Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Study Overview
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Brief Summary
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The investigators will test the hypothesis that, in adults with type 1 diabetes (T1D), glucagon-like peptide-1 receptor agonism (GLP-1RA, i.e. dulaglutide) and exercise training each enhance insulin-mediated skeletal muscle microvascular perfusion via attenuating endothelial oxidative stress and thereby improving endothelial function.

Detailed Description
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In this study, 64 (n=48 needed to complete) adult participants with type 1 diabetes will be randomized (1:1:1) to 14-weeks of one of 3 interventions: 1) dulaglutide, 2) placebo, or 3) exercise training. Participants will undergo two study admissions at baseline and 14 weeks. Prior to each admission, participants will wear a continuous glucose monitor (Dexcom G6 Professional) for 10 days to assess glycemic variability (GV). Prior to admissions, they will undergo cardiorespiratory fitness testing. On study admission days, participants will undergo an antecubital vein endothelial cell biopsy prior to commencing vascular testing. From the harvested endothelial cells, the investigators will quantify endothelial cell reactive oxygen species (ROS) and protein expression relevant to insulin-mediated endothelial function. Vascular testing will include contrast enhanced ultrasound of quadriceps muscle to determine microvascular blood volume (MBV). The investigators will also measure brachial artery flow mediated dilation (FMD). Quadriceps skeletal muscle oxygenation (HHb) will also be measured. These vascular and muscle oxygenation measurements will be conducted before and after a 120-minute euglycemic insulin clamp which will measure insulin sensitivity based on glucose infusion rate (GIR). This randomized, placebo-controlled study will assess whether GLP-1 receptor agonism with dulaglutide or exercise training improves insulin-mediated skeletal muscle microvascular perfusion. The investigators will assess for predictive relationships between microvascular perfusion and cardiorespiratory fitness (VO2max), insulin sensitivity (GIR), endothelial reactive oxygen species (ROS), and glycemic variability (GV).

Official Title
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Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1, Endothelial Dysfunction

Intervention / Treatment
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* Drug: Dulaglutide
* Drug: Placebo
* Behavioral: exercise training


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: History of type 1 diabetes, duration > 5 years Age 18-40 years HbA1c < 8.5% BMI 19-34.9 kg/m2 Using insulin for diabetes treatment only (multiple daily injections or insulin pump with or without sensor augmentation) On stable regimen of non-diabetic medications for the last 6 months All screening labs within normal limits or not clinically significant C-peptide <0.6 ng/ml Exclusion criteria: Pregnancy or currently breastfeeding Smoking history within 6 months History of microvascular (microalbuminuria, retinopathy, neuropathy) or macrovascular diabetes complications (coronary artery disease, stroke, peripheral vascular disease) as well as clinically significant cardiac arrhythmias or conduction disorders Taking vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha-blockers). Known hypersensitivity to perflutren (contained in Definity© contrast) Screening O2 saturation <90% Musculoskeletal condition preventing participation in exercise testing or exercise training Acute or unstable disease other than T1D Hypoglycemia unawareness (based on Clarke's questionnaire) History of gastroparesis, severe gastroesophageal reflux, pancreatitis, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 Anemia (hemoglobin <12 g/dL in women, hemoglobin <13 g/dL in men), eosinophilia (absolute eosinophil count >500 cells/microliter) leukopenia (total white blood cells <4,000 cells/microliter) Diabetic ketoacidosis (DKA) on presentation to screening visits or study admission days Hospital admission for DKA within 1 year

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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No

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Saline subcutaneous injection, volume matched to dulaglutide, i.e. 0.5 mL weekly for 14 weeks | Drug: Placebo<br>* Saline placebo<br>|
| Active Comparator: Dulaglutide<br>Dulaglutide (0.75 mg/0.5 mL weekly for 2 weeks, then 1.5 mg/0.5 mL weekly for 12 weeks) subcutaneous injection | Drug: Dulaglutide<br>* GLP1-RA<br>|
| Active Comparator: Exercise training<br>Supervised high intensity interval training on a stationary bicycle will be conducted 3 days per week for 14 weeks. Participants will warm up at low intensity for 3 min then repeat 1-min bouts of 100% peak power output followed by 1-min recovery at 50 W. Training will start with 6 intervals per session, increasing by 2 intervals every 2 weeks. Sessions will end with a 10-min cool-down. | Behavioral: exercise training<br>* supervised high intensity interval training<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular blood volume (MBV) | Insulin mediated change in muscle microvascular blood volume (MBV). A measure of microvascular nitric oxide dependent endothelial function | At baseline and after 14 weeks of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial artery flow mediated dilation (FMD) | Post-occlusive percent (%) change in diameter. A measure of conduit artery nitric oxide-dependent endothelial function. | At baseline and after 14 weeks of treatment | 
| Glucose infusion rate (GIR) | Mean GIR over the final 30 minutes of euglycemic insulin clamp; a measure of insulin sensitivity | At baseline and after 14 weeks of treatment | 
| Cardiorespiratory fitness, maximum consumption of oxygen (VO2max) | Assessed by cycle ergometer exercise testing. | At baseline and after 14 weeks of treatment | 
| Skeletal muscle oxygenation, deoxyhemoglobin (HHb) | Assessed by frequency domain multi-distance near-infrared spectroscopy (NIRS) monitor at the quadriceps muscle | At baseline and after 14 weeks of treatment. Measured before and after insulin clamp. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microvessels, oxidative stress, Dulaglutide, Glucagon-like peptide-1, Exercise therapy