.

Exclusion Criteria (post Run-in and Randomization):

• Refractory hypertension: average systolic blood pressure ≥ 150 mmHg or average diastolic blood pressure ≥ 95 mmHg despite appropriate medical therapy.
• Refractory hyperlipidemia: total cholesterol > 300 mg/dL or LDL > 190 mg/dL or triglycerides > 800 mg/dL, despite appropriate medical therapy.
• Refractory anemia: hematocrit < 30% or hemoglobin < 10 gm/dL despite appropriate medical therapy.
• Patient on a thiazolidinedione (TZD) within the last 12 weeks.
• Patient on non-study diabetes medications within the past 6 weeks.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on oral steroids more than 20 days during the past year.
• Patient on medication(s) that are known to affect insulin sensitivity or secretion within the last 30 days.
• Patient on medication(s) that are known to cause weight gain within the last 30 days.
• Patient on any weight-loss medication(s) within the last 30 days.
• Patient on medication(s) known to affect the metabolism of study drug.
• Inability to comprehend the lowest grade level at which lifestyle intervention materials are prepared, for both child and participating family member, assessed by mastery of standard diabetes education program administered during run-in.
• Inability to comply with requirements of study during run-in period.
• Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
• Calculated creatinine clearance < 70 mL/min.
• Physical limitations preventing patient from being randomized to the lifestyle intervention.
• Patient plans to leave the geographic area within one calendar year.
• Admitted use of anabolic steroids within 60 days.
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that would prevent participation in the opinion of the investigator.
• Patient participates in a formal weight loss program.
• Episode of DKA during the run-in.30.
• Edema at the time of randomization (a participant who experiences edema during run-in must have recovered within 2 weeks and be edema free for 1 week prior to randomization).

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

United States, Colorado

University of Colorado Health Sciences Center, The Children's Hospital

Denver, Colorado, United States, 80262

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Maryland

George Washington University Biostatistics Center

Rockville, Maryland, United States, 20852

United States, Massachusetts

Massachusetts General Hospital Diabetes Center

Boston, Massachusetts, United States, 02114

Joslin Diabetes Center

Boston, Massachusetts, United States, 02215

United States, Missouri

Saint Louis University Health Sciences Center

Saint Louis, Missouri, United States, 63104

Washington University Department of Pediatrics

Saint Louis, Missouri, United States, 63110

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

State University of New York Upstate Medical University

Syracuse, New York, United States, 13210

United States, Ohio

Case Western Reserve

Cleveland, Ohio, United States, 44106

United States, Oklahoma

University of Oklahoma

Oklahoma City, Oklahoma, United States, 93104

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Phil Zeitler, MD, PhD; University of Colorado, Denver
• Principal Investigator: Kathryn Hirst, PhD; George Washington University

More Information

Additional Information:

public access to intervention materials used in TODAY 

Publications of Results:

Klingensmith GJ, Pyle L, Arslanian S, Copeland KC, Cuttler L, Kaufman F, Laffel L, Marcovina S, Tollefsen SE, Weinstock RS, Linder B; TODAY Study Group. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study. Diabetes Care. 2010 Sep;33(9):1970-5. doi: 10.2337/dc10-0373. Epub 2010 Jun 2.

Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, Kaufman FR, Linder B, Marcovina S, McGuigan P, Pyle L, Tamborlane W, Willi S; TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011 Jan;96(1):159-67. doi: 10.1210/jc.2010-1642. Epub 2010 Oct 20.

TODAY Study Group; Wilfley D, Berkowitz R, Goebel-Fabbri A, Hirst K, Ievers-Landis C, Lipman TH, Marcus M, Ng D, Pham T, Saletsky R, Schanuel J, Van Buren D. Binge eating, mood, and quality of life in youth with type 2 diabetes: baseline data from the today study. Diabetes Care. 2011 Apr;34(4):858-60. doi: 10.2337/dc10-1704. Epub 2011 Feb 28.

Anderson BJ, Edelstein S, Abramson NW, Katz LE, Yasuda PM, Lavietes SJ, Trief PM, Tollefsen SE, McKay SV, Kringas P, Casey TL, Marcus MD. Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study. Diabetes Care. 2011 Oct;34(10):2205-7. doi: 10.2337/dc11-0431. Epub 2011 Aug 11.

