Cardiovascular Diseases, Diabetic Kidney Disease, Endothelial Dysfunction, Insulin Sensitivity, Type 1 Diabetes
Conditions
Keywords
Type 1 diabetes, Youth, Insulin sensitivity, Cardiovascular function, Diabetic kidney disease
Brief summary
Diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in people with type 1 diabetes and are exacerbated with longer duration of diabetes and time outside goal glycemic range. Yet, type 1 diabetes is a complex disease with pathophysiology that extends beyond beta-cell injury and insulin deficiency to include insulin resistance and renal vascular resistance, factors that accelerate cardiovascular disease risk. We have shown that metformin improved peripheral insulin sensitivity and vascular stiffness in youth with type 1 diabetes on multiple daily insulin injections or standard insulin pumps. However, metformin's effect on kidney and endothelial outcomes, and the effects of type 1 diabetes technologies, with or without metformin, on any cardiovascular or kidney outcome, remains unknown. Automated insulin delivery systems combine an insulin pump, continuous glucose monitor, and control algorithm to modulate background insulin delivery and decrease peripheral insulin exposure while improving time in target range and reducing hypoglycemia. We hypothesize that automated insulin delivery systems, particularly when combined with metformin, may modulate renal vascular resistance and insulin sensitivity, thereby impacting cardiometabolic function. MANATEE-T1D is a randomized, double-blind, placebo-controlled trial of 4 months of metformin 2,000 mg daily in 40 youth aged 12-25 years with type 1 diabetes on automated insulin delivery systems vs. 20 control youth with type 1 diabetes on multiple daily injections plus a continuous glucose monitor or an insulin pump in manual mode plus a continuous glucose monitor which will assess for changes in calculated renal vascular resistance and gold standard measures of whole-body and adipose insulin sensitivity, arterial stiffness, and endothelial function.
Interventions
DRUGMetformin Hcl 1000Mg Tab
Agent used to modify insulin sensitivity
DRUGAminohippurate Sodium 20 % Injection
Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance
DRUGIohexol 300 Mg/mL Injectable Solution
Diagnostic aid/agent used to measure glomerular filtration rate
DRUGPlacebo
Identical to Metformin Hcl 1000Mg Tab but without metabolic effects
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Colorado, Denver
Kalie Tommerdahl
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* T1D and using an automated insulin delivery system or multiple daily insulin injections/manual insulin pump plus continuous glucose monitor for \> 6 months * Age 12-25 years * Use of an automated insulin delivery system or multiple daily insulin injections plus a continuous glucose monitor or an insulin pump in manual mode plus a continuous glucose monitor for \> 6 months * Hemoglobin A1c \< 11% * No recent episodes of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS) (within 30 days) * Pubertal (Tanner stage ≥ 2) * Weight \> 54 kg and BMI \> 5th percentile for age and sex
Exclusion criteria
* Blood pressure \> 140/90 mm Hg * Hemoglobin \< 9 g/dL * Estimated glomerular filtration rate \< 60 mL/min/1.73 m2 or serum creatinine \> 1.2 mg/dL or history of urinary albumin to creatinine ratio ≥ 300mg/g or history of acute kidney injury * Use of anti-diabetic agents except insulin, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB's), diuretics, daily non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin, sulfonamides, procaine, thiazosulfone or probenecid * Seafood or iodine allergy * Pregnancy or breast feeding for females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal vascular resistance | 4 months | Renal plasma flow will be measured by para-aminohippurate clearance and used to calculate renal vascular resistance |
| Glomerular filtration rate | 4 months | Measured by iohexol clearance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arterial stiffness | 4 months | Measured by SphygmoCor |
| Insulin sensitivity | 4 months | Measured by hyperinsulinemic-euglycemic clamp |
Countries
United States
Contacts
Primary ContactKalie Tommerdahl, MD
Outcome results
None listed