Characterization of the Variability of Insulin Secretory Parameters in the Meal Tolerance and the Maximal Stimulation Tests of Healthy Subjects

Characterization of the Variability of Insulin Secretory Parameters in the Meal Tolerance and the Maximal Stimulation Tests of Healthy Subjects

A multi-year clinical study to improve tools for measuring the function of insulin-producing beta cells in people with type 2 diabetes mellitus.

A three-year observational study to standardize the meal tolerance and maximum stimulational tests for measuring beta cell function in the clinical setting. It also aims to improve methods for the early prediction of the long-term response to an intervention and for identification of patients at risk for rapid beta cell function deterioration, thereby enabling future clinical studies that examine diabetes progression.

Inclusion Criteria:

1. Ability to give informed consent and comply with all study requirements

2. Overweight and obese, generally healthy men and women. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests.

3. Women of child-bearing potential are allowed (but must agree to use non-hormonal contraception and not plan to become pregnant for the duration of the study. Must agree to maintain the same contraceptive measures throughout the study. Acceptable contraceptive methods for female subjects of childbearing potential include one of the following:

   • Abstinence.

   • One (1) of the following methods:

     • Tubal ligation
     • Copper-containing intrauterine device (IUD)
     • Condom AND spermicidal foam/gel/film/cream/suppository
     • Male partner who has had a vasectomy for at least 6 months.

4. It is required that all male subjects use an acceptable method of contraception (as outlined below), starting from the first dose of study medication and continuing for at least 28 days after the last dose of study drug:

   • Abstinence
   • A condom AND one of the following:
   • Vasectomy for more than 6 months. Female partner who meets one of the following conditions: has had a tubal ligation, hysterectomy, or bilateral oophorectomy; or is post menopausal

5. BMI 27-40; stable weight (less than 3% change in past 3 months) Age Range: 30-65

6. No history of diabetes mellitus or impaired glucose tolerance (and impaired fasting glucose)

7. Other conditions may be allowed, if medically stable and controlled within acceptable limits, including: hypertension, dyslipidemia, osteoarthritis, osteoporosis

8. Smokers allowed, but must be able to participate on inpatient stay and not smoke

9. Normal oral glucose tolerance test response (see exclusion criteria)

Exclusion Criteria:

Subjects presenting with any of the following will not be included in the study:

1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic or clinical findings at Screening.
2. Any condition possibly affecting absorption (eg, gastrectomy, malabsorption syndromes, abdominal surgery other than appendectomy, cholecystectomy or hysterectomy).
3. Use of unacceptable medications (see Appendix A)
4. A positive urine drug screen.
5. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
6. Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study medication.
7. 12 lead ECG demonstrating QTc >450 msec at Screening for males, 470 msec for females. If QTc exceeds 450/470 msec, the ECG should be repeated two more times and the average of the three QTc values should be used to determine the subject's eligibility.
8. Supine blood pressure >=140 mm Hg (systolic) or 90 mm Hg (diastolic), on a single measurement. If elevated, confirm by a single repeat, following at least 10 minutes of rest.
9. Screening fasting serum glucose >=100 mg/dL or HbA1c >6.5%, confirmed by a single repeat if deemed necessary.
10. Abnormal oral glucose tolerance test (see below for definition of abnormal).
11. Screening serum alanine transaminase (ALT) or serum aspartate transaminase (AST) greater than 2X the upper limit of the laboratory reference range.
12. Elevated fasting triglycerides at screening (>500 mg/dL), confirmed by a single repeat if deemed necessary.
13. Pregnant or nursing females; inability to use effective contraception.
14. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.
15. Participation in a clinical biomedical research study within prior two months may be excluded, depending on study type and details.
16. History of sensitivity to heparin or heparin-induced thrombocytopenia, if utilized by the site for blood draws.
17. Unwilling or unable to comply with directions and procedures described in this protocol.
18. Subject is the Investigator or a sub-Investigator, research assistant, pharmacist, study coordinator, other staff, or a relative of study personnel directly involved with the conduct of the study.
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.