-The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) ϩ type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K ϩ (KATP) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3Ϫ/Ϫ mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3 ϩ/ϩ , but not T1R3 Ϫ/Ϫ , ileum explants; this secretion was not mimicked by the K ATP channel blocker glibenclamide. T1R2 Ϫ/Ϫ mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was K ATP channeldependent and glucose-specific emerged in the large intestine of T1R3 Ϫ/Ϫ mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.glucagon-like peptide-1; insulin; T1R3; glucose-stimulated potassium ion channel; enteroendocrine l cells THE BODY TIGHTLY REGULATES blood glucose levels, and disruption of the homeostatic mechanisms that underlie normal glycemic control can have significant deleterious effects. For example, the prolonged hyperglycemia associated with type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease, neuropathy, retinopathy, kidney disease, and death (66). Hormonal signals arising in the gastrointestinal tract are key components of the homeostatic mechanisms controlling blood glucose levels after a meal. Ingestion of carbohydrate and other nutrients promotes the secretion of insulinotropic hormones such as glucagon-like peptide-1 (GLP-1) from the gut, resulting in a surge of insulin production before blood glucose levels rise (11,32). This early response contributes to increased glucose disposal during absorption and helps to prevent hyperglycemia. GLP-1 mimetics and inhibitors of GLP-1 degradation help increase insulin biosynthesis and secretion from pancreatic ␤-cells and are valuable additions to previous treatment regimens for T2DM patients (11,32).Despite the importance of intestinal glucose sensing and glucose-stimulated gut hormone secretion, the mechanisms underlying these processes have remained elusive. The distinct glucose-sensing mechanisms found in the pancreas and in the gustat...

This study showed that specific intact, or partially digested proteins, in contrast to protein-hydrolysates and synthetic-peptides, stimulated hormone release. We conclude that intact proteins exert strong effects on satiety hormone release, and may therefore provide potent dietary supplements for prevention or treatment of obesity.

The peripheral sensory organ of the gustatory system, the taste bud, contains a heterogeneous collection of sensory cells. These taste cells can differ in the stimuli to which they respond and the receptors and other signaling molecules they employ to transduce and encode gustatory stimuli. This molecular diversity extends to the expression of a varied repertoire of bioactive peptides that appear to play important functional roles in signaling taste information between the taste cells and afferent sensory nerves and/or in processing sensory signals within the taste bud itself. Here, we review studies that examine the expression of bioactive peptides in the taste bud and the impact of those peptides on taste functions. Many of these peptides produced in taste buds are known to affect appetite, satiety or metabolism through their actions in the brain, pancreas and other organs, suggesting a functional link between the gustatory system and the neural and endocrine systems that regulate feeding and nutrient utilization.

Hypoxia impairs skeletal muscle function, but the precise mechanisms are incompletely understood. In hypoxic rat diaphragm muscle, generation of peroxynitrite is elevated. Peroxynitrite and other reactive nitrogen species have been shown to impair contractility of skinned muscle fibers, reflecting contractile protein dysfunction. We hypothesized that hypoxia induces contractile protein dysfunction and that reactive nitrogen species are involved. In addition, we hypothesized that muscle reoxygenation reverses contractile protein dysfunction. In vitro contractility of rat soleus muscle bundles was studied after 30 min of hyperoxia (Po2 approximately 90 kPa), hypoxia (Po2 approximately 5 kPa), hypoxia + 30 microM N(G)-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor), hyperoxia + 30 microM L-NMMA, and hypoxia (30 min) + reoxygenation (15 min). One part of the muscle bundle was used for single fiber contractile measurements and the other part for nitrotyrosine detection. In skinned single fibers, maximal Ca2+-activated specific force (Fmax), fraction of strongly attached cross bridges (alphafs), rate constant of force redevelopment (ktr), and myofibrillar Ca2+ sensitivity were determined. Thirty minutes of hypoxia reduced muscle bundle contractility. In the hypoxic group, single fiber Fmax, alphafs, and ktr were significantly reduced compared with hyperoxic, L-NMMA, and reoxygenation groups. Myofibrillar Ca2+ sensitivity was not different between groups. Nitrotyrosine levels were increased in hypoxia compared with all other groups. We concluded that acute hypoxia induces dysfunction of skinned muscle fibers, reflecting contractile protein dysfunction. In addition, our data indicate that reactive nitrogen species play a role in hypoxia-induced contractile protein dysfunction. Reoxygenation of the muscle bundle partially restores bundle contractility but completely reverses contractile protein dysfunction.

The site of intestinal fat delivery affects satiety and may affect food intake in humans. Animal data suggest that the length of the small intestine exposed to fat is also relevant. The aim of the present study was to investigate whether increasing the areas of intestinal fat exposure and the way it is exposed would affect satiety parameters and food intake. In the present single-blind, randomised, crossover study, fifteen volunteers, each intubated with a naso-ileal tube, received four treatments on consecutive days. The oral control (control treatment) was a liquid meal (LM) containing 6 g fat ingested at t ¼ 0 min, with saline infusion at t ¼ 30-120 min. Experimental treatments were a fat-free LM at t ¼ 0 min, with either 6 g oil delivered sequentially (2 g duodenal, t ¼ 30 -60 min; 2 g jejunal, t ¼ 60-90 min; 2 g ileal, t ¼ 90 -120 min), simultaneously (2 g each to all sites, t ¼ 30-120 min) or ileal only (6 g ileal, t ¼ 30-120 min). Satiety parameters (hunger and fullness) and cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY) secretion were measured until t ¼ 180 min, when ad libitum food intake was assessed. Only the ileum treatment reduced food intake significantly over the control treatment. The ileum and simultaneous treatments significantly reduced hunger compared with the control treatment. Compared with control, no differences were observed for PYY, CCK and GLP-1 with regard to 180 min integrated secretion. Ileal fat infusion had the most pronounced effect on food intake and satiety. Increasing the areas of intestinal fat exposure only affected hunger when fat was delivered simultaneously, not sequentially, to the exposed areas. These results demonstrate that ileal brake activation offers an interesting target for the regulation of ingestive behaviour.