Mechanisms of Cerebrovascular Control: Acute Insulin Surges Lead to Brain Hypoperfusion in Human Metabolic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 59
- 试验地点
- 1
- 主要终点
- Change in cerebrovascular blood flow in response to NOS inhibition.
研究概览
简要总结
The objective of this study is to identify insulin-specific cerebral blood flow (CBF) control mechanisms, and establish cerebrovascular responsive baseline in younger (18-45 yrs) metabolic syndrome adults (MetSyn) who are at substantial risk of stroke and other types of cardiovascular mortality even if they never develop diabetes. The central hypothesis is that vasodilator actions of insulin are impaired in MetSyn due to loss of dilator and gain of constrictor signals. This study will focus on 2 mechanisms that likely limit CBF in MetSyn: 1) Disruption of nitric oxide (NO) vasodilation, and 2) Exaggerated endothelin (ET-1) constriction. Three specific aims will be addressed: Aim 1: To test the hypothesis that physiologic surges of insulin acutely increase CBF in young adults, but adults with MetSyn exhibit paradoxical insulin-mediated vasoconstriction. Aim 2: To test the hypotheses that key mechanisms responsible for poor CBF in MetSyn are shifts in NO and ET-1 signaling. Specifically, in healthy controls, NO mediates robust dilation, with little to no ET-1 constriction. In contrast, adults with MetSyn exhibit uncoupled NO synthase (NOS) and exaggerated ET-1 constriction. Aim 3: To test the hypothesis that insulin regulation of CBF is regionally distinct (e.g. Middle Cerebral Artery (MCA) reactive than Anterior Cerebral Artery (ACA) or basilar), and the negative effects of insulin resistance (IR) are similarly regionally specific.
详细描述
Introduction It is widely accepted that insulin resistance in MetSyn increases the risk of cerebrovascular disease (CVD) and stroke. Additionally, MetSyn is associated with cognitive impairments and increased risk of neurodegenerative diseases. Despite strong association of poor cerebrovascular health in MetSyn, the cerebral blood flow (CBF) response to acute insulin surges in humans remains largely unexplored. Cerebrovascular dysfunction in response to insulin and potential mechanism(s) that attenuate CBF may not only highlight the central underpinnings of the pathophysiology of stroke and CVD, it may provide key insights to understanding cognitive decline strongly linked to older individuals with MetSyn. Therefore, establishing the mechanisms of insulin-mediated cerebrovascular control are not only important for decreasing mortality in MetSyn, it may be profoundly important to maintaining brain health. Insulin-meditated vasodilation is largely a vascular endothelium-dependent process. Elegant experiments using animal models suggests insulin resistance disrupts six endothelial signaling pathways, with the strongest evidence implicating a loss of nitric oxide (NO) vasodilation, and exaggerated endothelin (ET-1) constriction. The literature indicates that in MetSyn, a spike in insulin leads to vasoconstriction and cerebral hypoperfusion. These findings are directionally opposite from no change or insulin-mediated vasodilation and increase in CBF reported in the literature. Evidence suggests that uncoupled function of nitric oxide synthase (NOS) leads to unfavorable balance between NO, reactive oxygen species, and ET-1. Normally, stimulation of insulin receptor on the vascular endothelium should provide an environment in which NOS manufactures NO leading to vasodilation and inhibition of ET-1. Instead, in MetSyn insulin stimulates the vasoconstrictor ET-1 to a greater extent while, NOS is uncoupled generating more reactive oxygen species that scavenges the NO that is generated leading to a greater vasoconstrictor signal rather than vasodilation.
Specific Aims/Study Objectives
Specific Aims:
The central hypothesis is that vasodilator actions of insulin are already impaired in metabolic syndrome due to loss of dilator and gain of constrictor signals. Cerebral vasodilation to insulin is largely endothelium-dependent. Emerging evidence in animal models suggests insulin resistance disrupts at least six endothelial signaling pathways that could be potential targets, and this proposal focuses on two that most likely reduce CBF in MetSyn: 1) Loss of nitric oxide (NO) vasodilation, and 2) Exaggerated endothelin (ET-1) constriction. These experiments will address three specific aims:
Aim 1: To test the hypothesis that physiologic surges of insulin acutely increase CBF in young adults, but adults with MetSyn exhibit paradoxical insulin-mediated vasoconstriction.
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
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •(Metabolic Syndrome):
- •Participants must qualify under the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) definition of metabolic syndrome as modified by the American Heart Association and International Diabetes Federation. Participants must meet 3 or more of the following 5 criteria:
- •fasting glucose ≥ 100 mg/dL,
- •fasting triglycerides ≥ 150 mg/dL,
- •elevated blood pressure (≥ 130 systolic and/or ≥ 85 diastolic mmHg),
- •waist circumference at the iliac crest > 102 cm (men) or ≥ 88 cm (women).
排除标准
- •Fasting glucose ≥ 126 mg/dL
- •Having ≥1- ≤ 2 of the above criteria for MetSyn.
- •Personal medical history of coronary artery disease, stroke, heart attack, heart valve disease, congestive heart failure, previous heart surgery, history of lung disease (Note: asthma that is not currently active and being treated is NOT considered an exclusion criteria) or peripheral artery disease, or history of renal/kidney and liver/hepatic disease.
- •Taking metabolic medications (insulin-sensitizing, lipid-lowering medications, etc.) or any medications for cardiovascular-related issues will be excluded.
- •Current use of tobacco (i.e. smoke, smokeless, and vapor). If participant has used tobacco products ≤10 in the last year and ≤1 time in the last month, he or she will still be considered eligible.
- •Females will be excluded if pregnant, lactating, or postmenopausal.
- •Participants having any contraindications of having an MRI (such as claustrophobia, metallic implant, etc.).
- •Participant has an abnormality or contraindication to study participation, which is not covered in the eligibility criteria.
研究组 & 干预措施
Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: NOS Inhibition (Drug)
Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: NOS Inhibition Placebo (Drug)
Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: 3 Tesla MRI (Device)
Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Intravenous Catheter (Device)
Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Oral Glucose Tolerance Test (Other)
Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: ET-1 Inhibition (Drug)
Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: 3 Tesla MRI (Device)
Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Intravenous Catheter (Device)
Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Oral Glucose Tolerance Test (Other)
Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: ET-1 Inhibition Placebo (Drug)
Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: NOS Inhibition (Drug)
Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: NOS Inhibition Placebo (Drug)
Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: 3 Tesla MRI (Device)
Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Intravenous Catheter (Device)
Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Oral Glucose Tolerance Test (Other)
Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: ET-1 Inhibition (Drug)
Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: 3 Tesla MRI (Device)
Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Intravenous Catheter (Device)
Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: Oral Glucose Tolerance Test (Other)
Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
干预措施: ET-1 Inhibition Placebo (Drug)
结局指标
主要结局
Change in cerebrovascular blood flow in response to NOS inhibition.
时间窗: Through study completion (an average of 2 years)
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.
Change in cerebrovascular blood flow in response to ET-1 inhibition.
时间窗: Through study completion (an average of 2 years)
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.
次要结局
未报告次要终点