Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes - the Role of Glucagon
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
- Differences in GIGD (%)
研究概览
简要总结
In patients with type 2 diabetes, the incretin effect is markedly reduced contributing to the relative insulin deficiency that characterizes these patients. This defect is believed to be due to a decreased effect of GLP-1 and an almost ceased effect of GIP. Nevertheless, the impact of the defect on glucose tolerance is not fully understood. The so-called gastrointestinal-mediated glucose disposal (GIGD) is a measure of glucose handling, which includes the incretin effect, but also other factors affecting glucose disposal (e.g. glucagon secretion). Interestingly, patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and glucagon concentrations fail to decrease appropriately and may even increase in response to ingestion of glucose and show exaggerated increases after a mixed meal. With the current project the investigators wish to elucidate how this paradoxical glucagon response observed in patients with type 2 diabetes affects the GIGD, the incretin effect and postprandial glucose excursions.
Ten patients with type 2 diabetes and 10 healthy matched control subjects will be enrolled in this randomised, placebo-controlled, double-blinded study. The aim is to examine the effect of a glucagon receptor antagonist (GRA) on gastrointestinal-mediated glucose disposal (GIGD), incretin effect and postprandial glucose excursions in patients with type 2 diabetes and healthy controls. Participants will attend two oral glucose tolerance tests (OGTT), two isoglycaemic iv glucose infusion (IIGI) and two standardised liquid meals.
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
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Patients with type 2 diabetes
- •Caucasians above 35 years of age with diet or metformin treated type 2 diabetes for at least 3 month (diagnosed according to the criteria of the World Health Organization (WHO)
- •Normal haemoglobin
- •Informed consent
- •Healthy subjects
- •Normal fasting plasma glucose (FPG) <6.1 mmol/l and HbA1c <42 mmol/mol (6.0%)
- •Normal haemoglobin
- •Age above 35 years
- •Informed consent
排除标准
- •Patients with type 2 diabetes
- •Inflammatory bowel disease
- •Intestinal resections
- •Nephropathy (serum creatinine above normal range and/or albuminuria)
- •Liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2×normal values)
- •Treatment with medicine that cannot be paused for 12 hours
- •Pregnancy and/or breastfeeding
- •Family history of pancreatic islet tumours
- •Age above 80 years
- •Healthy subjects
- •Diabetes or prediabetes with reduced glucose tolerance: FPG >6.0 mmol/l and/or HbA1c >42 mmol/mol
- •First degree relatives with type 2 diabetes
- •Inflammatory bowel disease
- •Intestinal resections
- •Treatment with medicine that cannot be paused for 12 hours
- •Pregnancy and/or breastfeeding
- •Age above 80 years
研究组 & 干预措施
T2D + OGTT + LY2409021
Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
T2D + OGTT + LY2409021
Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.
干预措施: OGTT (Procedure)
T2D + OGTT + placebo
Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
T2D + OGTT + placebo
Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: OGTT (Procedure)
T2D + IIGI + LY2409021
Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
T2D + IIGI + LY2409021
Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.
干预措施: IIGI (Procedure)
T2D + IIGI + placebo
Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
T2D + IIGI + placebo
Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: IIGI (Procedure)
T2D + MEAL + LY2409021
Type 2 diabetes patients + Standardised liquid meal + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
T2D + MEAL + LY2409021
Type 2 diabetes patients + Standardised liquid meal + the human antagonist of the glucagon receptor.
干预措施: Standardised liquid meal (Procedure)
T2D + MEAL + placebo
Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
T2D + MEAL + placebo
Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor.
干预措施: Standardised liquid meal (Procedure)
CTRL + OGTT + LY2409021
Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
CTRL + OGTT + LY2409021
Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.
干预措施: OGTT (Procedure)
CTRL + OGTT + placebo
Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
CTRL + OGTT + placebo
Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor.
干预措施: OGTT (Procedure)
CTRL + IIGI + LY2409021
Healthy controls + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
CTRL + IIGI + LY2409021
Healthy controls + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.
干预措施: IIGI (Procedure)
CTRL + IIGI + placebo
Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
CTRL + IIGI + placebo
Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor.
干预措施: IIGI (Procedure)
CTRL + MEAL + LY2409021
Healthy controls + Standardised liquid meal + the human antagonist of the glucagon receptor.
干预措施: LY2409021 (Drug)
CTRL + MEAL + LY2409021
Healthy controls + Standardised liquid meal + the human antagonist of the glucagon receptor.
干预措施: Standardised liquid meal (Procedure)
CTRL + MEAL + placebo
Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor.
干预措施: LY2409021 placebo (Drug)
CTRL + MEAL + placebo
Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor.
干预措施: Standardised liquid meal (Procedure)
结局指标
主要结局
Differences in GIGD (%)
时间窗: Comparison between experimental days with and without the glucagon receptor antagonist . The glucose disposal at time 240 minutes will be used.
GIGD = Gastrointestinal glucose disposal. GIGD (%) = 100% × (glucoseOGTT-glucoseIIGI)/glucoseOGTT.
Difference in postprandial glucose excursions
时间窗: Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with and without the glucagon receptor antagonist.
Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).
次要结局
- Incretin effect(Insulin AUC time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes. Comparison between experimental days with and without the glucagon receptor antagonist)
- Endogenous glucose production(Plasma concentration of 6,6^2 H2-glucose and U-13C^6-glucose at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.)
- Lipolysis(Plasma concentration of 1,1,2,3,3-^2-H5 - glycerol measured at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.)
- Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.(Time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.)
- Energy intake (kcal/kJ)(At time 240 to 270, the participants will eat an ad libitum meal. Comparison between experimental days with and without the glucagon receptor antagonist)
- Changes in blood pressure (mmHg)(Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist)
- Free fatty acids(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
- Fibroblast growth factor-21(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
- Appetite(VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.)
- Changes in pulse rate (beat per minute)(Measured at time 0 and at time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist)
- Differences in gastric emptying(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
研究者
Sofie Hædersdal
MD, PhD student
University Hospital, Gentofte, Copenhagen