Study design: Twenty healthy men, age 21-50, will be recruited for this study. This is a randomized, double-blinded, 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 (cannabinoid receptor CBR agonist), cannabinoid receptor 1 (CB1R) antagonist low dose, or CB1R antagonist high dose. A sequential hyperglycemic-euglycemic clamp procedure and a 3-hr oral glucose tolerance test will be used to study the effect of CB1R antagonist and nabilone on insulin secretion and insulin action in healthy men. A functional MRI will be used to assess brain activation in response to visual stimuli consisted of food images and in relation to insulin secretion. 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. We have identified a CB1R antagonist that can be administered to humans and have obtained FDA approval for the use of the drug. This protocol is currently awaiting IRB approval.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Chia, Chee W; Carlson, Olga D; Liu, David D et al. (2017) Incretin Secretion in Humans is under the Influence of Cannabinoid Receptors. Am J Physiol Endocrinol Metab :ajpendo.00080.2017
González-Mariscal, Isabel; Krzysik-Walker, Susan M; Kim, Wook et al. (2016) Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Mol Cell Endocrinol 423:1-10
Kim, Jihye; Lee, Kyung Jin; Kim, Jung Seok et al. (2016) Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic ? Cells. PLoS One 11:e0150981