Incretin secretion in humans is under the influence of cannabinoid receptors

• Published in: American journal of physiology: endocrinology and metabolism Vol. 313; no. 3; pp. E359 - E366
• Main Authors: Chia, Chee W, Carlson, Olga D, Liu, David D, González-Mariscal, Isabel, Santa-Cruz Calvo, Sara, Egan, Josephine M
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.09.2017
• Series: Endocannabinoids and Cannabinoid Receptors as Regulators of Endocrine Functions and Tissue Metabolism
• Subjects: Adult; Blood Glucose - metabolism; Cannabinoid Receptor Agonists - pharmacology; Cannabinoid receptors; Case-Control Studies; Cells; Clinical trials; Correlation analysis; Cross-Over Studies; Double-Blind Method; Dronabinol - analogs & derivatives; Dronabinol - pharmacology; Fasting; Female; Gastric Inhibitory Polypeptide - blood; Gastric Inhibitory Polypeptide - drug effects; Gastric Inhibitory Polypeptide - metabolism; GIP protein; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - drug effects; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose tolerance; Glucose Tolerance Test; Hormones; Humans; Incretins - blood; Incretins - metabolism; Laboratory testing; Longitudinal Studies; Male; Middle Aged; Neurotransmitters; Obesity; Obesity - metabolism; Peptides; Prospective Studies; Receptors; Receptors, Cannabinoid - drug effects; Receptors, Cannabinoid - metabolism; Rodents; Secretion; Young Adult; incretins; endocannabinoids; GLP-1; obesity; GIP
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00080.2017

The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids.