The Role of Endocannabinoids in Insulin Production and Action

Sponsor

National Institute on Aging (NIA) (NIH)

Overall Status

Completed

CT.gov ID

NCT01517100

Collaborator

(none)

Enrollment

Location

Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Nabllone Drug: CP-945,598 Procedure: Hypoglycemic Clamp Drug: Euglycemic-Hyperinsulinemic Clamp	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Diagnostic

Official Title:

The Roles of Endocannabinoids in Insulin Secretion and Action

Study Start Date :

Jan 5, 2012

Actual Primary Completion Date :

Oct 6, 2014

Actual Study Completion Date :

Oct 6, 2014

Outcome Measures

Primary Outcome Measures

Changes in insulin sensitivity. [CB1R antagonist CP-945,598 will enhance while CR receptor agonist nabilone will suppress first phase insulin response fromB cells in humans]
This study will give us a better understanding of the regulators of insulin secretion from B cells and insulin sensitivity in humans and this new understanding is of importance to finding new treatments for type 2 diabetes

Secondary Outcome Measures

Changes in insulin and other hormones and the brain response to pictures of food items as evidenced by a functional MRI of the brain. [90 minutes]
Changes in insulin and other hormones and the brain response to pictures of food items as evidenced by a functional MRI of the brain.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 55 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

Healthy men only

(We want to study men because the magnitude of acute insulin response for men and women is different. In addition, as women may become pregnant in the course of the study, and since this is a physiology study only, and not one related to treatments, we want to remove any confounders and lessen any chance of drop-out.)

Age 21-55 (Age restriction is used to remove age as a confounding factor because Beta cells function tends to deteriorate and first phase secretion becomes less defined with age.
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, free T4)
urinalysis
urine drug screen
BMI less than 30 (Men with BMI greater than or equal to 30 are excluded because obesity has been associated with altered beta cell function.
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:

Women
FPG greater than or equal to 100 mg/dl or 2-hr OGTT greater than or equal to 140 mg/dL
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 greater than 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 malignancy
History of coronary disease
History of seizures or other neurologic diseases
History of psychiatric illnesses including major depressive disorder, schizophrenia, bipolar disorder
Any lifetime history of suicide attempt
History of suicidal behavior in the last year
Any suicidal behavior during any follow-up visits
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 liver or renal diseases
History of gastrointestinal or endocrine disorders
History of glucocorticoid use (over one month) or other immunosuppressive agents (any)
Any condition or non-removable device contraindicated for MRI (pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments, or history of working as a welders or metal worker)
Any medical history that, in the opinion of the investigator(s), will make participation of the subject in the study unsafe