KML002: Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Sponsor

University of Virginia (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05478707

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

We 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1 Endothelial Dysfunction	Drug: Dulaglutide Drug: Placebo Behavioral: exercise training	Phase 2

Detailed Description

In this study, 64 (n=42 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, we 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). We 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. We will assess for predictive relationships between microvascular perfusion and cardiorespiratory fitness (VO2max), insulin sensitivity (GIR), endothelial reactive oxygen species (ROS), and glycemic variability (GV).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Outcomes Assessor)

Masking Description:

Participants randomized to dulaglutide or placebo and study personnel who analyze data and instruct patients regarding insulin adjustments will be blinded to treatment allocation.

Primary Purpose:

Basic Science

Official Title:

Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Anticipated Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Saline subcutaneous injection, volume matched to dulaglutide, i.e. 0.5 mL weekly for 14 weeks	Drug: Placebo Saline placebo
Active Comparator: Dulaglutide 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 GLP1-RA
Active Comparator: Exercise training 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 supervised high intensity interval training

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Saline subcutaneous injection, volume matched to dulaglutide, i.e. 0.5 mL weekly for 14 weeks

Drug: Placebo

Saline placebo

Active Comparator: Dulaglutide

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

GLP1-RA

Active Comparator: Exercise training

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

supervised high intensity interval training

Outcome Measures

Primary Outcome Measures

Microvascular blood volume (MBV) [At baseline and after 14 weeks of treatment.]
Insulin mediated change in muscle microvascular blood volume (MBV). A measure of microvascular nitric oxide dependent endothelial function

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

History of type 1 diabetes, duration > 5 years
Age 18-40 years
HbA1c < 8.5%
BMI 19-27 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
Performing less than 150 minutes of moderate intensity physical activity or less than 70 minutes of high intensity physical activity per week (i.e. achieving less physical activity than recommended by the American Diabetes Association)

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