Ignite Creation Date:
2024-05-06 @ 12:29 PM
Last Modification Date:
2024-10-26 @ 12:59 PM
Study NCT ID:
NCT03774095
Status:
UNKNOWN
Last Update Posted:
2018-12-14
First Post:
2018-12-11
Brief Title:
Effect of Dietary Oils as G-protein-coupled Receptor Agonists on Glucose Tolerance
Sponsor:
Karina Vejrum Sørensen
Organization:
Odense University Hospital
Study Overview
Official Title:
Effects of Pine Nut and Olive Oil as FFA1FFA4 and GPR119 Agonists on Glucose Tolerance in Healthy Overweight or Obese Subjects
Status:
UNKNOWN
Status Verified Date:
2018-12
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 FFA1FFA4 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
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
Detailed Description:
During the last decade several G protein-coupled receptors GPCR that respond to dietary lipid metabolites including free fatty acids FFAs have been discovered These receptors have been implicated in metabolic processes and inflammation Consequently several of the receptors have attracted interest as potential targets for the treatment of metabolic and inflammatory diseases including obesity and type 2 diabetes T2D
Free fatty acid receptor 1 FFA1 or GPR40 is activated by long-chain FFAs and is highly expressed in pancreatic β-cells where it increases glucose-stimulated insulin secretion GSIS FFA1 is also expressed on intestinal enteroendocrine cells where it promotes secretion of incretin hormones such as glucagon like peptide-1 GLP-1 and glucose-dependent insulinotropic peptide GIP GLP-1 is highly interesting for treatment of obesity and T2D because of its ability to increase GSIS enhance β-cell growth increase insulin sensitivity reduce gastric motility increase satiety and reduce body weight The published phase II clinical trial with the selective FFA1 agonist TAK-875 demonstrated high efficacy in reducing plasma glucose without increased incidence of hypoglycemia and has caused considerable interest in the receptor as a new target for treatment of type 2 diabetes Free fatty acid receptor 4 FFA4 or GPR120 is activated by unsaturated long-chain FFAs and is expressed in the gastrointestinal system and adipose tissue It is reported to promote GLP-1 secretion from intestinal cells to counteract inflammation and to increase insulin sensitivity in adipose tissue Notably dysfunctional FFA4 was recently connected to the development of obesity in both mice and humans This has considerably increased the interest on the receptor as a target for obesity and metabolic diseases
Another GPCR receptor G-protein-coupled receptor-119 GPR119 which reacts to different degradation products of triacylglycerol including monoacylglycerols has similar functions as FFA1 and FFA4 It is also expressed in enteroendocrine cells in the gastrointestinal tract and on pancreatic β-cells where it stimulates GLP-1 secretion and GSIS respectively
In summary these receptors are expressed in different tissues in the body where they potentially can affect metabolic and inflammatory conditions such as type 2 diabetes and obesity
Prior to this study an in in vitro screening of 36 relevant FFAs and their ability to act as FFA1 and FFA4 agonists was carried out to identify the most potent naturally occurring dual FFA1FFA4 agonist for clinical studies Of these the polyunsaturated fatty acid pinolenic acid showed the highest efficacy and a good potency on both receptors and was therefore selected for further studies
To further support this choice the effect of pinolenic acid was tested using a small dose 100 mgkg given 30 min prior to an oral glucose tolerance test OGTT in mice Convincingly purified pinolenic acid significantly improved glucose tolerance by reducing OGTT glucose levels when compared to control corn oil The efficacy was similar to that obtained with a pharmaceutical selective FFA1 agonist TUG-905 Pinolenic acid is a fatty acid contained in Siberian Pine nuts Korean Pine nuts and the seeds of other pines The highest percentage of pinolenic acid 20 is found in Siberian Pine nuts and the oil produced from them Korean Pine nut oil given as hydrolyzed FFAs but not as triglycerides has been reported to increase secretion of GLP-1 and decrease appetite in overweight females This supports the indication that purified pinolenic acid may be superior in improving glucose metabolism
