Human Models of Selective Insulin Resistance: Diazoxide, Part I
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Hepatic de novo lipogenesis (absolute values)
研究概览
简要总结
The goal of this clinical trial is to compare a one-week course of diazoxide (2 mg/kg per dose x 14 doses) and placebo in people with obesity and insulin resistance (IR) with metabolic dysfunction-associated steatotic liver disease (MASLD). The main question it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects hepatic de novo lipogenesis, a major contributor to MASLD pathophysiology.
Participants will:
- Take 14 doses of placebo over 7 days, followed 4-12 weeks later by either 14 doses of diazoxide (at 2 mg per kg of body weight per dose [mpk]) or another 14 doses of placebo, over 7 days
- Take 18 doses of heavy (deuterated) water (50 mL each) over 7 days, twice
- Have blood drawn and saliva collected after an overnight fast on four mornings over the course of the study
- Undergo insulin suppression tests (IST) to assess the degree of insulin resistance at the end of each 1-week study period
- Consume their total calculated daily caloric needs as divided into three meals per day
Researchers will compare blood tests at the beginning and end of each 1-week study period in participants randomized (like the flip of a coin) to receive either placebo followed by diazoxide or placebo followed by placebo, to see how the drug treatment affects de novo lipogenesis, serum insulin, plasma glucose, and other serum lipid parameters (triglycerides, free fatty acids), among others.
详细描述
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the pathophysiology of its connection to unhealthy fat accumulation in the liver remains unclear. The investigators propose that the hyperinsulinemia that accompanies IR drives the excess hepatic de novo lipogenesis (DNL) that characterizes IR-associated MASLD. In other words, hepatic IR may be "selective," such that DNL is more sensitive to stimulation by insulin than is suppression of endogenous glucose production. As such, despite its potential impact on glucose metabolism, lowering insulin levels might attenuate the pro-steatotic drive in patients with IR. The investigators' objective, therefore, is to blunt endogenous insulin secretion using the insulin anti-secretagogue diazoxide in order to assess the impact on DNL.
This is a single-center, randomized, double-blinded, placebo-controlled, crossover clinical trial to determine the lipogenic impact of hyperinsulinemia reduction with diazoxide oral suspension in participants with obesity and insulin resistance (prediabetic state or elevated Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score, + fasting hyperinsulinemia) who are diagnosed with MASLD. Participants will be randomized to one of two groups. Both groups will receive 14 doses of placebo over 7 days. Then, 4-12 weeks later, one group will cross over to receive 14 doses of diazoxide 2 mg per kg of body weight for 7 days, while the other group will receive a second 1-week course of placebo. Participants will consume heavy (deuterated) water for a total of 18 doses of 50 ml over each 1-week study period to measure de novo lipogenesis. They will present for outpatient blood draws and saliva collections after an overnight fast at the start and conclusion of each study period (Study Days 1, 8, 9 and 16), and will undergo formal assessment of insulin resistance by the insulin suppression test (IST) at the end of each study period (Days 8 and 16).
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)
盲法说明
Participants will be masked to treatment during both 1-week study periods, while investigators will be masked only during the second 1-week study period, when participants will receive either diazoxide or placebo. Routine unblinding will occur to investigators only after all of a participant's samples have been submitted for laboratory analysis. It should be noted that investigators may get a sense of group allocation based on changes in blood glucose. However, due to interindividual variability in extent of insulin resistance and body mass index, it will not be possible to assuredly decode the randomization prior to unblinding. The blinding of the study Principal Investigator (PI) will be repealed only in the case of early withdrawal and/or medical emergency (e.g., severe hyperglycemia), which in most cases will result in study termination anyway. Participants will be notified of their group assignment once all relevant data are collected and analyzed if opted in.
