The Role of Phosphodiesterase Inhibitors in Incretin Secretion

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.

• 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