Role of Hyperinsulinemia in Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis: Diazoxide Pilot & Feasibility Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Fasting plasma/serum insulin (relative change)
研究概览
简要总结
The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with overweight/obesity and insulin resistance (IR) with, or at high risk for, non-alcoholic fatty liver disease (NAFLD). The main questions it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects parameters of glucose and lipid metabolism (how people with IR and NAFLD respond to lowering high insulin levels so that the investigators can see what happens to how the liver handles fat and sugar).
Participants will:
- Take 27 doses of diazoxide (at 1 mg per kg of body weight per dose [mpk] or 2 mpk) or of placebo, over 14 days
- Take 32 doses of heavy (deuterated) water (50 mL each) over 14 days
- Have blood drawn and saliva collected after an overnight fast on four mornings over the two-week study period
- Consume their total calculated daily caloric needs as divided into three meals per day
- Wear a continuous glucose monitor for the two-week study period
Researchers will compare fasting blood tests at intervals during the study period in participants randomized (like the flip of a coin) to diazoxide 1 mpk, diazoxide 2 mpk, or placebo, to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B). They will also consume heavy (deuterated) water to assess de novo lipogenesis (building of new fatty acids by the liver).
详细描述
Non-alcoholic fatty liver disease (NAFLD) 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 NAFLD (IR-NAFLD). As such, despite its potential impact on glucose tolerance, lowering insulin levels might attenuate the pro-steatotic drive in patients with IR. The investigators' long-term objective, therefore, is to blunt endogenous insulin secretion using the insulin anti-secretagogue diazoxide in order to assess the impact on DNL. However, in order to optimize diazoxide treatment conditions, the investigators must first perform a pilot & feasibility study.
This is a single-center, randomized, double blinded, placebo-controlled clinical trial to provide pilot and feasibility data on the use of diazoxide oral suspension to ameliorate hyperinsulinemia in participants with overweight/obesity and insulin resistance (prediabetic state or elevated Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score, + fasting hyperinsulinemia) who are diagnosed with, or clinically judged to be at high risk of, NAFLD. Participants will be randomized to one of three parallel arms: placebo, diazoxide at 1 mg per kg of body weight (mpk) per dose, or diazoxide at 2 mpk per dose, for a total of 27 doses over 14 days. They will also consume heavy (deuterated) water for a total of 32 doses of 50 ml over 14 days to measure de novo lipogenesis, an exploratory endpoint. They will present for outpatient blood draws and saliva collections after an overnight fast at four time points during the study course. Additionally, participants will follow a weight-maintaining diet and wear a professional continuous glucose monitor (CGM) throughout.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Both investigators and participants will be blinded to the assigned treatment group. 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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults aged 18-70 years (using highly effective contraception if of childbearing potential)
- •Body mass index of 27-50 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 30 days of informed consent
- •Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified physician
- •Evidence of insulin resistance, represented by any or all of the following criteria:
- •i. Meeting either of the American Diabetes Association's definitions for prediabetes or IFG on screening labs:
- •Prediabetes: Hemoglobin A1c 5.7-6.4%
- •IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast
- •ii. Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
- •Fasting hyperinsulinemia (fasting insulin level ≥ 13 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. Documented weight loss of ≥ 5.0% of baseline within the previous 6 months
- •ii. Abnormal blood pressure (including on treatment, if prescribed) • Systolic blood pressure < 95 mm Hg or > 160 mm Hg, and/or
- •Diastolic blood pressure < 65 mm Hg or > 100 mm Hg
- •iii. Abnormal resting heart rate < 60 bpm or ≥ 100 bpm
- •Sinus brady- or tachycardia that has been appropriately evaluated and considered benign by the recruit's personal physician may be permitted at PI's discretion
- •iv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d):
- •Non-sinus rhythm
- •Significant corrected QT segment (QTc) prolongation (≥ 480 ms)
- •New or previously unknown ischaemic changes that persist on repeat EKG:
- •• ST segment elevations
- •• T-wave inversions