Laffel L, Chang N, Grey M, Hale D, Higgins L, Hirst K, Izquierdo R, Larkin M, Macha C, Pham T, Wauters A, Weinstock RS; TODAY Study Group. Metformin monotherapy in youth with recent onset type 2 diabetes: experience from the prerandomization run-in phase of the TODAY study. Pediatr Diabetes. 2012 Aug;13(5):369-75. doi: 10.1111/j.1399-5448.2011.00846.x. Epub 2012 Feb 27.

Bacha F, Pyle L, Nadeau K, Cuttler L, Goland R, Haymond M, Levitsky L, Lynch J, Weinstock RS, White NH, Caprio S, Arslanian S; TODAY Study Group. Determinants of glycemic control in youth with type 2 diabetes at randomization in the TODAY study. Pediatr Diabetes. 2012 Aug;13(5):376-83. doi: 10.1111/j.1399-5448.2011.00841.x. Epub 2012 Feb 15.

TODAY Study Group; Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012 Jun 14;366(24):2247-56. doi: 10.1056/NEJMoa1109333. Epub 2012 Apr 29.

Kriska A, Delahanty L, Edelstein S, Amodei N, Chadwick J, Copeland K, Galvin B, El ghormli L, Haymond M, Kelsey M, Lassiter C, Mayer-Davis E, Milaszewski K, Syme A. Sedentary behavior and physical activity in youth with recent onset of type 2 diabetes. Pediatrics. 2013 Mar;131(3):e850-6. doi: 10.1542/peds.2012-0620. Epub 2013 Feb 11.

Delahanty L, Kriska A, Edelstein S, Amodei N, Chadwick J, Copeland K, Galvin B, El Ghormli L, Haymond M, Kelsey MM, Lassiter C, Milaszewski K, Syme A, Mayer-Davis E. Self-reported dietary intake of youth with recent onset of type 2 diabetes: results from the TODAY study. J Acad Nutr Diet. 2013 Mar;113(3):431-439. doi: 10.1016/j.jand.2012.11.015.

TODAY Study Group. Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1735-41. doi: 10.2337/dc12-2420. Erratum In: Diabetes Care. 2013 Aug;36(8):2448.

TODAY Study Group. Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1742-8. doi: 10.2337/dc12-2534.

TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and beta-cell function in TODAY. Diabetes Care. 2013 Jun;36(6):1749-57. doi: 10.2337/dc12-2393.

TODAY Study Group. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1758-64. doi: 10.2337/dc12-2388.

TODAY Study Group. Safety and tolerability of the treatment of youth-onset type 2 diabetes: the TODAY experience. Diabetes Care. 2013 Jun;36(6):1765-71. doi: 10.2337/dc12-2390.

TODAY Study Group. Retinopathy in youth with type 2 diabetes participating in the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1772-4. doi: 10.2337/dc12-2387.

Levitt Katz L, Gidding SS, Bacha F, Hirst K, McKay S, Pyle L, Lima JA; TODAY Study Group. Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes participating in the TODAY clinical trial. Pediatr Diabetes. 2015 Feb;16(1):39-47. doi: 10.1111/pedi.12119. Epub 2014 Jan 22.

Narasimhan S, Weinstock RS. Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study. Mayo Clin Proc. 2014 Jun;89(6):806-16. doi: 10.1016/j.mayocp.2014.01.009. Epub 2014 Apr 3.

Walders-Abramson N, Venditti EM, Ievers-Landis CE, Anderson B, El Ghormli L, Geffner M, Kaplan J, Koontz MB, Saletsky R, Payan M, Yasuda P; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Relationships among stressful life events and physiological markers, treatment adherence, and psychosocial functioning among youth with type 2 diabetes. J Pediatr. 2014 Sep;165(3):504-508.e1. doi: 10.1016/j.jpeds.2014.05.020. Epub 2014 Jun 16.

Tryggestad JB, Willi SM. Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial. J Diabetes Complications. 2015 Mar;29(2):307-12. doi: 10.1016/j.jdiacomp.2014.10.009. Epub 2014 Oct 29.

Weinstock RS, Trief PM, El Ghormli L, Goland R, McKay S, Milaszewski K, Preske J, Willi S, Yasuda PM. Parental Characteristics Associated With Outcomes in Youth With Type 2 Diabetes: Results From the TODAY Clinical Trial. Diabetes Care. 2015 May;38(5):784-92. doi: 10.2337/dc14-2393. Epub 2015 Mar 17.

