Human Models of Primary Hyperinsulinemia: Diazoxide Suppression Test (DzST) Pilot & Feasibility Study
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Fasting serum insulin
研究概览
简要总结
The goal of this study is to learn about how the hormone insulin controls blood sugar. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. People with obesity and high insulin levels will receive eight doses of diazoxide, a drug that suppresses the pancreas's production of insulin, and will have their fasting blood sugar and insulin levels checked daily while taking the drug.
详细描述
The investigators are interested in determining to what extent the hyperinsulinemia commonly associated with insulin resistance (IR) in those at risk for type 2 diabetes (T2D) is a primary phenomenon, rather than merely a secondary, compensatory response to IR. The study hypothesis is that some people with obesity and hyperinsulinemia exhibit a primary, non-compensatory hyperinsulinemia that may foment IR and its dysmetabolic sequelae. If this were the case, lowering insulin levels should not result in a proportional rise in blood glucose as might be expected if the hyperinsulinemia truly were purely compensatory. This hypothesis has been difficult to prove, however, because of the tight feedback mechanism between blood glucose and insulin secretion; under normal circumstances insulin secretion declines only alongside blood glucose. As such, an attempt to lower insulin levels independently of blood glucose will raise blood glucose and trigger further insulin secretion, negating the purpose of the experiment. In order to circumvent this feedback regulation of glucose-stimulated insulin secretion, the study team has developed a modification of the insulin suppression test (IST) called the "graded IST" (GIST) that suppresses endogenous insulin secretion with octreotide and then measures steady-state plasma glucose (SSPG) at both replacement euinsulinemia and hyperinsulinemia. It is expected that some people with high insulin levels at baseline will not demonstrate a prominent rise in SSPG even when their insulin levels are lowered. However, the GIST is a cumbersome procedure that is difficult to scale for larger study populations. As such, the investigators are also working to develop an outpatient diazoxide suppression test (DzST) that suppresses endogenous insulin secretion with the oral insulin anti-secretagogue diazoxide rather than octreotide, and will validate it against the incipient "gold-standard" GIST. GIST participants found to have evidence of primary hyperinsulinemia (i.e., euinsulinemic euglycemia or near-euglycemia despite baseline hyperinsulinemia) will, several weeks later, take diazoxide 3 mg/kg per dose, twice daily, for four days. The investigators will check fasting glucose and insulin levels daily at baseline and then after each of the four days of diazoxide administration. The investigators expect that suppression of insulin secretion with diazoxide will, in accordance with the GIST, lead to no significant rise in blood glucose in people who have true primary hyperinsulinemia.
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
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, aged 18-65 years
- •Body mass index of 30-45 kg/m2
- •Able to understand written and spoken English and/or Spanish
- •Fasting hyperinsulinemia (fasting serum insulin ≥ 13 μU/mL)
- •Completion of the graded insulin suppression test (GIST) protocol (Group H)
- •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
- •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 on GIST screening (or if on file, performed within previous 90 d):
- •Non-sinus rhythm
- •Heart conduction blocks
- •Previously unknown ischaemic changes that persist on repeat EKG:
- •ST elevations
- •T-wave inversions in a vascular distribution
- •Laboratory evidence of dysglycemia on GIST screening:
- •Hemoglobin A1c ≥ 5.7%, and/or
- •Fasting plasma glucose ≥ 100 mg/dL
- •Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential (both on the day of screening and on the first day of the DzST, prior to receipt of diazoxide doses)
- •Positive urine drug screen during GIST screening or on first day of DzST, except for lawfully prescribed medications and/or marijuana, provided that participant agrees to refrain from marijuana use during the period that they refrain from alcohol.
- •Liver function abnormalities (either of the following) on GIST screening:
- •Transaminases (AST or ALT) > 3.0 x the upper limit of normal
- •Total bilirubin > 1.25 x the upper limit of normal
- •These exclusion criteria may be waived if the recruit's personal hepatologist approves an exception
- •Abnormal screening serum electrolytes (any of the following) on GIST screening:
- •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
- •Uric acid level above the upper limit of normal
- •Women currently pregnant, measured by serum and/or urine β-hCG at DzST screening (and on first study visit of DzST)
- •Women currently breastfeeding
- •History of having met any of the American Diabetes Association's definitions of prediabetic state or diabetes mellitus (i.e., overt diabetes):
- •Hemoglobin A1c ≥ 5.7%, 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
- •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, 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
- •Pancreatic pathology, including but not limited to:
- •Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones
- •Chronic pancreatitis
- •History of acute pancreatitis within the past 5 years
- •Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
- •Atherosclerotic cardiovascular disease
- •Stable or unstable angina
- •Myocardial infarction
- •Ischaemic or hemorrhagic stroke
- •Peripheral arterial disease (claudication)
- •Use of dual antiplatelet therapy
- •History of percutaneous coronary intervention
- •Heart rhythm abnormalities (non-sinus)
- •Congestive heart failure of any New York Heart Association class
- •Severe valvular heart disease (e.g., aortic stenosis)
- 另有 38 项未显示
研究组 & 干预措施
Diazoxide
Subjects will take diazoxide oral suspension at 3 mg/kg per dose for 4 days (total of 8 doses)
干预措施: Diazoxide, 3 mg/kg per dose (Drug)
结局指标
主要结局
Fasting serum insulin
时间窗: Baseline and after 4 days of diazoxide treatment
Serum insulin level after overnight fast (units: µU/mL)
Fasting plasma glucose
时间窗: Baseline and after 4 days of diazoxide treatment
Plasma glucose level after overnight fast (units: mg/dL)
次要结局
- Fasting serum C-peptide(Baseline and after 4 days of diazoxide treatment)
- Fasting serum triglyceride(Baseline and after 4 days of diazoxide treatment)
- Fasting plasma free fatty acids (FFA)(Baseline and after 4 days of diazoxide treatment)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University