- •v. Laboratory evidence of diabetes mellitus:
- •Hemoglobin A1c ≥ 6.5%, and/or
- •Fasting plasma glucose ≥ 126 mg/dL
- •vi. Positive qualitative serum β-hCG (human chorionic gonadotropin, beta subunit; i.e., pregnancy test) in women of childbearing potential
- •vii. Liver function abnormalities
- •Transaminases (AST or ALT) > 3.0 x the upper limit of normal, and/or
- •Total bilirubin > 1.25 x the upper limit of normal
- •viii. Abnormal screening triglycerides > 500 mg/dL
- •ix. Abnormal screening serum electrolytes (any of the following) • Sodium, potassium, chloride, or bicarbonate levels 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
- •x. Uric acid level above the upper limit of normal
- •xi. Glucose-6-phosphate dehydrogenase below the lower limit of normal
- •COVID-19 precautions
- •i. Unwillingness to comply with masking requirements per hospital policy
- •ii. Active, documented COVID-19 at any time after screening
- •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)
- •Combined oral contraceptive pills taken daily, including during the study
- •Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study
- •Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study
- •Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
- •Etonogestrel/ethinyl estradiol vaginal rings (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 (tested by serum and/or urine β-hCG)
- •iii. Women currently breastfeeding
- •Concerns related to glucose metabolism
- •i. 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
- •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 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)
- •Concerns related to lipid metabolism
- 另有 77 项未显示
研究组 & 干预措施
Placebo
Participants will ingest a placebo solution (27 doses over 14 days) formulated to approximate the taste of diazoxide oral suspension. Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Placebo (Drug)
Placebo
Participants will ingest a placebo solution (27 doses over 14 days) formulated to approximate the taste of diazoxide oral suspension. Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: FreeStyle Libre Pro (Device)
Placebo
Participants will ingest a placebo solution (27 doses over 14 days) formulated to approximate the taste of diazoxide oral suspension. Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Deuterated water (2H2O/D2O) (Drug)
Diazoxide oral suspension, 1 mg per kg per dose
Participants will ingest diazoxide oral suspension at 1 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Diazoxide oral suspension, 1 mg per kg per dose (Drug)
Diazoxide oral suspension, 1 mg per kg per dose
Participants will ingest diazoxide oral suspension at 1 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: FreeStyle Libre Pro (Device)
Diazoxide oral suspension, 1 mg per kg per dose
Participants will ingest diazoxide oral suspension at 1 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Deuterated water (2H2O/D2O) (Drug)
Diazoxide oral suspension, 2 mg per kg per dose
Participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Diazoxide oral suspension, 2 mg per kg per dose (Drug)
Diazoxide oral suspension, 2 mg per kg per dose
Participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: FreeStyle Libre Pro (Device)
Diazoxide oral suspension, 2 mg per kg per dose
Participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.
干预措施: Deuterated water (2H2O/D2O) (Drug)
结局指标
主要结局
Fasting plasma/serum insulin (relative change)
时间窗: Up to Study Day 15
Measurement of fasting endogenous insulin levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: fold difference and/or ΔµIU/mL versus other groups).
Fasting plasma/serum insulin (absolute values)
时间窗: Up to Study Day 15
Measurement of fasting endogenous insulin levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: micro-international units \[µIU\] per mL).
Fasting plasma glucose (absolute values)
时间窗: Up to Study Day 15
Measurement of fasting plasma glucose levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: mg/dL).
Fasting plasma glucose (relative/change)
时间窗: Up to Study Day 15
Measurement of fasting plasma glucose during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: fold difference and/or Δmg/dL versus other groups).
次要结局
- Fasting serum or plasma free fatty acids (FFA) (absolute values)(Up to Study Day 15)
- Fasting serum/plasma apolipoprotein B (ApoB) (relative/change)(Up to Study Day 15)
- Fasting serum or plasma triglycerides (TG) (absolute values)(Up to Study Day 15)
- Fasting serum/plasma triglycerides (TG) (relative/change)(Up to Study Day 15)
- Fasting serum or plasma free fatty acids (FFA) (relative/change)(Up to Study Day 15)
- Continuous glucose monitoring (CGM) profile(Up to Study Day 15)
- Fasting serum/plasma apolipoprotein B (ApoB) (absolute values)(Up to Study Day 15)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University