The Role of Phosphodiesterase Inhibitors in Incretin Secretion
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Placebo; Roflumilast/Sitagliptin; Sitagliptin; Roflumilast
Intervention type(s): Other; Other; Other; Other
Intervention description(s): mixed meal; Both Roflumilast and Sitagliptin together; This is already known to increase GLP-1 &amp; GIP secretion.; This is already known to increase GLP-1 &amp; GIP secretion
Intervention MeSH terms: Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: GLP-1; Phosphodiesterase Inhibitor; GIP