MANATEE-T1D: Metformin ANd AutomaTEd Insulin Delivery System Effects on Renal Vascular Resistance, Insulin Sensitivity, and Cardiometabolic Function in Youth With Type 1 Diabetes

NCT ID: NCT05065372

Last Updated: 2025-06-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-01
• Study Completion Date: 2027-07-31

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.

Conditions

Type 1 Diabetes; Diabetic Kidney Disease; Cardiovascular Diseases; Endothelial Dysfunction; Insulin Sensitivity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Metformin plus automated insulin delivery system

Some participants with type 1 diabetes using an automated insulin delivery system will be randomized to receive treatment with metformin and will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Group Type: ACTIVE_COMPARATOR

Metformin Hcl 1000Mg Tab

Intervention Type: DRUG

Agent used to modify insulin sensitivity

Aminohippurate Sodium 20 % Injection

Intervention Type: DRUG

Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance

Iohexol 300 Mg/mL Injectable Solution

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular filtration rate

Placebo plus automated insulin delivery system

Some participants with type 1 diabetes using an automated insulin delivery system will be randomized to receive treatment with a placebo pill which is identical in appearance to the metformin pill and will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Group Type: PLACEBO_COMPARATOR

Aminohippurate Sodium 20 % Injection

Intervention Type: DRUG

Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance

Iohexol 300 Mg/mL Injectable Solution

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular filtration rate

Placebo

Intervention Type: DRUG

Identical to Metformin Hcl 1000Mg Tab but without metabolic effects

Multiple daily insulin injections or manual insulin pump plus continuous glucose monitor

Participants with type 1 diabetes using multiple daily injections or an insulin pump in manual mode plus a continuous glucose monitor will not be randomized to receive medication treatment but will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Group Type: OTHER

Aminohippurate Sodium 20 % Injection

Intervention Type: DRUG

Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance

Iohexol 300 Mg/mL Injectable Solution

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular filtration rate

Interventions

Metformin Hcl 1000Mg Tab

Agent used to modify insulin sensitivity

Intervention Type: DRUG

Aminohippurate Sodium 20 % Injection

Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance

Intervention Type: DRUG

Iohexol 300 Mg/mL Injectable Solution

Diagnostic aid/agent used to measure glomerular filtration rate

Intervention Type: DRUG

Placebo

Identical to Metformin Hcl 1000Mg Tab but without metabolic effects

Intervention Type: DRUG

Other Intervention Names

Fortamet; Glucophage; Glumetza; Riomet; Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL); Para-aminohippurate; Aminohippuric acid; Omnipaque 300

Eligibility Criteria

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

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

Kalie Tommerdahl

OTHER

Sponsor Role: lead

Responsible Party

Kalie Tommerdahl

Associate Professor of Pediatric Endocrinology

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Children's Hospital Colorado/University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Site Status: ACTIVE_NOT_RECRUITING

Seattle Children's Hospital

Seattle, Washington, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kalie Tommerdahl, MD

Role: CONTACT

ktomme@uw.edu

(206) 616-9015

Facility Contacts

Kalie Tommerdahl, MD

Role: primary

ktomme@uw.edu

(206) 616-9015

Other Identifiers

K23HL159292

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21-3483

Identifier Type: -

Identifier Source: org_study_id