GPR119 is activated by different endogen ligands one of them being 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 of 5 ml olive oil approximately 2g 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
Roux-en-Y gastric bypass RYGB surgery used to treat severe obesity frequently results in immediate beneficial effects on glucose metabolism in type 2 diabetes often with complete remission These effects are in part independent of weight loss but may be explained by a significant increase in GLP-1 levels immediately after surgery Thus it appears that the effect depends on the delivery of nutrients to the lower parts of the intestine Fat metabolites are normally rapidly absorbed in the upper parts of the gastrointestinal tract It is therefore possible that the RYGB effects are partly due to enteroendocrine stimulation of FFA1 GPR119 and perhaps FFA4 by direct nutrient delivery that is delivery of fat metabolites to the lower intestines A hypothesis to be investigated in this study is that the delivery of pinolenic acid and 2OG to the lower intestines can mimic the beneficial effects observed after RYGB with less expense and fewer adverse effects
Delivery of nutrients beyond the proximal small intestine can be achieved by the use of delayed release capsules The potential positive effect of this principle was recently reported in a small cohort of patients with T2D Where delivery of small amounts of lauric acid a C12 fatty acid to the distal gut using enteric-coated pellets stimulated GLP-1 secretion and lowered postprandial glucose levels in response to meals No chronic effects where tested in this study Although not suggested by the authors the increased release of GLP-1 could involve direct stimulation of FFA1 andor FFA4 by lauric acid in the distal gut
Hypotheses As described the expression of FFA1 FFA4 and GPR119 on intestinal enteroendocrine cells and pancreatic beta-cells has been linked to 1 increased secretion of GLP-1 and GIP hence the incretin-mediated increase in GSIS and 2 a direct positive effect on GSIS The investigators hypothesize that a combination of pinolenic acid and 2OG administered in delayed release capsules will act in synergy and 1 enhance GLP-1 secretion by stimulating FFA1FFA4 and GPR119 on enteroendocrine cells causing improved GSIS 2 enhance GSIS by directly stimulating FFA1 and GPR119 on beta-cells and 3 increase satiety
To test the hypotheses the aim of this project is to investigate the acute effect of pinolenic acid hydrolyzed pine nut oil combined with 2OG olive oil versus pinolenic acid hydrolyzed pine nut oil alone on glucose tolerance insulin GLP-1 GIP and ghrelin secretion appetite and gastrointestinal tolerability in overweight and obese healthy humans
Free fatty acid receptor 1 FFA1 or GPR40 is activated by long-chain FFAs and is highly expressed in pancreatic β-cells where it increases glucose-stimulated insulin secretion GSIS FFA1 is also expressed on intestinal enteroendocrine cells where it promotes secretion of incretin hormones such as glucagon like peptide-1 GLP-1 and glucose-dependent insulinotropic peptide GIP GLP-1 is highly interesting for treatment of obesity and T2D because of its ability to increase GSIS enhance β-cell growth increase insulin sensitivity reduce gastric motility increase satiety and reduce body weight The published phase II clinical trial with the selective FFA1 agonist TAK-875 demonstrated high efficacy in reducing plasma glucose without increased incidence of hypoglycemia and has caused considerable interest in the receptor as a new target for treatment of type 2 diabetes Free fatty acid receptor 4 FFA4 or GPR120 is activated by unsaturated long-chain FFAs and is expressed in the gastrointestinal system and adipose tissue It is reported to promote GLP-1 secretion from intestinal cells to counteract inflammation and to increase insulin sensitivity in adipose tissue Notably dysfunctional FFA4 was recently connected to the development of obesity in both mice and humans This has considerably increased the interest on the receptor as a target for obesity and metabolic diseases
Another GPCR receptor G-protein-coupled receptor-119 GPR119 which reacts to different degradation products of triacylglycerol including monoacylglycerols has similar functions as FFA1 and FFA4 It is also expressed in enteroendocrine cells in the gastrointestinal tract and on pancreatic β-cells where it stimulates GLP-1 secretion and GSIS respectively