Weinstock RS, Drews KL, Caprio S, Leibel NI, McKay SV, Zeitler PS; TODAY Study Group. Metabolic syndrome is common and persistent in youth-onset type 2 diabetes: Results from the TODAY clinical trial. Obesity (Silver Spring). 2015 Jul;23(7):1357-61. doi: 10.1002/oby.21120. Epub 2015 Jun 5.

Ievers-Landis CE, Walders-Abramson N, Amodei N, Drews KL, Kaplan J, Levitt Katz LE, Lavietes S, Saletsky R, Seidman D, Yasuda P; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Longitudinal Correlates of Health Risk Behaviors in Children and Adolescents with Type 2 Diabetes. J Pediatr. 2015 May;166(5):1258-1264.e3. doi: 10.1016/j.jpeds.2015.01.019. Epub 2015 Feb 20.

Larkin ME, Walders-Abramson N, Hirst K, Keady J, Ievers-Landis CE, Venditti EM, Yasuda PM. Effects of comorbid conditions on health-related quality of life in youth with Type 2 diabetes: the TODAY clinical trial. Diabetes Manag (Lond). 2015 Nov;5(6):431-439. doi: 10.2217/dmt.15.35.

Zeitler P, Hirst K, Copeland KC, El Ghormli L, Levitt Katz L, Levitsky LL, Linder B, McGuigan P, White NH, Wilfley D; TODAY Study Group. HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes. Diabetes Care. 2015 Dec;38(12):2285-92. doi: 10.2337/dc15-0848. Epub 2015 Nov 4.

Walders-Abramson N, Anderson B, Larkin ME, Chang N, Venditti E, Bzdick S, Tryggestad JB, Tan K, Geffner ME, Hirst K. Benefits and barriers to participating in longitudinal research of youth-onset type 2 diabetes: Results from the TODAY retention survey. Clin Trials. 2016 Apr;13(2):240-3. doi: 10.1177/1740774515613949. Epub 2015 Nov 3.

Chernausek SD, Arslanian S, Caprio S, Copeland KC, El ghormli L, Kelsey MM, Koontz MB, Orsi CM, Wilfley D. Relationship Between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth With Type 2 Diabetes: Baseline Findings From the TODAY Trial. Diabetes Care. 2016 Jan;39(1):110-7. doi: 10.2337/dc15-1557. Epub 2015 Nov 17.

Klingensmith GJ, Pyle L, Nadeau KJ, Barbour LA, Goland RS, Willi SM, Linder B, White NH; TODAY Study Group. Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience. Diabetes Care. 2016 Jan;39(1):122-9. doi: 10.2337/dc15-1206. Epub 2015 Dec 1.

Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler PS, White NH; Treatment Options for Type 2 Diabetes in Adolescents and Youth Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatr Diabetes. 2016 May;17(3):212-21. doi: 10.1111/pedi.12264. Epub 2015 Feb 17.

Rockette-Wagner B, Storti KL, Edelstein S, Delahanty LM, Galvin B, Jackson A, Kriska AM. Measuring Physical Activity and Sedentary Behavior in Youth with Type 2 Diabetes. Child Obes. 2017 Feb;13(1):72-77. doi: 10.1089/chi.2015.0151. Epub 2016 Feb 9.

Arslanian S, El Ghormli L, Bacha F, Caprio S, Goland R, Haymond MW, Levitsky L, Nadeau KJ, White NH, Willi SM; TODAY Study Group. Adiponectin, Insulin Sensitivity, beta-Cell Function, and Racial/Ethnic Disparity in Treatment Failure Rates in TODAY. Diabetes Care. 2017 Jan;40(1):85-93. doi: 10.2337/dc16-0455. Epub 2016 Nov 1.

Marcus MD, Wilfley DE, El Ghormli L, Zeitler P, Linder B, Hirst K, Ievers-Landis CE, van Buren DJ, Walders-Abramson N; TODAY Study Group. Weight change in the management of youth-onset type 2 diabetes: the TODAY clinical trial experience. Pediatr Obes. 2017 Aug;12(4):337-345. doi: 10.1111/ijpo.12148. Epub 2016 May 10.