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
- •Adults aged 18-65 years
- •Body mass index of 30-45 kg/m2
- •Able to understand written and spoken English and/or Spanish
- •Able to have pre-randomization screening labs drawn and study protocol initiated within 60 days of eligibility determination
- •Presence of uncomplicated metabolic dysfunction-associated steatotic liver disease (MASLD) by vibration-controlled transient elastography (VCTE)
- •Steatosis score of S1-S3
- •Fibrosis score of F0-F2 (Note that if VCTE result is available from within past 6 months, then do not have to repeat VCTE for study purposes)
- •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) on screening labs:
- •Prediabetes: Hemoglobin A1c 5.7-6.4%
- •IFG: plasma glucose of 100-125 mg dL-1 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
- •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):
- •Documented weight loss of ≥ 5.0% of baseline within the previous 3 months
- •Abnormal blood pressure (including on treatment, if prescribed)
- •Systolic blood pressure (SBP) < 90 mm Hg or > 160 mm Hg, and/or
- •Diastolic blood pressure (DBP) < 60 mm Hg or > 100 mm Hg
- •Resting heart rate < 55 bpm or ≥ 110 bpm
- •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 serum β-human chorionic gonadotropin (β-hCG, i.e., pregnancy test) in women of childbearing potential
- •Liver function abnormalities: transaminases (aspartate aminotransferase or alanine aminotransferase) > 3.0 x the upper limit of normal, and/or total bilirubin > 1.25 x the upper limit of normal
- •Abnormal screening fasting triglycerides > 500 mg/dL
- •Abnormal screening serum electrolytes that are considered clinically significant according to the clinical judgment of the PI
- •Creatinine equating to estimated glomerular filtration rate < 60 mL/min/1.73 m2
- •Abnormal screening blood counts (any of the following):
- •Hemoglobin < 10 g/dL
- •White blood cell count below the lower limit of normal for sex
- •Platelet count below the lower limit of normal for sex
- •Uric acid level above the upper limit of normal
- •Reproductive concerns
- •Women currently pregnant (tested by serum and/or urine β-hCG)
- •Women currently breastfeeding
- •Concerns related to glucose metabolism
- •History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):
- •Hemoglobin A1c ≥ 6.5%
- •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 antidiabetic medications except metformin within the 90 days prior to screening
- •Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
- •Concerns related to lipid metabolism
- •Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia
- •Use of fibrates, prescription-strength omega-3 fatty acids, or high-dose niacin within the 90 days prior to screening:
- •Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions:
- •Pancreatic pathology, including but not limited to neoplasia, pancreatitis, pancreatectomy
- •Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary)
- •Atherosclerotic cardiovascular disease: stable or unstable angina, myocardial infarction, ischaemic or hemorrhagic stroke, or transient ischaemic attack, peripheral arterial disease (claudication), use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor), history of percutaneous coronary intervention
- •Heart rhythm abnormalities
- •Congestive heart failure of any New York Heart Association class
- •Symptomatic valvular heart disease (e.g., aortic stenosis)
- •Pulmonary hypertension
- •Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate < 60 mL/min/ 1.73 m2), of any cause
- •Chronic liver disease other than uncomplicated MASLD, including but not limited to:
- •Advanced liver fibrosis, as determined by non-invasive testing, including fibrosis scores of F3-F4 on VCTE
- •Cirrhosis of any etiology
- •Autoimmune hepatitis or other rheumatologic disorder affecting the liver
- •Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
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研究组 & 干预措施
Placebo first, then Diazoxide
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 80% of participants will be randomized to this arm.
干预措施: Placebo (Drug)
Placebo / Placebo
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will again ingest placebo solution (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 20% of participants will be randomized to this arm.
干预措施: Insulin Suppression Test (IST) (Diagnostic Test)
Placebo first, then Diazoxide
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 80% of participants will be randomized to this arm.
干预措施: Diazoxide Oral Suspension, 2 mg per kg per dose (Drug)
Placebo first, then Diazoxide
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 80% of participants will be randomized to this arm.
干预措施: Deuterated water (2H2O/D2O), 70% (Drug)
Placebo first, then Diazoxide
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 80% of participants will be randomized to this arm.
干预措施: Insulin Suppression Test (IST) (Diagnostic Test)
Placebo / Placebo
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will again ingest placebo solution (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 20% of participants will be randomized to this arm.
干预措施: Placebo (Drug)
Placebo / Placebo
During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will again ingest placebo solution (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 20% of participants will be randomized to this arm.
干预措施: Deuterated water (2H2O/D2O), 70% (Drug)
结局指标
主要结局
Hepatic de novo lipogenesis (absolute values)
时间窗: Study Days 8 and 16
Percent incorporation of newly synthesized fatty acids into serum or very low-density lipoprotein (VLDL) triglyceride (TG) (units: %)
Hepatic de novo lipogenesis (relative/change)
时间窗: Study Days 8 and 16
Percent incorporation of newly synthesized fatty acids into serum or VLDL TG (units: fold difference and/or ∆%)
Hepatic de novo lipogenesis (absolute values)
时间窗: Up to study day 7 during each 1-week study period
Percent incorporation of newly synthesized fatty acids into serum or very low-density lipoprotein (VLDL) triglyceride (TG) (units: %)
Hepatic de novo lipogenesis (relative/change)
时间窗: Up to study day 7 during each 1-week study period
Percent incorporation of newly synthesized fatty acids into serum or VLDL TG (units: fold difference and/or ∆%)
次要结局
- Fasting plasma/serum insulin (absolute values)(Study Days 8 and 16)
- Fasting plasma/serum insulin (relative/change)(Study Days 8 and 16)
- Fasting plasma glucose(Study Days 8 and 16)
- Fasting serum or plasma triglycerides(Study Days 8 and 16)
- Fasting plasma free fatty acids(Study Days 8 and 16)
- Fasting plasma/serum insulin (absolute values)(Up to study day 7 during each 1-week study period)
- Fasting plasma/serum insulin (relative/change)(Up to study day 7 during each 1-week study period)
- Fasting plasma glucose(Up to study day 7 during each 1-week study period)
- Fasting serum or plasma triglycerides(Up to study day 7 during each 1-week study period)
- Fasting plasma free fatty acids(Up to study day 7 during each 1-week study period)
- Steady state plasma glucose (SSPG) during IST(At time points of 150, 160, 170, and 180 minutes during each 3-hour IST protocol)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University