Olive Oil Before Oral Glucose Delays Gastric Emptying and Lowers Glycemia Through Partially Redundant Glucagon and GLP-1 Signaling in Mice

Consumption of fat before carbohydrate (preload) attenuates postprandial glucose excursions, although the underlying mechanisms remain unclear. We investigated whether an olive oil preload (OG) reduces glycemia by engaging endocrine and neural regulation of gastric emptying. Wild-type C57BL/6J mice received OG or olive oil after (GO) an oral glucose load, with a water preload (WG) as control. Glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and gastric emptying were assessed. Studies were also performed in streptozotocin-induced diabetic mice, NSY diabetic mice, Gcg-deficient and Glp1r-deficient mice, mice receiving glucagon and/or GLP-1 receptor blockade, and mice subjected to bilateral subdiaphragmatic vagus nerve ligation (VNL). Compared with WG and GO, OG reduced the early glucose excursion and slowed gastric emptying, accompanied by increased glucagon, GIP, and GLP-1 secretion. Similar effects were evident in diabetic mice. The response was absent in Gcg-deficient mice but largely preserved in Glp1r-deficient mice and following blockade of either receptor alone. Combined receptor blockade attenuated glucose lowering and eliminated detectable gastric slowing, supporting partially redundant signaling. VNL attenuated these effects, despite preserved or enhanced hormone secretion, supporting a contribution of vagal signaling. These findings identify nutrient timing as an integrated endocrine-neural regulator of postchallenge blood glucose homeostasis. Article Highlights We undertook this study to define how fat consumed before oral glucose attenuates postchallenge glycemia. We asked whether olive oil reduces glycemia by slowing gastric emptying and investigated contributing endocrine and neural pathways. Olive oil increased glucagon, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1; slowed gastric emptying; and reduced early glycemia in mice. Glucagon and glucagon-like peptide-1 signaling acted redundantly, with vagal involvement. Nutrient timing integrates endocrine-neural regulation of gastric emptying and glycemia, supporting evaluation of meal sequencing in humans.