Effect of GLP-1 on Microvascular Insulin Responses in Type 1 Diabetes

Study Overview
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Brief Summary
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GLP-1 increases skeletal and cardiac microvascular perfusion and improves insulin's microvascular responses in human subjects with T1DM, leading to improved metabolic insulin responses, endothelial function, and increased muscle oxygenation

Detailed Description
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The proposed study will determine the effect of GLP-1 infusion on microvascular perfusion and microvascular insulin responses in both skeletal and cardiac muscle microvasculature in humans with T1DM. The investigators will study 20 participants with T1DM using a state-of-the-art technology, contrast enhanced ultrasound (CEU), to assess whether GLP-1 augments skeletal and cardiac microvascular blood flow (MBF) as a representation of microvascular perfusion, flow-mediated dilation (FMD) as a measurement of endothelial function, and augmentation index (AI) and pulse wave velocity (PWV) as surrogates for large vessel compliance. The investigators will use the combined CEU and euglycemic-hyperinsulinemic clamp approach to determine if microvascular and metabolic IR improves as a result.

Official Title
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Effect of GLP-1 on Microvascular Insulin Responses in Type 1 Diabetes

Conditions
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Type 1 Diabetes, Insulin Sensitivity/Resistance

Intervention / Treatment
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* Drug: GLP-1
* Drug: Insulin
* Drug: Dextrose 20 % in Water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of type 1 diabetes, duration > 1 year Age 18-40 years HbA1c < 8.5% BMI >/=18, <30 kg/m2 Using insulin for diabetes treatment only On stable regimen of non-diabetic medications for the last 6 months, excluding oral contraceptives (OCP) All screening labs within normal limits or not clinical significant Exclusion Criteria: 1) Pregnancy or currently breastfeeding 2) Smoking history within 6 months 3) History of microvascular (microalbuminuria, retinopathy, neuropathy) or macrovascular diabetes complications (coronary artery disease, stroke, peripheral vascular disease) 4) Taking vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha-blockers) 5) OCP use within 3 months or 1 month if menses has subsequently occurred 6) Known hypersensitivity to perflutren (contained in Definity© contrast) 7) Screening O2 saturation<90% 8) Anemia (hemoglobin <12 g/dL in women, hemoglobin <13 g/dL in men) 9) Diabetic ketoacidosis (DKA) on presentation to screening visits or study admission days -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Parallel Assignment
Interventional Model Description: Each subject is studied 3 times in randomized order
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GLP-1<br>GLP-1 infusion 1.2 pmol/kg/min for 150 min | Drug: GLP-1<br>* glucagon-like peptide 1<br>|
| Active Comparator: GLP-1 + Insulin clamp<br>GLP-1 infusion 1.2 pmol/kg/min for 150 min and insulin 1 mU/kg/min + Dextrose 20% at variable rate to maintain euglycemia for 120 min | Drug: GLP-1<br>* glucagon-like peptide 1<br>Drug: Insulin<br>* we are using to replace basal insulin and to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20 % in Water<br>* We are using Dextrose to maintain Euglycemia during the insulin clamp<br>|
| Active Comparator: Saline + Insulin clamp<br>Saline infusion at 30 ml/hr for 150 min and insulin 1 mU/kg/min + Dextrose 20% at variable rate to maintain euglycemia for 120 min. | Drug: Insulin<br>* we are using to replace basal insulin and to raise insulin concentrations during the insulin clamp<br>Drug: Dextrose 20 % in Water<br>* We are using Dextrose to maintain Euglycemia during the insulin clamp<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in microvascular blood volume between baseline and 2 hour insulin clamp | vascular measurement | baseline and after 2 hour insulin clamp | 
| change in insulin sensitivity between baseline and 2 hour insulin clamp | vascular measurement | baseline and after 2 hour insulin clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in augmentation index between baseline and 2 hour insulin clamp | vascular measurement | baseline and after 2 hour insulin clamp | 
| change in flow-mediated dilation between baseline and 2 hour insulin clamp | vascular measurement | baseline and after 2 hour insulin clamp | 
| change in pulse wave velocity between baseline and 2 hour insulin clamp | vascular measurement | baseline and after 2 hour insulin clamp |