The Role of Phosphodiesterase Inhibitors in Incretin Secretion
The Role of Phosphodiesterase Inhibitors in Incretin Secretion
Background:

 The drug Roflumilast (Daliresp) is used to treat Chronic Obstructive Pulmonary Disease
 (COPD). COPD is a lung disease that makes it difficult to breathe. Studies have shown that
 this drug decreased the blood sugar of people with type 2 diabetes. Sitagliptin (Januvia) is
 a medication presently used to treat diabetes. Researchers think that both of these drugs may
 decrease blood sugar by causing an increase in the hormone GLP-1.This hormone is secreted in
 the small intestines and stomach and is also known as an incretin. Researchers want to study
 how these drugs affect blood sugar, insulin, and other hormones in the blood.

 Objectives:

 -  To study the effects of Roflumilast (Daliresp) and Sitagliptin (Januvia) on blood sugar
 and insulin.

 -  To better understand GLP-1 and other gut hormones. This may lead to new treatments for
 type 2 diabetes.

 Eligibility:

 -  Healthy volunteers age 21 55.

 -  Body Mass Index (BMI) less than 30

 Design:

 -This study will require one screening visit and four study visits, scheduled about 3-weeks
 apart.

 Screening visit requires participants to arrive after fasting for 10 hours and have the
 following:

 -  Medical history, physical exam, height, weight, blood pressure measurements and blood
 and urine tests.

 -  A 2-hour oral glucose tolerance test (OGTT). Participants will drink an orange-flavored
 drink containing 75 grams of sugar (300 calories). A blood sample will be taken prior to
 drinking the beverage and 2-hours later.

 -  An electrocardiogram (EKG) to measure the electrical activity of the heart.

 -  Questionnaires about risk for depression or suicide.

 Study visits 1to 4:

 -  Participants will arrive the evening prior and blood work will be done to confirm
 eligibility. They will not eat or drink anything except water starting at 8:00 p.m.

 -  About 6:30 a.m. the following day, an I.V. (small plastic tube) will be placed in an arm
 vein and used to take 20 blood samples over a period of about 11 hours.

 -  Participants will receive one of the following study medication/placebo groupings in
 random order:

 1. Roflumilast (Daliresp) 500 mcg pill; and 1 placebo pill

 2. Sitaglipitin (Januvia) 100 mg pill; and 1 placebo pill

 3. Roflumilast (Daliresp) 500 mcg pill; and Sitagliptin (Januvia) 100 mg pill

 4. 2 placebo pills

 -  One hour later, they will have a 10-hour mixed meal test (MMT). They will be asked to
 drink a nutritional shake (Ensure Plus). Blood samples will be taken over the next 10
 hours to measure blood sugar, insulin and other hormones. At the end of the test, they
 will be given a meal.

 -  Participants will answer questions about side effects and symptoms. They will receive a
 follow-up phone call within 10 days.
Objectives and Specific Aims:

 We plan to investigate whether phosphodiesterases are involved in the regulation of
 glucagon-like peptide-1 (GLP-1) secretion from L cells in humans. We hypothesize that: (1)
 phosphodiesterase-4D (PDE4D) inhibitor (roflumilast) enhance GLP-1 secretion from L cells;
 (2) PDE4D inhibitor (roflumilast) and DPP4 inhibitor (sitagliptin) have synergistic effect on
 increasing the amount of circulating active GLP-1.

 Experimental Design and Methods:

 Twenty healthy adults, age 21-55, will be recruited for this study. This is a randomized,
 double-blind, placebo-controlled cross-over study. Each subject will serve as his/her own
 control and each person will have four different study visits spaced about 3 weeks apart.
 During each visit, they will receive one of the following medications (oral route) in random
 order:

 1. Roflumilast (Daliresp) 500 mcg + Placebo

 2. Sitagliptin (Januvia) 100 mg + Placebo

 3. Roflumilast (Daliresp) 500 mcg + Sitagliptin (Januvia) 100 mg

 4. Placebo

 A 10-hr mixed-meal test will be administered 1 hour after the medications and frequent
 blood-samplings will be done over 10 hours.