Gandica R, Zeitler P. Update on Youth-Onset Type 2 Diabetes: Lessons Learned from the Treatment Options for Type 2 Diabetes in Adolescents and Youth Clinical Trial. Adv Pediatr. 2016 Aug;63(1):195-209. doi: 10.1016/j.yapd.2016.04.013. Epub 2016 Jun 3. No abstract available.

Katz LL, Anderson BJ, McKay SV, Izquierdo R, Casey TL, Higgins LA, Wauters A, Hirst K, Nadeau KJ; TODAY Study Group. Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes. Diabetes Care. 2016 Nov;39(11):1956-1962. doi: 10.2337/dc15-2296. Epub 2016 Jun 28.

Bacha F, Gidding SS, Pyle L, Levitt Katz L, Kriska A, Nadeau KJ, Lima JAC; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes. J Pediatr. 2016 Oct;177:159-166.e1. doi: 10.1016/j.jpeds.2016.06.048. Epub 2016 Aug 4.

Kriska A, El Ghormli L, Copeland KC, Higgins J, Ievers-Landis CE, Levitt Katz LE, Trief PM, Wauters AD, Yasuda PM, Delahanty LM; TODAY Study Group. Impact of lifestyle behavior change on glycemic control in youth with type 2 diabetes. Pediatr Diabetes. 2018 Feb;19(1):36-44. doi: 10.1111/pedi.12526. Epub 2017 Apr 4.

Berkowitz RI, Marcus MD, Anderson BJ, Delahanty L, Grover N, Kriska A, Laffel L, Syme A, Venditti E, Van Buren DJ, Wilfley DE, Yasuda P, Hirst K; TODAY Study Group. Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial. Pediatr Diabetes. 2018 Mar;19(2):191-198. doi: 10.1111/pedi.12555. Epub 2017 Jun 30.

Bjornstad P, Nehus E, El Ghormli L, Bacha F, Libman IM, McKay S, Willi SM, Laffel L, Arslanian S, Nadeau KJ; TODAY Study Group. Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial. Am J Kidney Dis. 2018 Jan;71(1):65-74. doi: 10.1053/j.ajkd.2017.07.015. Epub 2017 Nov 20. Erratum In: Am J Kidney Dis. 2019 Apr;73(4):580.

Gidding SS, Bacha F, Bjornstad P, Levitt Katz LE, Levitsky LL, Lynch J, Tryggestad JB, Weinstock RS, El Ghormli L, Lima JAC; TODAY Study Group. Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. J Pediatr. 2018 Jan;192:86-92.e5. doi: 10.1016/j.jpeds.2017.09.012.

Kleinberger JW, Copeland KC, Gandica RG, Haymond MW, Levitsky LL, Linder B, Shuldiner AR, Tollefsen S, White NH, Pollin TI. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018 Jun;20(6):583-590. doi: 10.1038/gim.2017.150. Epub 2017 Oct 12.

Van Buren DJ, Wilfley DE, Marcus MD, Anderson B, Abramson NW, Berkowitz R, Ievers-Landis C, Trief P, Yasuda P, Hirst K; TODAY Study Group. Depressive symptoms and glycemic control in youth with type 2 diabetes participating in the TODAY clinical trial. Diabetes Res Clin Pract. 2018 Jan;135:85-87. doi: 10.1016/j.diabres.2017.11.008. Epub 2017 Nov 13.

Levitt Katz LE, Bacha F, Gidding SS, Weinstock RS, El Ghormli L, Libman I, Nadeau KJ, Porter K, Marcovina S; TODAY Study Group. Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes. J Pediatr. 2018 May;196:208-216.e2. doi: 10.1016/j.jpeds.2017.12.052. Epub 2018 Feb 2.

Inge TH, Laffel LM, Jenkins TM, Marcus MD, Leibel NI, Brandt ML, Haymond M, Urbina EM, Dolan LM, Zeitler PS; Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) Consortia. Comparison of Surgical and Medical Therapy for Type 2 Diabetes in Severely Obese Adolescents. JAMA Pediatr. 2018 May 1;172(5):452-460. doi: 10.1001/jamapediatrics.2017.5763.

Venditti EM, Tan K, Chang N, Laffel L, McGinley G, Miranda N, Tryggestad JB, Walders-Abramson N, Yasuda P, Delahanty L; TODAY Study Group. Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes. Diabetes Res Clin Pract. 2018 May;139:24-31. doi: 10.1016/j.diabres.2018.02.001. Epub 2018 Feb 8.

