Effect of Dietary Oils as G-protein-coupled Receptor Agonists on Glucose Tolerance

Agonistic activation of fat metabolite responsive G-protein-coupled receptors (GPCR) has been linked to improved glucose metabolism through increased glucose-stimulated-insulin-secreting (GSIS) and incretin release, improved insulin sensitivity and reduced low grade inflammation. In vitro studies have demonstrated that pinolenic acid (20% of pine nut oil) is a potent dual agonist of two GPCRs: free fatty acid receptor-1 (FFA1, formerly GPR40) and free fatty acid receptor-4 (FFA4, formerly GPR120). Moreover, pinolenic acid was able to improve glucose tolerance in mice. G-protein-coupled receptor-119 (GPR119) is known to be activated by the monoacylglycerol: 2-oleoylglycerol (2OG), which is a glycerol molecule attached to oleic acid in the second position. Olive oil contains 61-80% oleic acid, and under digestion 2OG is produced. 2OG has been shown to stimulate GLP-1 release in humans and interestingly, it has recently been suggest that simultaneous activation of GPR119 and FFA1 acts in synergy and enhances enteroendocrine GLP-1 secretion more than the summarized individual agonistic activation. However, this remains to be evaluated in humans. The investigators hypothesize that a combination of pinolenic acid and 2OG administered in delayed release capsules will act in synergy and enhance 1) GLP-1 secretion by stimulating FFA1/FFA4 and GPR119 on enteroendocrine cells causing improved GSIS and increased satiety and 2) enhance GSIS by directly stimulating FFA1 and GPR119 on beta-cells. Study aim: To investigate the acute effects of pinolenic acid combined with 2OG (olive oil) versus pinolenic acid alone on changes in glucose tolerance, insulin, GLP-1, GIP and ghrelin secretion, appetite and gastrointestinal tolerability in overweight and obese healthy humans.