Effect of Short-Term Beta-Cell Rest in Adolescents and Young Adults With Type 2 Diabetes Mellitus

Condition(s) targeted: Obesity; Insulin Resistance; Overweight; Diabetes Mellitus, Type 2

Intervention: Metformin (Drug); Insulin (Drug); Diazoxide (Drug); Nutrition counseling (Behavioral); Exercise counseling (Behavioral)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

This study will determine whether resting beta cells (cells in the pancreas that produce insulin) for 2 weeks will improve the ability of patients with Type 2 diabetes mellitus (T2DM) to make insulin. Beta cells can rest by giving patients insulin shots and diazoxide (a medicine that blocks cells from releasing insulin). The study will also examine how teenagers with T2DM feel about having diabetes and explore differences between young people with and without T2DM.

This study includes patients 12 to 20 years of age with T2DM who are overweight and who were diagnosed within 1 year of enrolling in the study. Healthy individuals of normal weight or who are overweight are also eligible. Candidates are screened with a medical history, physical examination and laboratory tests.

Participants with T2DM are assigned to one of two groups. Group 1 takes an anti-diabetes medicine called metformin and follows a diet prescribed by a study staff dietitian for 2 weeks. Group 2 takes metformin, follows the prescribed diet, and receives insulin through a pump under the skin and diazoxide by mouth for 2 weeks. All patients are hospitalized for this 2-week period. During this time, they have the following tests:

- Frequent blood sugar checks.

- Oral glucose tolerance test (routine diabetes test in which blood samples are drawn

before and several times after the subject drinks a sugary solution).

- Arginine stimulation to test the response of the body to arginine, a normal ingredient

of food that stimulates the release of insulin. Two catheters are placed into veins in the arms, one to administer a liquid containing arginine, the other to draw the blood samples.

- Ultrasound of the blood vessels in the neck to check for hardening of the arteries.

- Metabolism test to measure the amount of oxygen used during rest. The subject breathes

normally during rest while wearing a canopy over his or her head for about 20 minutes.

- MRI scans of the abdomen to examine the amount of fat in the belly (at the beginning and

end of the study)

- DEXA scan to determine percent body fat.

- Tests to explore quality of life and feelings about health, work or school, friends and

family.

- Exercise testing on a treadmill or stationary bicycle.

- Genetic studies for information on diabetes and obesity.

Normal volunteers have blood draws, oral glucose tolerance testing, MRI scan, DEXA scan, psychological testing, exercise testing, and genetic testing.

Official title: Effect of Short-Term Beta-Cell Rest in Adolescents and Young Adults With Type 2 Diabetes Mellitus

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety Study

Primary outcome: Change in glucose-stimulated insulin secretion.

Secondary outcome: Change in indices of beta-cell function and insulin sensitivity; effect of beta-cell rest on glycemia control and markers of inflammation and oxidative stress: natural history of type 2 diabetes in young people with comparison to normal volunteers.

Detailed description: Background:

Type 2 diabetes mellitus (T2DM) is a condition characterized by insulin resistance and progressive failure of the insulin-secreting beta-cells. Previously considered a disease of adults, it is now becoming increasingly prevalent in children and adolescents. Patients with childhood onset T2DM are at very high risk for diabetes-related morbidity and mortality, due to a longer life-time duration of diabetes, as well as possible increased rapidity of beta-cell failure.

In part, the impairment in insulin secretion is caused by beta-cell exhaustion due to a constant, unsuccessful attempt to compensate for the existing insulin resistance. In addition, beta-cell function is affected by glucotoxicity, generating a downward cycle of hyperglycemia leading to decreased insulin secretion, which further worsens hyperglycemia. Results from two recent studies in adults with newly diagnosed T2DM suggest that intensive insulin treatment for 2 weeks may break this cycle, resulting in significant, long-term improvement of beta-cell function. Both reports documented that approximately 50 percent of patients maintained euglycemia on diet alone at 12-month follow-up.

Aims:

In this study, we will address the following questions:

1. Does short-term beta-cell rest induced by intensive insulin therapy and diazoxide (a potassium channel opener and inhibitor of insulin secretion) result in prolonged improvement in beta-cell function in adolescents and young adults with T2DM compared to patients who receive conventional treatment?

