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

Abstract

The endocannabinoid (eCB) system is involved in a vast array of physiological processes including regulating metabolism through insulin secretion and action. In this physiological study of 21 healthy men, we investigated the acute effects of a nonspecific cannabinoid receptor agonist nabilone (NAB 2 mg) and a specific cannabinoid receptor 1 (CB_1R) antagonist CP-945,598 at two concentrations (low dose CP, LDCP 15 mg and high dose CP, HDCP 45 mg) on insulin secretion, insulin action, and glucose disposal—all compared with 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 wk apart. We used the sequential hyperglycemic, euglycemic-hyperinsulinemic clamp procedure carried out after 10 h 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. In addition, 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 with PL; 2) insulin sensitivity was significantly increased by NAB but decreased by HDCP, both compared with 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. NEW & NOTEWORTHY Under controlled environment of the clamps in healthy, non-obese men, cannabinoid receptor agonist enhanced whereas cannabinoid receptor 1 antagonist diminished insulin sensitivity in a dose-dependent manner. During the clamps, elevated plasma insulin levels had a suppressive effect on circulating non-esterified fatty acids (NEFAs), anandamides (AEAs), and several N-acylethanolamines. Insulin, however, had no impact on circulating 2-arachidonoylglycerol (2-AG) levels. Neither the cannabinoid receptor agonist nor the cannabinoid receptor-1 antagonist had an effect on insulin secretion.