Kelsey MM, Braffett BH, Geffner ME, Levitsky LL, Caprio S, McKay SV, Shah R, Sprague JE, Arslanian SA; TODAY Study Group. Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2309-2318. doi: 10.1210/jc.2018-00132.

Shah AS, El Ghormli L, Gidding SS, Bacha F, Nadeau KJ, Levitt Katz LE, Tryggestad JB, Leibel N, Hale DE, Urbina EM. Prevalence of arterial stiffness in adolescents with type 2 diabetes in the TODAY cohort: Relationships to glycemic control and other risk factors. J Diabetes Complications. 2018 Aug;32(8):740-745. doi: 10.1016/j.jdiacomp.2018.05.013. Epub 2018 May 25.

Arslanian S, El Ghormli L, Young Kim J, Bacha F, Chan C, Ismail HM, Levitt Katz LE, Levitsky L, Tryggestad JB, White NH; TODAY Study Group. The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in beta-Cell Function in TODAY. Diabetes Care. 2019 Jan;42(1):164-172. doi: 10.2337/dc18-1122. Epub 2018 Nov 19.

Weinstock RS, Braffett BH, McGuigan P, Larkin ME, Grover NB, Walders-Abramson N, Laffel LM, Chan CL, Chang N, Schwartzman BE, Barajas RA, Celona-Jacobs N, Haymond MW; TODAY Study Group. Self-Monitoring of Blood Glucose in Youth-Onset Type 2 Diabetes: Results From the TODAY Study. Diabetes Care. 2019 May;42(5):903-909. doi: 10.2337/dc18-1854. Epub 2019 Mar 4.

Bjornstad P, Laffel L, Lynch J, El Ghormli L, Weinstock RS, Tollefsen SE, Nadeau KJ; TODAY Study Group. Elevated Serum Uric Acid Is Associated With Greater Risk for Hypertension and Diabetic Kidney Diseases in Obese Adolescents With Type 2 Diabetes: An Observational Analysis From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. Diabetes Care. 2019 Jun;42(6):1120-1128. doi: 10.2337/dc18-2147. Epub 2019 Apr 9.

Dhaliwal R, Shepherd JA, El Ghormli L, Copeland KC, Geffner ME, Higgins J, Levitsky LL, Nadeau KJ, Weinstock RS, White NH; TODAY Study Group. Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study. Diabetes Care. 2019 Aug;42(8):1549-1559. doi: 10.2337/dc18-1935. Epub 2019 Jun 5.

Bacha F, El Ghormli L, Arslanian S, Zeitler P, Laffel LM, Levitt Katz LE, Gandica R, Chang NT, Sprague JE, Macleish SA; TODAY Study Group. Predictors of response to insulin therapy in youth with poorly-controlled type 2 diabetes in the TODAY trial. Pediatr Diabetes. 2019 Nov;20(7):871-879. doi: 10.1111/pedi.12906. Epub 2019 Aug 27.

Shah AS, El Ghormli L, Vajravelu ME, Bacha F, Farrell RM, Gidding SS, Levitt Katz LE, Tryggestad JB, White NH, Urbina EM. Heart Rate Variability and Cardiac Autonomic Dysfunction: Prevalence, Risk Factors, and Relationship to Arterial Stiffness in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. Diabetes Care. 2019 Nov;42(11):2143-2150. doi: 10.2337/dc19-0993. Epub 2019 Sep 9.

Bjornstad P, Hughan K, Kelsey MM, Shah AS, Lynch J, Nehus E, Mitsnefes M, Jenkins T, Xu P, Xie C, Inge T, Nadeau K. Effect of Surgical Versus Medical Therapy on Diabetic Kidney Disease Over 5 Years in Severely Obese Adolescents With Type 2 Diabetes. Diabetes Care. 2020 Jan;43(1):187-195. doi: 10.2337/dc19-0708. Epub 2019 Nov 4.

Shah R, McKay SV, Levitt Katz LE, El Ghormli L, Anderson BJ, Casey TL, Higgins L, Izquierdo R, Wauters AD, Chang N; TODAY Study Group. Adherence to multiple medications in the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) cohort: effect of additional medications on adherence to primary diabetes medication. J Pediatr Endocrinol Metab. 2020 Feb 25;33(2):191-198. doi: 10.1515/jpem-2019-0315.

