Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Diabetes Mellitus, Type 1 Clinical Trial

— KML002  

Official title:

Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05478707
• Other study ID #: 210198
• Status: Recruiting
• Phase: Phase 2
• Start date: October 5, 2023
• Est. completion date: November 30, 2027

Study information

• Verified date: November 2023
• Source: University of Virginia
• Contact: Kaitlin Love, MD
• Phone: 434-924-9651
• Email: KML2W[@]hscmail.mcc.virginia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 64
• Est. completion date: November 30, 2027
• Est. primary completion date: November 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Endothelial Dysfunction

Intervention

Drug:
• Dulaglutide
GLP1-RA
• Placebo
Saline placebo

Behavioral:
• exercise training
supervised high intensity interval training

Locations

Country	Name	City	State
United States	University of Virginia	Charlottesville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
University of Virginia

Country where clinical trial is conducted

United States, 

References & Publications (58)

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* Note: There are 58 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Cardiorespiratory fitness, maximum consumption of oxygen (VO2max)	Assessed by cycle ergometer exercise testing.	At baseline and after 14 weeks of treatment
Secondary	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.