Protocol III: SGLT2i, Ketoacidosis, Volume Contraction, and Insulinopenia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 29
- 试验地点
- 2
- 主要终点
- Ketone Body Turnover (ketogenesis)
研究概览
简要总结
To examine the 2-HIT hypothesis that the SGLT2i-induced stimulation of EGP, lipolysis, and ketone production requires the combination of volume depletion plus insulinopenia in T2D individuals.
详细描述
After screening visit, subjects will participate in four additional visits and or at least one of the four visits that will be performed in random order starting at 6:00 AM to the Clinical Research Center at University Hospital-Texas Diabetes Institute.
Visit 2 (Study 1): At 6:00AM at (Study 1), a prime-continuous infusions of 6,6, D2-Glucose or U-3H-glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic glucose production (HGP) and fat break down (lipolysis).3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg). Plasma substrate, hormone concentrations, U-3H-glucose and U-14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minutes. If Principal Investigator (PI) use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 54, if PI will use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 54.
Visit 3 (Study 2, Optional): At 6:00AM prime-continuous infusions of 6,6, D2-Glucose or U-3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic glucose production (HGP) and lipolysis. 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At 7 AM an infusion of normal saline will be started at the rate of 150 ml/hour and continued to the end of study at 2 PM (total volume = 1050 ml; total Na and Cl = 154 meq) to provide volume replacement for blood loss. At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg). Plasma substrate, hormone concentrations, 3H-glucose and 14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 55. If PI use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 55.
Visit 4 (Study 3, Optional): At 6:00AM prime-continuous infusions 6,6, D2-Glucose or U-3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of Hepatic Glucose Production (HGP) and fat break down (lipolysis). 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg) and octreotide or somatostatin with insulin and glucagon will be given to reduce volume without insulinopenia. Plasma substrate and hormone concentrations and 3H-glucose/14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 55-56. If PI uses U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 56.
Visit 5 (Study 4, Optional): At 6:00AM prime-continuous infusions of 6,6, D2-Glucose or 3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic (liver) glucose production (HGP) and fat break down (lipolysis). 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At 7 AM an infusion of normal saline will be started at the rate of 150 ml/hour and continued to the end of study at 2 PM (total volume = 1050 ml; total Na and Cl = 154 meq) to provide volume replacement for blood loss. At time zero (9:00 AM) subjects will ingest empagliflozin (25 mg) and octreotide or somatostatin with insulin and glucagon will be given. Plasma substrate and hormone concentrations and 3H-glucose/14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI uses U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 56. If PI use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 56.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
盲法说明
None (Open Label)
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
- •Patients with T2D
- •Inclusion Criteria:
- •Ages 30-75
- •BMI (Body Mass Index) 21-45 kg/m2
- •HbA1c = 7.0-11%
- •eGFR (estimated glomerular filtration rate)> 60 ml/min/1.73m2
- •Blood Pressure (BP)≤160/90 mmHg
- •Participants must be in general good health based on medical history, physical exam, screening blood chemistries, CBC (Complete Blood Count), TSH/T4 (thyroid/thyroxine hormone), EKG (electrocardiogram), and urinalysis (UA)
- •Stable body weight (±1.5 kg) over the last 3 months and must not participate in an excessively heavy exercise program
- •Patients treated with diet, Sulfonylureas, Metformin, or Sulfonylureas/Metformin (Sulfo/MET)
- •Participants receiving a Glucagon like peptide -1 receptor agonist (GLP1-RA) must be on a stable dose for at least three months prior to study enrollment.
- •Participants receiving a Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitor) must be on a stable dose for at least two months prior to study enrollment.
- •SGLT2 inhibitors must be discontinued at least two months prior to study enrollment.
- •Statin therapy is permissible if the dose has been stable for at least 3 months
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Patients treated with Thiazolidinediones (TZDs), or Insulin are excluded.
- •Patients taking medications other than Sulfonylureas/Metformin (SU/MET), stable dose of GLP1-RA and DPP4i known to affect glucose metabolism are excluded. Patients taking SGLT2i within 2 months of screening visit will be excluded from participating in this study, however they may be asked whether they would agree to discontinue the medication for two months to become eligible. (Please see clarification below.) *
- •Subjects with evidence of proliferative retinopathy or estimated glomerular filtration rate (eGFR) < 60 are excluded
- •Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices * Only participants who are taking SGLT2 inhibitors during the prescreening period will be asked to discontinue the medication at least two months prior to the screening visit. If they agree, they will return for an HbA1c measurement four weeks after stopping the SGLT2 inhibitor.
- •If their HbA1c rises to greater than 10%, treatment will be initiated with either metformin, a DPP-4 inhibitor, or a sulfonylurea. We do not anticipate any adverse effects during this initial period, provided the HbA1c remains below 10%.
- •HbA1c will be measured using a fingerstick test, which requires only a minimal amount of blood. No compensation will be provided during this phase.
- •After two months of medication discontinuation, participants will return for a screening visit. If they meet all eligibility criteria, they will be enrolled in the study and payment done by protocol.
研究组 & 干预措施
Empagliflozin
Empagliflozin 25 mg/day
干预措施: Empagliflozin 25 MG (Drug)
结局指标
主要结局
Ketone Body Turnover (ketogenesis)
时间窗: 0 and 300 minutes
Measurement of ketone body turnover rate during the baseline state and 240-300-minute time period, before and after Empagliflozin administration.
次要结局
未报告次要终点