 Medical Relevance and Expected Outcome:

 Preliminary clinical data have shown that phosphodiesterase inhibitors improved glycemic
 control in type 2 diabetes, and pre-clinical animal data have shown that phosphodiesterase
 inhibitors enhanced GLP-1 secretion from L cells. The application of novel, pre-clinical
 findings to an understanding of human biology and pathobiology is of fundamental and critical
 importance. This study will give us a better understanding of the regulators of GLP-1
 secretion in humans, and this new understanding may lead to new treatments for type 2
 diabetes.
-  INCLUSION CRITERIA:

 1. Age 21-55 (Age restriction is used to remove age as a confounding factor because
 (beta) cells function and insulin resistance tend to deteriorate with age and may
 affect GLP-1 and GIP levels.

 2. Screening laboratory evaluations with no clinically significant abnormal results
 (minor deviations from normal lab results will be at the discretion of the
 principal investigator):

 1. fasting comprehensive metabolic panel

 2. complete blood count with differential and platelet

 3. thyroid function test (TSH)

 4. urine drug screen

 5. Point of care urine pregnancy test (for women who are not surgically
 sterile)

 3. BMI < 30 (participants with BMI greater than or equal to 30 are excluded because
 obesity has been associated with attenuation in GLP-1 secretion.

 4. Have had a history of stable weight (maintained weight within +/- 5%) over the
 past year

 5. Have NOT participated in another clinical trial involving any pharmacologic
 agents within the past 30 days

 6. Able to complete an inform consent

 7. Agree to not participate in other clinical trials within the study period (at the
 discretion of the study investigator)

 EXCLUSION CRITERIA:

 1. FPG greater than or equal to 100 mg/dl or 2-hr OGTT greater than or equal to 140 mg/dL
 (evidence of glucose intolerance or diabetes)

 2. History of anemia, or Hemoglobin < 12.5 mg/dL for men and < 11.5 mg/dL for women
 during screening visit

 3. Weight < 110 pounds (due to blood volume requirement)

 4. Evidence of illicit drug use

 5. History of substance abuse including marijuana within the past 6 months

 6. History of smoking any tobacco products within six months prior to screening

 7. Alcohol intake > 30 grams (drink more than 2 beers per day OR equivalent amount of
 alcohol)

 8. History of Human Immunodeficiency Virus (HIV) infection

 9. History of active or chronic Hepatitis B and/or C infection

 10. History of psychiatric illnesses including major depressive disorder, schizophrenia,
 bipolar disorder

 11. Any lifetime history of suicide attempt

 12. History of any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity
 Rating Scale (C-SSRS) in the last year

 13. Any suicidal ideation of type 4 or 5 on the C-SSRS during any follow-up visits.

 14. Patient Health Questionnaire-9 (PHQ-9) score greater than or equal to 10 during
 screening visit or any follow-up study visits

 15. Generalized Anxiety Disorder-7 (GAD-7) score greater than or equal to 10 during
 screening visit or any follow-up visits

 16. History of pancreatitis

 17. History of liver or renal diseases

 18. History of gastrointestinal or endocrine disorders

 19. History of malignancy (unless P.I. determines that there is no impact of the prior
 malignancy on study outcomes, i.e. basal cell skin cancer)

 20. History of coronary disease or clinically significant abnormalities on
 electrocardiogram

 21. History of seizures or other neurologic diseases

 22. History of glucocorticoid use (over one month) or other immunosuppressive agents
 (any), i.e. Imuran, Neoral, Sandimmune, SangCya, basiliximab (Simulect), daclizumab
 (Zenapax), muromonab (Orthocolone OKT(3)) prednisone (Deltasone, Orasone) within the
 past six months

 23. Use of proton pump inhibitors (PPI s), i.e. Prilosec, Prevacid, Achiphex, Protonix,
 Nexium, Zegarid

 24. Women who are pregnant or nursing/breast-feeding a child

 25. Any medical history that, in the opinion of the investigator(s), may make
 participation of the subject in the study unsafe