Effects of Pine Nut and Olive Oil as FFA1/FFA4 and GPR119 Agonists on Glucose Tolerance in Healthy Overweight or Obese Subjects
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- Glucose
研究概览
简要总结
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.
详细描述
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 FFA1/FFA4 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 40 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •body mass index (BMI) of 27.5-40 kg/m2, normal glucose tolerance (two hours OGTT plasma glucose ≤ 7.8 mmol/l), normal blood pressure and normal screening blood samples (kidney and liver function, lipids and hematology) and written informed consent -
排除标准
- •any chronic disease including past gastrointestinal diseases or gastrointestinal surgery, first degree relatives with diabetes, food allergies of relevance, need for prescriptive medicine, smoking, body weight changes (> 3 kg within three month prior), intake of dietary supplements (<1 month prior) or any type of restrictive diet for example calorie restriction, vegan diet etc.
研究组 & 干预措施
No oil
6-hour oral glucose tolerance test
Hydrolyzed pine nut oil
6g hydrolyzed pine nut oil in delayed release capsules given 30 min prior to an 6-hour oral glucose tolerance test
干预措施: Hydrolyzed pine nut oil (Dietary Supplement)
Hydrolyzed pine nut oil and olive oil
3g hydrolyzed pine nut oil and 3g olive oil in delayed release capsules given 30 min prior to an 6-hour oral glucose tolerance test
干预措施: Hydrolyzed pine nut oil and olive oil (Dietary Supplement)
结局指标
主要结局
Glucose
时间窗: 6 hours
Glucose area under the curve
C-peptide
时间窗: 6 hours
C-peptide area under the curve
Appetite
时间窗: 6 hours
Appetite is measured by the use of Visual analog scales. Respondents specify their level of agreement to a statement on hunger, satiety, fullness, prospective food consumption and thirst by indicating a position along a continuous 100 mm line between two end-points (0 and 100 mm) which represent the extreme feelings related to the statement. In example: How hungry do you feel? 0mm represents: Not hungry at all and 100 mm represents: I have never been hungrier.
Insulin
时间窗: 6 hours
Insulin area under the curve
GLP-1
时间窗: 6 hours
GLP-1 area under the curve
Ghrelin
时间窗: 6 hours
Ghrelin area under the curve
Gastrointestinal tolerability
时间窗: 24 hours
Gastrointestinal tolerability is measured by the use of Visual analog scales. Respondents specify their level of nausea, flatulence, abdominal pain, diarrhea and constipation by indicating a position along a continuous 100 mm line between two end-points (0 and 100 mm) which represent the extreme feelings related to the symptom in question. In example: Have you been constipated? 0mm represents: No,not at all and 100 mm represents: Yes, severely.
GIP
时间窗: 6 hours
GIP area under the curve
次要结局
未报告次要终点
研究者
Karina Vejrum Sørensen
MSc
Odense University Hospital