Involvement of Dipeptidyl Peptidase-4 and Sodium-glucose Co-transporter-2 in Extrapancreatic Glucagon Secretion
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- glucagon excursions measured as incremental area under the curve (iAUC)
研究概览
简要总结
Glucagon is a 29-amino acid peptide hormone of essential importance for glucose homeostasis. Hitherto glucagon has been believed to be secreted only from the pancreas, but recent studies show that glucagon is also secreted from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data). This has fundamentally changed the understanding of glucagon physiology and provides new avenues for the investigation of several metabolic disorders in which hyperglucagonaemia represents a common and important pathophysiological characteristic (including type 2 diabetes). To delineate the physiological role of gut-derived glucagon and its potential pathophysiological implications, and thereby clear the way for new treatment modalities targeting gut glucagon, it is of importance to understand how glucagon secretion from the gut is regulated. In contrast to the regulation of pancreatic glucagon secretion, very little is known about the regulation of gut-derived glucagon.
Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) which under normal circumstances degrades, and thereby inactivates the two gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), has been shown to decrease pancreatic glucagon secretion. This is most likely brought about by increased levels of intact, active GLP-1, which is known to suppress pancreatic glucagon secretion. Furthermore, the sodium-glucose transporter 2 (SGLT-2) seems to be implicated in pancreatic glucagon secretion as inhibitors of SGLT-2 have been shown to increase the secretion of pancreatic glucagon secretion.
The present project will employ further investigations of totally pancreatectomised patients to delineate the regulation of gut-derived glucagon secretion with focus on the well-known modulators of pancreatic glucagon secretion, the enzyme DPP-4 and the sodium-glucose co-transporter SGLT-2, respectively.
The study is designed as a randomised, double-blinded, crossover study. 10 healthy persons and 10 totally pancreatectomized patients will be subjected to 3 experimental days. All participants will undergo a screening visit and three experimental days (day A (meal test during DPP-4 inhibition), B (meal test during SGLT-2 inhibition) and C (meal test with placebo)). A liquid meal test will be followed by a fasting period and finished off with an ad libitum meal.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Pancreatectomised patients
- •Caucasian above 30 years of age who have undergone total pancreatectomy
- •Blood haemoglobin >7.0 mmol/l for males and >6.5 mmol/l for females
- •Informed consent
- •Non-diabetic control subjects
- •Normal fasting plasma glucose and normal HbA1c (according to the World Health Organization (WHO) criteria)
- •Normal blood haemoglobin
- •Caucasian above 30 years of age
- •Informed consent
排除标准
- •Pancreatectomised patients
- •Pancreatectomy within the last 3 months
- •Ongoing chemotherapy or chemotherapy within the last 3 months
- •Treatment with GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors within the last 3 months
- •eGFR<60 ml/min/1,73m2 and/or albuminuria
- •Known liver disease (excluding simple steatosis) and/or serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >3 × upper normal limit)
- •Pregnancy and/or breastfeeding
- •Age above 85 years
- •Uncontrolled hypertension and/or significant cardiovascular disease
- •Any condition that the investigator feels would interfere with trial participation
- •Non-diabetic control subjects
- •Diabetes or prediabetes (according to WHO criteria)
- •First-degree relatives with diabetes
- •eGFR<60 ml/min/1,73m2 and/or albuminuria
- •Known liver disease (excluding simple steatosis) and/or serum ALAT and/or serum ASAT >3 × upper normal limits)
- •Pregnancy and/or breastfeeding
- •Age above 85 years
- •Uncontrolled hypertension and/or significant cardiovascular disease
- •Any condition that the investigator feels would interfere with trial participation
研究组 & 干预措施
Pancreatectomized + Placebo
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
Before the meal (1 h and 12 h) 1+1 placebo tablets will be administered orally.
干预措施: Placebo tablet (Other)
Pancreatectomized + DPP-4 inhibitor
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
Before the meal (1 h and 12 h) 1+1 DPP4-inhibitor tablets will be administered orally.
干预措施: Sitagliptin 100mg (Drug)
Pancreatectomized + SGLT-2 inhibitor
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
Before the meal (1 h and 12 h) 1+1 SGLT-2 tablets will be administred orally.
干预措施: Empagliflozin 25 MG (Drug)
Healthy + Placebo
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
干预措施: Placebo tablet (Other)
Healthy + DPP-4 inhibitor
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
干预措施: Sitagliptin 100mg (Drug)
Healthy + SGLT-2 inhibitor
During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
干预措施: Empagliflozin 25 MG (Drug)
结局指标
主要结局
glucagon excursions measured as incremental area under the curve (iAUC)
时间窗: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
次要结局
- PPG excurions measured as incremental area under the curve (iAUC)(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- Differences in gastric emptying, meassurement of s-paracetamol(-120-180 minutes)
- satiety, appetite, thirst,(-30, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- p-glucose mmol/L(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- food intake(180 and 210 minutes)
- Resting energy expenditure (REE)(-90, 150 and 150 minutes)
- endogenous glucose production(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- GLP-1, gastrin, cholecystokinin, GIP, oxyntomodulin(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- s-insulin(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- s-peptide pmol/l(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
- Pulse and blood pressure(-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes)
研究者
Filip Krag Knop
Consultant endocrinologist, Professor of Clinical Endocrinology and Director of Center for Clinical Metabolic Research
University Hospital, Gentofte, Copenhagen