Effect of Hyperglycemia on Microvascular Perfusion in Healthy Adults

Study Overview
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Brief Summary
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The investigators are studying the effects of Hyperglycemia on vascular function and insulin sensitivity on healthy adults

Detailed Description
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The investigators will study 22 healthy subjects (18-35 yrs) four times as follows: Saline + Octreotide + euglycemia; Octreotide + hyperglycemia; Octreotide + hyperglycemia + insulin clamp and Octreotide + Euglycemia + insulin clamp. The sequence of admissions will be assigned randomly. The investigators will assess function in conduit (pulse wave velocity-PWV, augmentation index-AI and flow-mediated dilation-FMD), resistance (post-ischemic flow velocity-PIFV) and heart and skeletal muscle microvascular (contrast enhanced ultrasound-CEU) vessels. This work will: a) identify whether vascular stiffness and indices of NO action are impaired throughout the arterial tree with hyperglycemia.

Official Title
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Effect of Hyperglycemia on Microvascular Perfusion in Healthy Adults

Conditions
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Vascular Stiffness, Insulin Sensitivity

Intervention / Treatment
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* Drug: Octreotide
* Drug: Insulin
* Drug: Dextrose 20% solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy with no chronic illness Age 18-35 Normal BMI (18-25) Normal screening labs or no clinically significant values Exclusion Criteria: First degree relative with Type 2 Diabetes Smoking presently or in the past 6 months Medications that affect the vasculature Overweight or other indications of insulin resistance Elevated LDL cholesterol > 160 Elevated BP > 140/90 History of congestive heart failure, ischemic heart disease, severe pulmonary disease, liver or kidney disease, bleeding disorders Any vascular disease such as myocardial infarction, stroke, peripheral vascular disease Presence of an intracardiac or intrapulmonary shunt (we will screen for this by auscultation during the physical exam by PI). Pregnant or breastfeeding. Known hypersensitivity to perflutren (contained in Definity)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each subject is studied 4 times in a randomized sequential order
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Octreotide- Euglycemia<br>octreotide is 30 ng/kg/min x 240 min insulin 0.15mU/kg/min x 240 min Dextrose 20% at variable rate to maintain euglycemia for 240 min | Drug: Octreotide<br>* we are using it to block insulin secretion from the pancreas<br>Drug: Insulin<br>* we are using to replace basal insulin and in two protocols to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20% solution<br>* We are using dextrose to maintain glycemia level<br>|
| Active Comparator: Octreotide - Euglycemia- insulin clamp<br>octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 210 min insulin 1.0mU/kg/min x 120 min Dextrose 20% at variable rate to maintain euglycemia for 330 min | Drug: Octreotide<br>* we are using it to block insulin secretion from the pancreas<br>Drug: Insulin<br>* we are using to replace basal insulin and in two protocols to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20% solution<br>* We are using dextrose to maintain glycemia level<br>|
| Active Comparator: Octreotide- hyperglycemia<br>octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 330 min Dextrose 20% at variable rate to maintain euglycemia for 90 min Dextrose 20% at variable rate to maintain hyperglycemia for 240 min | Drug: Octreotide<br>* we are using it to block insulin secretion from the pancreas<br>Drug: Insulin<br>* we are using to replace basal insulin and in two protocols to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20% solution<br>* We are using dextrose to maintain glycemia level<br>|
| Active Comparator: Octreotide- hyperglycemia - insulin clamp<br>octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 210 min insulin 1.0mU/kg/min x 120 min Dextrose 20% at variable rate to maintain euglycemia for 90 min Dextrose 20% at variable rate to maintain hyperglycemia for 240 min | Drug: Octreotide<br>* we are using it to block insulin secretion from the pancreas<br>Drug: Insulin<br>* we are using to replace basal insulin and in two protocols to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20% solution<br>* We are using dextrose to maintain glycemia level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Flow Mediated Dilation (FMD) Between Baseline and After 2 Hour Insulin Clamp | Flow mediated dilation measures the change in brachial diameter in response to 5 minutes of ischemia using B-mode ultrasound. It provides an index of nitric oxide generation by the endothelium . | baseline and after 2 hour insulin clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Augmentation Index Between Baseline and After 2 Hour Insulin Clamp | The augmentation index (AIx) measured at the radial artery is a measure of systemic arterial stiffness, and is defined as the ratio of augmentation (Δ P) to central pulse pressure and expressed as percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Higher percentages indicate increased arterial stiffness. | baseline and after 2 hour insulin clamp | 
| Change in Pulse Wave Velocity (PWV) Between Baseline and After 2 Hour Insulin Clamp | The time required for a blood pressure wave to travel from the carotid to the femoral artery was measured in meter/sec. This is a measurement of central artery stiffness. Higher numbers indicate stiffer vessels | baseline and after 2 hour insulin clamp |