Role of Hyperinsulinemia in NAFLD: Dexamethasone-Pancreatic Clamp Pilot & Feasibility Study
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Absolute values of plasma glucose
研究概览
简要总结
This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study in the setting of dexamethasone-induced insulin resistance. The investigators will recruit participants with a history of overweight/obesity but no history of prediabetes or diabetes. Participants will be rendered temporarily insulin resistant by taking seven doses of dexamethasone. They will then undergo two pancreatic clamp procedures in which individualized basal IIR are identified, followed in one by maintenance of basal IIR (maintenance hyperinsulinemia, MH) and in the other by a stepped decline in IIR (reduction toward euinsulinemia, RE). In both clamps the investigators will closely monitor plasma glucose and various metabolic parameters. The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR.
详细描述
Although high blood sugar and risk of heart disease are the most well-known health effects of type 2 diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, NAFLD can progress to severe liver inflammation, liver failure, and even liver cancer. The investigators suspect that high levels of the blood sugar-lowering hormone insulin leads to excessive fat production by the liver, and so lowering insulin levels might help to improve NAFLD. In order to answer this question, the investigators will temporarily render volunteers insulin resistant -- that is, simulating the risk of T2DM and NAFLD -- using seven doses of dexamethasone. They will then perform a "pancreatic clamp" - a procedure in which the body's production of insulin is temporarily shut off and then replaced at the same or lower levels. Again, the investigators expect that lowering insulin levels will lower fat production. Because this is a new research approach, the investigators first need to understand how lowering insulin levels affects blood sugar. Research participants in this pilot study will therefore undergo two pancreatic clamps, each following seven doses of dexamethasone, in random order: one roughly maintaining their own internal ("basal") insulin level and one in which the investigators lower that basal insulin level by 10%, 20%, and 40%. In each case, the investigators will observe the absolute and relative changes in blood sugar and the levels of certain fats as the investigators change the insulin level. Once the investigators have found a lower insulin level that they can safely maintain, the investigators will go on to study its effect on fat production in a later study.
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
- Single (Participant)
盲法说明
Participant will be blinded to study group assignment.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women (using highly effective contraception if of childbearing potential) aged 18-65 years
- •Body mass index of 25.0-39.9 kg/m2
- •Able to understand written and spoken English and/or Spanish
- •Evidence of normal glucose metabolism (euglycemia), represented by not meeting the American Diabetes Association's definitions for prediabetes, impaired fasting glucose (IFG), or diabetes on screening labs. Thus, participants must meet both of the following conditions on screening labs:
- •i. Prediabetes: Hemoglobin A1c < 5.7% ii. IFG: plasma glucose of < 100 mg/dL after 8-h fast
- •Normal fasting serum insulin (fasting insulin level < 12 μIU/mL) on screening labs
- •Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
排除标准
- •Unable to provide informed consent in English or Spanish
- •Concerns arising at screening visit (any of the following):
- •i. Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the clamp ii. Unwillingness to fast (except water) for up to 24 hours iii. Documented weight loss of ≥ 5% of baseline within the previous 6 months iv. Abnormal blood pressure (including on treatment, if prescribed)
- •Systolic blood pressure < 90 mm Hg or > 160 mm Hg, and/or
- •Diastolic blood pressure < 60 mm Hg or > 100 mm Hg v. Abnormal resting heart rate: < 60 or ≥100 bpm
- •Sinus brady- or tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion vi. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d):
- •Non-sinus rhythm
- •Significant QTc prolongation (≥ 480 ms)
- •New or previously unknown ischaemic changes that persist on repeat EKG: ST elevations, T-wave inversions vii. Laboratory evidence of impaired glucose metabolism:
- •Hemoglobin A1c ≥ 5.7%, and/or
- •Fasting plasma glucose ≥ 100 mg/dL viii. Positive qualitative human chorionic gonadotropin, beta subunit (β-hCG) in women of childbearing potential ix. Positive urine drug screen, except for lawfully prescribed medications and/or marijuana x. Liver function abnormalities (either of the following)
- •Transaminases (AST or ALT) > 2.0 x the upper limit of normal
- •Total bilirubin > 1.25 x the upper limit of normal xi. Abnormal fasting lipids at screening (either of the following)
- •Triglycerides ≥ 400 mg/dL
- •LDL-cholesterol ≥ 190 mg/dL xii. Abnormal screening serum electrolytes (any of the following)
- •Abnormal sodium, potassium, chloride, or bicarbonate levels that are considered potentially significant according to the clinical judgment of the PI.
