The Role of Endocannabinoids in Insulin Production and Action

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.