In summary these receptors are expressed in different tissues in the body where they potentially can affect metabolic and inflammatory conditions such as type 2 diabetes and obesity
Prior to this study an in in vitro screening of 36 relevant FFAs and their ability to act as FFA1 and FFA4 agonists was carried out to identify the most potent naturally occurring dual FFA1FFA4 agonist for clinical studies Of these the polyunsaturated fatty acid pinolenic acid showed the highest efficacy and a good potency on both receptors and was therefore selected for further studies
To further support this choice the effect of pinolenic acid was tested using a small dose 100 mgkg given 30 min prior to an oral glucose tolerance test OGTT in mice Convincingly purified pinolenic acid significantly improved glucose tolerance by reducing OGTT glucose levels when compared to control corn oil The efficacy was similar to that obtained with a pharmaceutical selective FFA1 agonist TUG-905 Pinolenic acid is a fatty acid contained in Siberian Pine nuts Korean Pine nuts and the seeds of other pines The highest percentage of pinolenic acid 20 is found in Siberian Pine nuts and the oil produced from them Korean Pine nut oil given as hydrolyzed FFAs but not as triglycerides has been reported to increase secretion of GLP-1 and decrease appetite in overweight females This supports the indication that purified pinolenic acid may be superior in improving glucose metabolism
GPR119 is activated by different endogen ligands one of them being 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 of 5 ml olive oil approximately 2g 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
Roux-en-Y gastric bypass RYGB surgery used to treat severe obesity frequently results in immediate beneficial effects on glucose metabolism in type 2 diabetes often with complete remission These effects are in part independent of weight loss but may be explained by a significant increase in GLP-1 levels immediately after surgery Thus it appears that the effect depends on the delivery of nutrients to the lower parts of the intestine Fat metabolites are normally rapidly absorbed in the upper parts of the gastrointestinal tract It is therefore possible that the RYGB effects are partly due to enteroendocrine stimulation of FFA1 GPR119 and perhaps FFA4 by direct nutrient delivery that is delivery of fat metabolites to the lower intestines A hypothesis to be investigated in this study is that the delivery of pinolenic acid and 2OG to the lower intestines can mimic the beneficial effects observed after RYGB with less expense and fewer adverse effects
Delivery of nutrients beyond the proximal small intestine can be achieved by the use of delayed release capsules The potential positive effect of this principle was recently reported in a small cohort of patients with T2D Where delivery of small amounts of lauric acid a C12 fatty acid to the distal gut using enteric-coated pellets stimulated GLP-1 secretion and lowered postprandial glucose levels in response to meals No chronic effects where tested in this study Although not suggested by the authors the increased release of GLP-1 could involve direct stimulation of FFA1 andor FFA4 by lauric acid in the distal gut
Hypotheses As described the expression of FFA1 FFA4 and GPR119 on intestinal enteroendocrine cells and pancreatic beta-cells has been linked to 1 increased secretion of GLP-1 and GIP hence the incretin-mediated increase in GSIS and 2 a direct positive effect on GSIS The investigators hypothesize that a combination of pinolenic acid and 2OG administered in delayed release capsules will act in synergy and 1 enhance GLP-1 secretion by stimulating FFA1FFA4 and GPR119 on enteroendocrine cells causing improved GSIS 2 enhance GSIS by directly stimulating FFA1 and GPR119 on beta-cells and 3 increase satiety
To test the hypotheses the aim of this project is to investigate the acute effect of pinolenic acid hydrolyzed pine nut oil combined with 2OG olive oil versus pinolenic acid hydrolyzed pine nut oil alone on glucose tolerance insulin GLP-1 GIP and ghrelin secretion appetite and gastrointestinal tolerability in overweight and obese healthy humans
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None