Yuya Takahashi

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.

Isthmin‐1 is an adipokine that has a potent glucose‐lowering effect by stimulating a common intracellular signaling pathway with insulin through a distinct receptor and has an inhibitory effect on lipogenesis in the liver, whereas insulin has the opposite effect. Isthmin‐1 is expected to have clinical benefits in the treatment of diabetes.

Triterpenes (C30) constitute one of the diverse class of natural products with potential applications in food, cosmetic and pharmaceutical industries. Soyasaponins are oleanane-type triterpenoids widespread among legumes and particularly abundant in soybean seeds. They have associated with various pharmacological implications and undesirable taste properties of soybean-based food products. Uncovering the biosynthetic genes of soyasaponins will provide new opportunities to control the pathway for human benefits. However, the pathway of soyasaponin biosynthesis has not been fully elucidated in part because of a paucity of natural mutants. Here, we applied a structured high-density soybean mutant library for the forward genetic screening of triterpenoid biosynthesis. The seed soyasaponin polymorphism in the mutant library was evaluated using a high-throughput thin-layer chromatography and liquid chromatography tandem mass spectrometry analysis. This screening identified 35 mutants (3.85% of 909 mutant lines) with seven unusual soyasaponin phenotypes (Categories 1-7), which was greater than the number of natural mutants reported previously (22 mutants, 0.18% of ∼12,428 accessions). Nine unique intermediates of soyasaponin biosynthesis were identified and their chemical structures were estimated based on their MS/MS fragment patterns. Based on published information, 19 mutants could be associated with loss of function of four individual soyasaponin biosynthesis genes identified through expressed sequence tag mining or positional cloning, whereas the remaining 16 mutants were novel and may facilitate discovery of the unknown biosynthetic genes of soyasaponins. Our approach and library may help to identify new phenotype materials and causative genes associated with specialized metabolite production and other traits.