The Role of Phosphodiesterase Inhibitors in Incretin Secretion

Study Overview
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Brief Summary
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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: Roflumilast (Daliresp) 500 mcg pill; and 1 placebo pill Sitaglipitin (Januvia) 100 mg pill; and 1 placebo pill Roflumilast (Daliresp) 500 mcg pill; and Sitagliptin (Januvia) 100 mg pill 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
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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: Roflumilast (Daliresp) 500 mcg + Placebo Sitagliptin (Januvia) 100 mg + Placebo Roflumilast (Daliresp) 500 mcg + Sitagliptin (Januvia) 100 mg 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.

Official Title
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The Role of Phosphodiesterase Inhibitors in Incretin Secretion

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Other: Placebo
* Other: Roflumilast/Sitagliptin
* Other: Sitagliptin
* Other: Roflumilast


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 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. Screening laboratory evaluations with no clinically significant abnormal results (minor deviations from normal lab results will be at the discretion of the principal investigator): fasting comprehensive metabolic panel complete blood count with differential and platelet thyroid function test (TSH) urine drug screen Point of care urine pregnancy test (for women who are not surgically sterile) BMI < 30 (participants with BMI greater than or equal to 30 are excluded because obesity has been associated with attenuation in GLP-1 secretion. Have had a history of stable weight (maintained weight within +/- 5%) over the past year Have NOT participated in another clinical trial involving any pharmacologic agents within the past 30 days Able to complete an inform consent Agree to not participate in other clinical trials within the study period (at the discretion of the study investigator) EXCLUSION CRITERIA: 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) History of anemia, or Hemoglobin < 12.5 mg/dL for men and < 11.5 mg/dL for women during screening visit Weight < 110 pounds (due to blood volume requirement) Evidence of illicit drug use History of substance abuse including marijuana within the past 6 months History of smoking any tobacco products within six months prior to screening Alcohol intake > 30 grams (drink more than 2 beers per day OR equivalent amount of alcohol) History of Human Immunodeficiency Virus (HIV) infection History of active or chronic Hepatitis B and/or C infection History of psychiatric illnesses including major depressive disorder, schizophrenia, bipolar disorder Any lifetime history of suicide attempt History of any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the last year Any suicidal ideation of type 4 or 5 on the C-SSRS during any follow-up visits. Patient Health Questionnaire-9 (PHQ-9) score greater than or equal to 10 during screening visit or any follow-up study visits Generalized Anxiety Disorder-7 (GAD-7) score greater than or equal to 10 during screening visit or any follow-up visits History of pancreatitis History of liver or renal diseases History of gastrointestinal or endocrine disorders 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) History of coronary disease or clinically significant abnormalities on electrocardiogram History of seizures or other neurologic diseases 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 Use of proton pump inhibitors (PPI s), i.e. Prilosec, Prevacid, Achiphex, Protonix, Nexium, Zegarid Women who are pregnant or nursing/breast-feeding a child Any medical history that, in the opinion of the investigator(s), may make participation of the subject in the study unsafe

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>randomized, double-blind, placebo-controlled cross-over study | Other: Placebo<br>* mixed meal<br>|
| Experimental: Roflumilast<br>randomized, double-blind, placebo-controlled cross-over study | Other: Placebo<br>* mixed meal<br>Other: Roflumilast<br>* This is already known to increase GLP-1 &amp; GIP secretion<br>|
| Experimental: Roflumilast/Sitaglip<br>randomized, double-blind, placebo-controlled cross-over study | Other: Placebo<br>* mixed meal<br>Other: Roflumilast/Sitagliptin<br>* Both Roflumilast and Sitagliptin together<br>|
| Experimental: Sitagliptin<br>randomized, double-blind, placebo-controlled cross-over study | Other: Placebo<br>* mixed meal<br>Other: Sitagliptin<br>* This is already known to increase GLP-1 &amp; GIP secretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PDE4 inhibitor roflumilast enhances GLP-1 secretion from L cells. | GIP &amp; GLP-1 response to a mixed meal. | 1-10 hours after ingestion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on glucose metabolism involving plasma glucose, insulin, ghrelin, glucagon, pancreatic polypeptide, C-peptide and fibroblast growth factor (FGF) 19, 21, 23. | The hormones listed are measured by ELISA | 1-10 hours after ingestion | 
| 4.PDE4 inhibitor roflumilast has an effect on glucose metabolism involving plasma glucose, insulin, ghrelin, glucagon, pancreatic polypeptide, C-peptide and fibroblast growth factor (FGF) 19, 21, 23. | The hormones listed are measured by ELISA | 1-10 hours after ingestion | 
| 3.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on elevating circulating active GIP levels. | GIP secretion in response to a mixed meal | 1-10 hours after ingestion | 
| 2.PDE4 inhibitor roflumilast enhances GIP secretion from K cells. | GIP secretion in response to a mixed meal | 1-10 hours after ingestion | 
| 1.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on elevating circulating active GLP-1 levels. | GLP-1 secretion in response to mixed meal | 1-10 hours after ingestion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, Phosphodiesterase Inhibitor, GIP