Kaar JL, Schmiege SJ, Drews K, Higgins J, Walders-Abramson N, Isganaitis E, Willi SM, Marcus MD, Zeitler PS, Kelsey MM. Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial. Pediatr Diabetes. 2020 Mar;21(2):224-232. doi: 10.1111/pedi.12976. Epub 2020 Jan 6.

Arslanian S, El Ghormli L, Haymond MH, Chan CL, Chernausek SD, Gandica RG, Gubitosi-Klug R, Levitsky LL, Siska M, Willi SM; TODAY Study Group. Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure. Pediatr Diabetes. 2020 Jun;21(4):575-585. doi: 10.1111/pedi.12998. Epub 2020 Mar 3.

Tryggestad JB, Shah RD, Braffett BH, Bacha F, Gidding SS, Gubitosi-Klug RA, Shah AS, Urbina EM, Levitt Katz LE; TODAY Study Group. Circulating adhesion molecules and associations with HbA1c, hypertension, nephropathy, and retinopathy in the Treatment Options for type 2 Diabetes in Adolescent and Youth study. Pediatr Diabetes. 2020 Sep;21(6):923-931. doi: 10.1111/pedi.13062. Epub 2020 Jul 2.

Ryder JR, Xu P, Nadeau KJ, Kelsey MM, Xie C, Jenkins T, Inge TH, Bjornstad P. Effect of surgical versus medical therapy on estimated cardiovascular event risk among adolescents with type 2 diabetes and severe obesity. Surg Obes Relat Dis. 2021 Jan;17(1):23-33. doi: 10.1016/j.soard.2020.09.002. Epub 2020 Sep 9.

Other Publications:

TODAY Study Group; Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, Tamborlane W, Wilfley D. 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 Apr;8(2):74-87. doi: 10.1111/j.1399-5448.2007.00237.x.

Songer T, Glazner J, Coombs LP, Cuttler L, Daniel M, Estrada S, Klingensmith G, Kriska A, Laffel L, Zhang P; the TODAY Study Group. Examining the economic costs related to lifestyle and pharmacological interventions in youth with Type 2 diabetes. Expert Rev Pharmacoecon Outcomes Res. 2006 Jun 1;6(3):315-324. doi: 10.1586/14737167.6.3.315.

Grey M, Schreiner B, Pyle L. Development of a diabetes education program for youth with type 2 diabetes. Diabetes Educ. 2009 Jan-Feb;35(1):108-16. doi: 10.1177/0145721708325156.

TODAY Study Group. Design of a family-based lifestyle intervention for youth with type 2 diabetes: the TODAY study. Int J Obes (Lond). 2010 Feb;34(2):217-26. doi: 10.1038/ijo.2009.195. Epub 2009 Oct 13.

Larkin ME, McGuigan P, Richards D, Blumenthal K, Milaszewski K, Higgins L, Schanuel J, Long C. Collaborative staffing model: reducing the challenges of study coordination in multi-site clinical trials. Applied Clinical Trials 2011, http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Articles/Collaborative-Staffing-Model/ArticleStandard/Article/detail/703023 (accessed 01/15/2011).

Chadwick JQ, Copeland KC, Daniel MR, Erb-Alvarez JA, Felton BA, Khan SI, Saunkeah BR, Wharton DF, Payan ML. Partnering in research: a national research trial exemplifying effective collaboration with American Indian Nations and the Indian Health Service. Am J Epidemiol. 2014 Dec 15;180(12):1202-7. doi: 10.1093/aje/kwu246. Epub 2014 Nov 11.

Chadwick JQ, Van Buren DJ, Morales E, Timpson A, Abrams EL, Syme A, Preske J, Mireles G, Anderson B, Grover N, Laffel L. Structure to utilize interventionists' implementation experiences of a family-based behavioral weight management program to enhance the dissemination of the standardized intervention: The TODAY study. Clin Trials. 2017 Aug;14(4):406-412. doi: 10.1177/1740774517707727. Epub 2017 May 9.

Chadwick JQ, Copeland KC, Branam DE, Erb-Alvarez JA, Khan SI, Peercy MT, Rogers ME, Saunkeah BR, Tryggestad JB, Wharton DF. Genomic Research and American Indian Tribal Communities in Oklahoma: Learning From Past Research Misconduct and Building Future Trusting Partnerships. Am J Epidemiol. 2019 Jul 1;188(7):1206-1212. doi: 10.1093/aje/kwz062.

