The Role of Endocannabinoids in Insulin Production and Action
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - The endocannabinoid system is involved in different body functions and processes. It helps
      regulate appetite and mood, and sends signals to the nervous system. It may also be involved
      in how the body produces insulin during digestion. Researchers want to test two drugs that
      work on the endocannabinoid system: nabilone and CP-945,598. These drugs may be able to
      affect insulin levels in the blood. This information may suggest possible new treatments for
      people with diabetes.

      Objectives:

      - To study how the endocannabinoid system is involved in insulin production and action.

      Eligibility:

      - Healthy men between 21 and 55 years of age.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will
           provide blood and urine samples. They will also have imaging studies to test their brain
           responses, especially to food-related cues. Some participants will also have a study
           visit to test their insulin resistance levels.

        -  Participants will have four separate study visits 6 weeks apart. They will keep a food
           diary before each visit. At each visit, they will have one of the following combinations
           of drugs:

        -  Double placebo

        -  Placebo and nabilone

        -  Placebo and low dose of CP-945,598

        -  Placebo and high dose of CP-945,598.

        -  Participants will have follow-up visits 1 week after each study visit. Blood samples
           will be taken.
    

Detailed description: 
      Objectives and Specific Aims:

      We plan to investigate whether the endocannabinoid system is involved in the regulation of
      insulin secretion from Beta cells and in the modulation of insulin action in peripheral
      tissues in humans. We hypothesize that cannabinoid receptor 1 (CB1R) antagonist CP-945,598
      will increase insulin secretion from Beta cells and improve insulin sensitivity in peripheral
      tissues while cannabinoid receptor (CBR) agonist nabilone will decrease insulin secretion
      from Beta cells and worsen insulin sensitivity in peripheral tissues. Moreover, we will
      investigate the brain s control over the initial phase of insulin secretion (cephalic insulin
      response) and the effect of central cannabinoid receptors.

      Experimental Design and Methods:

      Twenty healthy men, 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 own control
      and each person will have four different intervention visits spaced at least 6 weeks apart.
      During each visit, they will receive one of the following medications in random order:
      placebo, nabilone 2 mg, CP-945,598 15 mg, or CP-945,598 45 mg. A sequential
      hyperglycemic-euglycemic clamp procedure and a 3-hr oral glucose tolerance test will be used
      to study the effect of CP-945,598 and nabilone on insulin secretion and insulin action in
      healthy men. To identify brain areas involved in cephalic insulin response, a functional MRI
      will be used to assess brain activation in response to food images in association with
      frequent blood sampling.

      Medical Relevance and Expected Outcome:

      Based on our pre-clinical animal data, CB1R antagonist enhances insulin secretion and action
      in response to glucose while CBR agonist virtually shuts off insulin secretion and worsens
      insulin action in response to glucose. 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 insulin secretion from
      Beta cells and insulin sensitivity in humans, and this new understanding is of importance to
      finding new treatments for type 2 diabetes.
    

Intervention name(s): Nabilone; CP-945,598; hyperglycemic clamp; euglycemic-hyperinsulinemic clamp; Nabilone
Intervention type(s): Other; Drug; Other; Other; Other
Intervention description(s): CB agonist; Cannabinoid Receptor 1 antagonist; assesses beta cell response; measures insulin sensitivity; cannabinoid receptor agonist
Intervention MeSH terms: Dronabinol; Nabilone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic
Keywords: Glucose; Insulin Secretion; Insulin Action; Endocannabinoids; Insulin; Metabolism