Human Models of Selective Insulin Resistance: Pancreatic Clamp
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Hepatic de novo lipogenesis (DNL) (absolute value)
研究概览
简要总结
This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the impact of lowering insulin levels on hepatic glucose production (HGP) vs de novo lipogenesis (DNL) in people with insulin resistance. The investigators will recruit participants with a history of overweight/obesity and evidence of insulin resistance (i.e., fasting hyperinsulinemia plus prediabetes and/or impaired fasting glucose and/or Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] score >=2.73), and with evidence of metabolic dysfunction-associated steatotic liver disease (MASLD). Participants will undergo two pancreatic clamp procedures -- one in which serum insulin levels are maintained near hyperinsulinemic baseline (Maintenance Hyperinsulinemia or "MH" Protocol) and the other in which serum insulin levels are lowered by 50% (Reduction toward Euinsulinemia or "RE" Protocol). In both clamps the investigators will use stable-isotope tracers to monitor hepatic glucose and triglyceride metabolism. The primary outcome will be the impact of steady-state clamp insulinemia on HGP vs DNL.
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), metabolic dysfunction-associated steatotic liver disease (MASLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, MASLD 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 MASLD. In order to answer this question, the investigators will recruit people with MASLD at risk for T2DM to 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 ("de novo lipogenesis" or DNL). Research participants in this prospective, randomized, controlled (crossover) study will therefore undergo two pancreatic clamps in random order: one roughly maintaining their own internal ("basal") insulin level ("MH Protocol") and one in which the investigators lower that basal insulin level by 50% ("RE Protocol"). In each case, the investigators will observe the absolute and relative changes in the liver's production of glucose (hepatic glucose production, HGP) and of triglycerides (de novo lipogenesis, DNL) using stable-isotope tracers.
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, ages 18-65 years
- •Body mass index of 27-50 kg/m2
- •Able to understand written and spoken English and/or Spanish
- •Evidence of insulin resistance, represented by any or all of the following criteria:
- •Meeting either of the American Diabetes Association's definitions for prediabetes or Impaired fasting glucose (IFG) within the previous year and on screening labs:
- •Prediabetes: Hemoglobin A1c 5.7-6.4%
- •IFG: plasma glucose of 100-125 mg/dL after 8-h fast
- •Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
- •Fasting hyperinsulinemia (fasting insulin level ≥ 13 µU/mL) on screening labs
- •Presence of uncomplicated MASLD, defined by vibration-controlled transient elastography (VCTE) as a steatosis score S1-S3 + fibrosis score F0-F2
- •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
- •Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the clamp
- •Documented weight loss of ≥ 5% of baseline within the previous 3 months
- •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
- •Abnormal resting heart rate: < 60 or ≥ 110 bpm
- •Sinus brady- or tachycardia that has been worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion
- •Abnormal screening electrocardiogram (or if on file, performed within previous 90 days)
- •Laboratory evidence of diabetes mellitus:
- •Hemoglobin A1c ≥ 6.5%, and/or
- •Fasting plasma glucose ≥ 126 mg/dL
- •Positive qualitative β-hCG (Human chorionic gonadotropin, β subunit) (i.e., pregnancy test) in women of childbearing potential
- •Positive urine drug screen, except for lawfully prescribed medications and/or marijuana
- •Liver function abnormalities (either of the following)
- •Transaminases (AST or ALT) > 3.0 x the upper limit of normal
- •Total bilirubin > 1.25 x the upper limit of normal
- •Fasting serum triglycerides at screening ≥ 400 mg/dL
- •Abnormal screening serum electrolytes that are considered potentially significant according to the clinical judgment of the PI
- •Abnormal complete blood count (CBC) (any of the following)
- •Hemoglobin < 10 g/dL or hematocrit < 30%
- •Platelet count < 100,000/µL
- •Women currently pregnant, measured by serum and/or urine β-hCG, or trying to become pregnant
- •Women currently breastfeeding
- •History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):
- •Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
- •Plasma glucose ≥ 126 mg/dL after 8-h fast
- •Plasma glucose of ≥ 200 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
- •History of gestational diabetes mellitus within the previous 5 years
- •Use of most antidiabetic medications within the 30 days prior to screening