Songer TJ, Haymond MW, Glazner JE, Klingensmith GJ, Laffel LM, Zhang P, Hirst K; TODAY Study Group. Healthcare and associated costs related to type 2 diabetes in youth and adolescence: the TODAY clinical trial experience. Pediatr Diabetes. 2019 Sep;20(6):702-711. doi: 10.1111/pedi.12869. Epub 2019 Jun 6.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Levitsky LL, Drews KL, Haymond M, Glubitosi-Klug RA, Levitt Katz LE, Mititelu M, Tamborlane W, Tryggestad JB, Weinstock RS; TODAY Study Group. The obesity paradox: Retinopathy, obesity, and circulating risk markers in youth with type 2 diabetes in the TODAY Study. J Diabetes Complications. 2022 Nov;36(11):108259. doi: 10.1016/j.jdiacomp.2022.108259. Epub 2022 Jul 19.

Shah AS, Gidding SS, El Ghormli L, Tryggestad JB, Nadeau KJ, Bacha F, Levitt Katz LE, Willi SM, Lima J, Urbina EM; TODAY Study Group. Relationship between Arterial Stiffness and Subsequent Cardiac Structure and Function in Young Adults with Youth-Onset Type 2 Diabetes: Results from the TODAY Study. J Am Soc Echocardiogr. 2022 Jun;35(6):620-628.e4. doi: 10.1016/j.echo.2022.02.001. Epub 2022 Feb 8.

TODAY Study Group; Shah RD, Braffett BH, Tryggestad JB, Hughan KS, Dhaliwal R, Nadeau KJ, Levitt Katz LE, Gidding SS. Cardiovascular risk factor progression in adolescents and young adults with youth-onset type 2 diabetes. J Diabetes Complications. 2022 Mar;36(3):108123. doi: 10.1016/j.jdiacomp.2021.108123. Epub 2022 Jan 3.

Trief PM, Uschner D, Tung M, Marcus MD, Rayas M, MacLeish S, Farrell R, Keady J, Chao L, Weinstock RS. Diabetes Distress in Young Adults With Youth-Onset Type 2 Diabetes: TODAY2 Study Results. Diabetes Care. 2022 Mar 1;45(3):529-537. doi: 10.2337/dc21-1689.

TODAY Study Group; Shah AS, El Ghormli L, Gidding SS, Hughan KS, Levitt Katz LE, Koren D, Tryggestad JB, Bacha F, Braffett BH, Arslanian S, Urbina EM. Longitudinal changes in vascular stiffness and heart rate variability among young adults with youth-onset type 2 diabetes: results from the follow-up observational treatment options for type 2 diabetes in adolescents and youth (TODAY) study. Acta Diabetol. 2022 Feb;59(2):197-205. doi: 10.1007/s00592-021-01796-6. Epub 2021 Sep 20.

TODAY Study Group. Health Care Coverage and Glycemic Control in Young Adults With Youth-Onset Type 2 Diabetes: Results From the TODAY2 Study. Diabetes Care. 2020 Oct;43(10):2469-2477. doi: 10.2337/dc20-0760. Epub 2020 Aug 10.

TODAY Study Group. Longitudinal Changes in Cardiac Structure and Function From Adolescence to Young Adulthood in Participants With Type 2 Diabetes Mellitus: The TODAY Follow-Up Study. Circ Heart Fail. 2020 Jun;13(6):e006685. doi: 10.1161/CIRCHEARTFAILURE.119.006685. Epub 2020 Jun 5.

Saletsky RD, Trief PM, Anderson BJ, Rosenbaum P, Weinstock RS. Parenting style, parent-youth conflict, and medication adherence in youth with type 2 diabetes participating in an intensive lifestyle change intervention. Fam Syst Health. 2014 Jun;32(2):176-85. doi: 10.1037/fsh0000008. Epub 2014 Feb 17.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00081328
• Other Study ID Numbers: IND - DK61230-TODAY; U01DK061230 ( U.S. NIH Grant/Contract )
• First Posted: April 12, 2004
• Results First Posted: December 16, 2014
• Last Update Posted: July 30, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data are available at the NIDDK Central Repository
• URL: https://repository.niddk.nih.gov/studies/today/?query=today

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Metformin; Rosiglitazone; Hypoglycemic Agents; Physiological Effects of Drugs