Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

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.

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).

Eligibility Criteria:
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