2. What mechanisms underlie the improvement of beta-cell function through beta-cell rest?

Methods:

In this randomized, controlled trial we will divide adolescents and young adults with T2DM of less than or equal to 2 years duration into 2 treatment groups:

Group 1 (control arm) will receive conventional therapy for T2DM (metformin plus diet and behavior modification).

Group 2 will undergo beta-cell rest using continuous subcutaneous insulin infusion (CSII) and oral diazoxide therapy for a period of 2 weeks, in addition to conventional therapy (metformin plus diet and behavior modification).

The primary outcome will be comparison of insulin secretion (assessed at one year) in the beta-cell rest group versus the conventional group.

Minimum age: 12 Years. Maximum age: 25 Years. Gender(s): Both.

Criteria:

- DIABETIC SUBJECTS:

INCLUSION CRITERIA:

1. Type 2 diabetes mellitus as defined by:

1. Fasting blood glucose greater than or equal to 126 mg/dL OR postprandial blood sugar greater than or equal to 200 mg/dL (either during OGTT at NIH or as previously documented on outside medical record)

Since subjects may already have been started on treatment with hypoglycemic agents at the time of enrollment, they may have blood glucose levels in the impaired glucose tolerance range (fasting glucose 100-125 mg/dL and postprandial 140-199 mg/dL). This is a sign of adequately controlled diabetes, rather than an incorrect diagnosis of diabetes. Therefore, prior documentation (on outside medical records) of blood glucose values documenting diabetes will be acceptable if the subject has impaired glucose tolerance rather than overt diabetes according to screening results at NIH.

2. Absence of insulin autoantibodies (in insulin naive patients only)

2. Duration of diabetes less than or equal to 2 years (since diagnosis)

3. BMI greater than or equal to 85th percentile for age

4. Age 12-25 years at enrollment

EXCLUSION CRITERIA:

1. Normal OGTT at NIH (fasting blood glucose less than 100 mg/dL AND 2-hour blood glucose less than 140 mg/dL)

2. Monogenic causes of diabetes (e. g. maturity-onset diabetes of the young [MODY] or mitochondrial diabetes). Subjects will be excluded if there is a known personal or family (first degree relative) history of monogenic diabetes. Genetic testing for monogenic causes of diabetes will be performed on potential subjects if the family history is suggestive of monogenic diabetes.

3. Significant comorbidity that, in the opinion of the investigators, will increase risk to the subject, such as coronary artery disease or any heart disease that increases risk associated with exercise (e. g. hypertrophic obstructive cardiomyopathy), renal impairment with serum creatinine greater than 1. 4 mg/dL, or current treatment for cancer. Specific obesity-related comorbidities are explicitly permitted, including hypertension, hyperlipidemia, obstructive sleep apnea and non-alcoholic steatohepatitis.

4. Current use of insulin

5. Current use of prescription or non-prescription weight-loss drugs

6. Positive urine pregnancy test or plans to become pregnant during the clinical trial

7. Known allergy, sensitivity or other contraindication to any study drug or its vehicle

8. Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to comply with study medications and monitoring

MATCHED VOLUNTEERS:

INCLUSION CRITERIA:

Two types of volunteers will be recruited:

1. Age, sex, race and BMI matched with study enrollees who have T2DM

2. Normal weight (BMI between 5th and 85th percentiles for age) volunteers who are age, sex and race matched to subjects with T2DM

EXCLUSION CRITERIA:

1. Diabetes and impaired glucose tolerance

2. Significant comorbidity that, in the opinion of the investigators, will increase risk to the subject (specific obesity-related comorbidities are explicitly permitted, including hypertension, hyperlipidemia, obstructive sleep apnea and non-alcoholic steatohepatitis)

3. Current or recent (past 2 months) use of drugs that alter glucose metabolism (e. g. metformin)

4. Current use of prescription or non-prescription weight-loss drugs

5. Positive urine pregnancy test

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia. 1998 Aug;41(8):904-10.

Fridlyand LE, Philipson LH. Does the glucose-dependent insulin secretion mechanism itself cause oxidative stress in pancreatic beta-cells? Diabetes. 2004 Aug;53(8):1942-8. Review.

Gungor N, Bacha F, Saad R, Janosky J, Arslanian S. Youth type 2 diabetes: insulin resistance, beta-cell failure, or both? Diabetes Care. 2005 Mar;28(3):638-44.

Starting date: March 2007
Last updated: November 25, 2008