- •Excluded: thiazolidinediones, sulfonylureas, meglitinides, DPP4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, amylin mimetics, acarbose, insulin
- •Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening
- •Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
- •Known diagnoses of familial combined hyperlipidemia or familial chylomicronemia syndrome
- •Use of certain lipid-lowering drugs within 30 d prior to screening visit:
- •Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
- •Prescription-strength omega-3 fatty acids (e.g., Lovaza®, Vascepa®)
- •Known, documented history, at the time of screening, of any of the following medical conditions:
- •Pancreatic pathology
- •Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
- •Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate < 60 mL min-1 1.73 m-2), of any cause
- •Advanced or severe liver disease (including fibrosis scores of F3-F4 on screening VCTE)
- •Gallstone disease
- •Chronic viral illness
- •Malabsorptive conditions (active)
- •Active seizure disorder (including controlled with antiepileptic drugs)
- •Psychiatric diseases causing functional impairment and/or requiring use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
- •Known adrenal disease
- •Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation
- 另有 23 项未显示
研究组 & 干预措施
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Insulin human (Drug)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Octreotide Acetate (Drug)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Glucagon (Drug)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Growth Hormone, Human (Drug)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: 20% D-glucose (aq) (Drug)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: [6,6-2H2] D-glucose (Diagnostic Test)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: [1-13C1] sodium acetate (Diagnostic Test)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Nestle BOOST Plus (Dietary Supplement)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: KIND Bar (Dietary Supplement)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Harvard Apparatus PHD ULTRA CP syringe pump (Device)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer (Device)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Insulin human (Drug)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Octreotide Acetate (Drug)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Glucagon (Drug)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Growth Hormone, Human (Drug)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: 20% D-glucose (aq) (Drug)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: [6,6-2H2] D-glucose (Diagnostic Test)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: [1-13C1] sodium acetate (Diagnostic Test)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Nestle BOOST Plus (Dietary Supplement)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: KIND Bar (Dietary Supplement)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Harvard Apparatus PHD ULTRA CP syringe pump (Device)
Reduction toward euinsulinemia (RE) protocol
On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
干预措施: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer (Device)
结局指标
主要结局
Hepatic de novo lipogenesis (DNL) (absolute value)
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Percent incorporation of newly synthesized fatty acids into plasma or very low-density lipoprotein (VLDL) triglyceride (TG) during pancreatic clamp procedures. (Unit: %)
Hepatic de novo lipogenesis (DNL) (relative value)
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG during pancreatic clamp procedures. (Unit: fold difference and/or ∆% versus other group)
Endogenous glucose production (EGP) (absolute value)
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min)
Endogenous glucose production (EGP) (relative value)
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group)
Plasma glucose level
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Plasma glucose level during pancreatic clamp procedures. (Units: mg/dL)
Serum insulin level
时间窗: Up to 6.5 hours of pancreatic clamp protocol
Serum insulin level during pancreatic clamp procedures (Units: µU/mL)
次要结局
- Glucose kinetics: rate of appearance (relative value)(Up to 6.5 hours of pancreatic clamp protocol)
- Serum or plasma triglyceride level(Up to 6.5 hours of pancreatic clamp protocol)
- Plasma free fatty acids level(Up to 6.5 hours of pancreatic clamp protocol)
- Glucose kinetics: rate of appearance (absolute value)(Up to 6.5 hours of pancreatic clamp protocol)
- Glucose kinetics: rate of disappearance (absolute value)(Up to 6.5 hours of pancreatic clamp protocol)
- Glucose kinetics: rate of disappearance (relative value)(Up to 6.5 hours of pancreatic clamp protocol)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University