Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (P2)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Measurement of the Change in Plasma Glucose (mg/dL): Study 1
研究概览
简要总结
To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.
详细描述
The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at least in part, for the increase in EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and T2DM subjects. This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of endogenous glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose production (HGP), which is the net release of glucose from the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase in HGP above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for 5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study 2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose concentration stable at each subject's fasting level). This study will define whether the decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin concentrations constant at the basal level). This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive placebo. Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •T2DM according to ADA criteria-HbA1C < 8.0%
- •BMI = 25-35 kg/m2
- •Subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis
- •Body weight has been stable (± 3 lbs) over the preceding three months
- •Do not participate in an excessively heavy exercise program
- •Taking stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea
排除标准
- •Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will be excluded
- •Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be excluded
研究组 & 干预措施
Dapagliflozin
32 subjects will receive dapagliflozin 10mg
干预措施: Dapagliflozin (Drug)
Placebo
16 subjects will receive placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Measurement of the Change in Plasma Glucose (mg/dL): Study 1
时间窗: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2
时间窗: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Change in Plasma Glucose Using a Pancreatic Clamp: Study 3
时间窗: Baseline to 240-300 minutes
Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Change in EGP: Study 1
时间窗: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in EGP
Change in EGP With Glucose Clamp: Study 2
时间窗: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Change in EGP With Pancreatic Clamp: Study 3
时间窗: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
次要结局
- Change in Plasma Insulin Concentrations: Study 1(Baseline to 240-300 minutes)
- Change in Glucagon: Study 1(Baseline to 240-300 minutes)
- Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2(Baseline to 240-300 minutes)
- Change in Plasma Insulin While Using Pancreatic Clamp: Study 3(Baseline to last hour of the study)
- Change in Glucagon Using Glucose Clamp: Study 2(Baseline to 240-300 minutes)
- Change in Glucagon Using Pancreatic Clamp: Study 3(Baseline to 240-300 minutes)