- •Creatinine equating to estimated glomerular filtration rate < 60 mL/min/1.73 m2 xiii. Abnormal complete blood count (CBC) (any of the following)
- •Hemoglobin < 10 g/dL or hematocrit < 30%
- •Platelet count < 100,000/μL
- •Exempt from CBC requirement if previously obtained value within 2 months of screening is available
- •Unwillingness to comply with masking and COVID-19 testing requirements per hospital policy
- •Reproductive concerns i. Women of childbearing potential not using highly effective contraception, defined as:
- •Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)
- •Oral contraceptive pills taken daily, including during the study
- •Intrauterine device (levonorgestrel-eluting or copper) active at the time of study
- •Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of study
- •Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
- •Etonogestrel/ethinyl estradiol vaginal ring (e.g., NuvaRing®, etc.) active at the time of the study
- •Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study ii. Women currently pregnant, measured by serum and/or urine β-hCG iii. Women currently breastfeeding
- •Concerns related to glucose metabolism i. Known, documented history of having met any of the American Diabetes Association's definitions of prediabetic state or of diabetes mellitus (i.e., overt diabetes):
- •Hemoglobin A1c ≥ 5.7%
- •o Or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
- •Plasma glucose ≥ 100 mg/dL after 8-h fast
- •Plasma glucose of ≥ 140 mg/dL at 2 h after ingestion of a 75-g glucose load
- •Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state ii. History of gestational diabetes mellitus within the previous 5 years iii. Use of most antidiabetic medications within the 90 days prior to screening
- •Excluded: thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin
- •Metformin used for weight control or polycystic ovarian syndrome is acceptable provided that recruits meet all of the inclusion criteria at screening iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) v. Fasting plasma glucose < 70 mg/dL at screening
- •Concerns related to lipid metabolism i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative ii. Use of certain lipid-lowering drugs within 90 d prior to screening visit:
- •Statins or PCSK9 inhibitors for secondary prevention or treatment of familial hypercholesterolemia
- •o Statins or PCSK9 inhibitors for primary prevention of ASCVD are acceptable
- •Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
- •High-dose niacin (>100 mg daily)
- •Known, documented history, at the time of screening, of any of the following medical conditions:
- •i. Pancreatic pathology, including but not limited to:
- •Pancreatic neoplasia
- •Chronic pancreatitis
- •Acute pancreatitis (or history of within the past 5 years)
- •Autoimmune pancreatitis
- •Surgical removal of any portion of the pancreas ii. Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
- •Atherosclerotic cardiovascular disease
- 另有 47 项未显示
研究组 & 干预措施
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Insulin human (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Octreotide Acetate (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Glucagon (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Human Growth Hormone (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Dexamethasone Oral (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: [6,6-2H2] D-glucose (Other)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: 20% D-glucose (aq) (Drug)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: BOOST Plus (Dietary Supplement)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Harvard Apparatus PHD ULTRA CP syringe pump (Device)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer (Device)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Normal saline (Other)
Maintenance hyperinsulinemia (MH) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.
干预措施: Human albumin (Other)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Insulin human (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Octreotide Acetate (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Glucagon (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Human Growth Hormone (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Dexamethasone Oral (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: [6,6-2H2] D-glucose (Other)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: 20% D-glucose (aq) (Drug)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: BOOST Plus (Dietary Supplement)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Harvard Apparatus PHD ULTRA CP syringe pump (Device)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer (Device)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Normal saline (Other)
Reduction toward euinsulinemia (RE) protocol
The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.
干预措施: Human albumin (Other)
结局指标
主要结局
Absolute values of plasma glucose
时间窗: Up to 425 minutes from the start of the procedure
Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the glucose levels that result from altering the basal IIR. Units: mg/dL
Relative change in plasma glucose
时间窗: Up to 425 minutes from the start of the procedure
Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the impact of altering the basal IIR on glycemia. Units: fold difference and/or ∆mg/dL relative to previous time points
Absolute values of serum insulin
时间窗: Up to 425 minutes from the start of the procedure
Investigators will assess the insulin levels attained at the basal IIR, and at each stepwise reduction in IIR during the intervention phase. Units: micro-international units per milliliter (µIU/mL)
Relative change in serum insulin
时间窗: Up to 425 minutes from the start of the procedure
Investigators will compare the baseline insulin level to that attained at the basal IIR, as well as comparing to the change in insulin level that occurs with alterations in the IIR during the intervention phase. Units: fold difference and/or ∆ µIU/mL relative to previous time points
Absolute values of serum C-peptide
时间窗: Up to 425 minutes from the start of the procedure
Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero. Units: ng/mL
Relative change in serum C-peptide
时间窗: Up to 425 minutes from the start of the procedure
Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero. Units: fold difference and/or ∆ µIU/mL relative to previous time points
次要结局
- Plasma glucose kinetics: endogenous glucose production(Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure)
- Plasma glucose kinetics: rate of disappearance(Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure)
- Absolute values of serum or plasma triglyceride (TG)(Up to 425 minutes from the start of the procedure)
- Relative change in absolute values of serum or plasma triglyceride (TG)(Up to 425 minutes from the start of the procedure)
- Absolute values of serum or plasma free fatty acid (FFA)(Up to 425 minutes from the start of the procedure)
- Relative change in serum or plasma free fatty acid (FFA)(Up to 425 minutes from the start of the procedure)
- Absolute values of serum or plasma apolipoprotein B (ApoB)(Up to 425 minutes from the start of the procedure)
- Relative change in serum or plasma apolipoprotein B (ApoB)(Up to 425 minutes from the start of the procedure)
- Plasma glucose kinetics: rate of appearance(Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University