The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Difference in postprandial glucose excursions (linagliptin)
研究概览
简要总结
In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and in response to ingestion of glucose or a mixed meal.glucagon, glucagon concentrations fail to decrease appropriately and may even increase. This diabetic hyperglucagonaemia may therefore contribute importantly to the hyperglycaemia of the patients.
Several glucose-lowering treatment modalities have been shown to affect glucagon levels in patients with type 2 diabetes, but the role of glucagon in the glucose-lowering effects of these treatment modalities has been difficult to discern. By using a glucagon receptor antagonist (GRA) the investigators will exploit glucagon receptor antagonism to delineate the role of glucagon during treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to increase and decrease plasma glucagon levels, respectively.
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
- 30 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Caucasians above 30 years of age with diet or metformin treated type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization)
- •Normal haemoglobin
- •Informed consent
排除标准
- •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 75 years
- •Treatment with loop-diuretics (applies only to arms with empagliflozin or empagliflozin placebo)
- •Chronic heart failure
研究组 & 干预措施
A1: GRA-placebo + MEAL + DPP4-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: LY2403021 placebo (Drug)
A1: GRA-placebo + MEAL + DPP4-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: Standardised liquid meal (Procedure)
A1: GRA-placebo + MEAL + DPP4-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: Linagliptin placebo (Drug)
A2: GRA-active + MEAL + DPP4-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: LY2403021 (Drug)
A2: GRA-active + MEAL + DPP4-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: Standardised liquid meal (Procedure)
A2: GRA-active + MEAL + DPP4-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
干预措施: Linagliptin placebo (Drug)
A3: GRA-placebo + MEAL + DPP4-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: LY2403021 placebo (Drug)
A3: GRA-placebo + MEAL + DPP4-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: Standardised liquid meal (Procedure)
A3: GRA-placebo + MEAL + DPP4-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: Linagliptin (Drug)
A4: GRA-active + MEAL + DPP4-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: LY2403021 (Drug)
A4: GRA-active + MEAL + DPP4-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: Standardised liquid meal (Procedure)
A4: GRA-active + MEAL + DPP4-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
干预措施: Linagliptin (Drug)
B1: GRA-placebo + MEAL + SGLT2-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: LY2403021 placebo (Drug)
B1: GRA-placebo + MEAL + SGLT2-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: Standardised liquid meal (Procedure)
B1: GRA-placebo + MEAL + SGLT2-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: Empagliflozin placebo (Drug)
B2: GRA-active + MEAL + SGLT2-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: LY2403021 (Drug)
B2: GRA-active + MEAL + SGLT2-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: Standardised liquid meal (Procedure)
B2: GRA-active + MEAL + SGLT2-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
干预措施: Empagliflozin placebo (Drug)
B3: GRA-placebo + MEAL + SGLT2-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: LY2403021 placebo (Drug)
B3: GRA-placebo + MEAL + SGLT2-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: Standardised liquid meal (Procedure)
B3: GRA-placebo + MEAL + SGLT2-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: Empagliflozin (Drug)
B4: GRA-active + MEAL + SGLT2-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: LY2403021 (Drug)
B4: GRA-active + MEAL + SGLT2-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: Standardised liquid meal (Procedure)
B4: GRA-active + MEAL + SGLT2-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
干预措施: Empagliflozin (Drug)
结局指标
主要结局
Difference in postprandial glucose excursions (linagliptin)
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 linagliptin (A1, A2, A3, A4)
Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).
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 empagliflozin (B1, B2, B3, B4)
Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve
次要结局
- 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.(: 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.)
- Changes in blood pressure (mmHg)(Measured at time 0 and time 210 minutes.)
- Differences in gastric emptying(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
- Free fatty acids(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
- Plasma Fibroblast growth factor-21(-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes)
- Resting energy expenditure(-60 to -50 and 35 to 45)
- 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.)
- 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.)
研究者
Sofie Hædersdal
MD, PhD student
University Hospital, Gentofte, Copenhagen