Acute metabolic effects of cannabinoid receptor modulators during sequential hyperglycemic, euglycemic-hyperinsulinemic clamps in healthy individuals

The endocannabinoid system is involved in a vast array of physiological processes including regulating metabolism through insulin secretion and action. In this physiological study of twenty-one healthy men, we investigated the acute effects of a non-specific cannabinoid receptor agonist nabilone (NAB 2mg) and a specific cannabinoid receptor 1 (CB1R) antagonist CP-945,598 at two concentrations (LDCP 15mg and HDCP 45 mg) on insulin secretion, insulin action, and glucose disposal – all compared to placebo (PL). One of the following compounds – NAB, LDCP, HDCP, or PL – was administered in a randomized and blinded fashion during each of the four visits, where in-between visit was spaced at least 6 weeks apart. We used the sequential hyperglycemic, euglycemic-hyperinsulinemic clamp procedure carried out after >10 hours of fasting to assess glucose-induced insulin secretion and insulin sensitivity, and we measured glucose utilization and production by means of the deuterated glucose disposal test. Additionally, we measured serum levels of endocannabinoids and various N-acylethanolamines over the course of the sequential clamps. Our major findings were as follows: (1) insulin secretion was not impacted by NAB or CP during the hyperglycemic clamp compared to PL; (2) insulin sensitivity was significantly increased by NAB but decreased by HDCP, both compared to PL, during the euglycemic-hyperinsulinemic clamp; (3) under the conditions of the experiments outlined, non-esterified fatty acids, and many circulating N-acylethanolamines levels, including the endocannabinoid anandamide (AEA), were reduced in a saturable insulin-dependent manner during the clamps.