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

NCT05065372 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 21-3483K23HL159292
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

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

Keywords

Type 1 diabetes; Youth; Insulin sensitivity; Cardiovascular function; Diabetic kidney disease

Outcome Measures

Primary Outcomes (2)

• Renal vascular resistance

  Renal plasma flow will be measured by para-aminohippurate clearance and used to calculate renal vascular resistance

  4 months

• Glomerular filtration rate

  Measured by iohexol clearance

  4 months

Secondary Outcomes (2)

• Arterial stiffness

  4 months

• Insulin sensitivity

  4 months

Study Arms (3)

Metformin plus automated insulin delivery system

ACTIVE COMPARATOR

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.

Drug: Metformin Hcl 1000Mg Tab; Drug: Aminohippurate Sodium 20 % Injection; Drug: Iohexol 300 Mg/mL Injectable Solution

Placebo plus automated insulin delivery system

PLACEBO COMPARATOR

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.

Drug: Aminohippurate Sodium 20 % Injection; Drug: Iohexol 300 Mg/mL Injectable Solution; Drug: Placebo

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

OTHER

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.

Drug: Aminohippurate Sodium 20 % Injection; Drug: Iohexol 300 Mg/mL Injectable Solution

Interventions

Metformin Hcl 1000Mg Tab DRUG

Agent used to modify insulin sensitivity

Also known as: Fortamet, Glucophage, Glumetza, Riomet

Metformin plus automated insulin delivery system

Aminohippurate Sodium 20 % Injection DRUG

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

Also known as: Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL), Para-aminohippurate, Aminohippuric acid

Metformin plus automated insulin delivery system; Multiple daily insulin injections or manual insulin pump plus continuous glucose monitor; Placebo plus automated insulin delivery system

Iohexol 300 Mg/mL Injectable Solution DRUG

Diagnostic aid/agent used to measure glomerular filtration rate

Also known as: Omnipaque 300

Metformin plus automated insulin delivery system; Multiple daily insulin injections or manual insulin pump plus continuous glucose monitor; Placebo plus automated insulin delivery system

Placebo DRUG

Identical to Metformin Hcl 1000Mg Tab but without metabolic effects

Placebo plus automated insulin delivery system

Eligibility Criteria

• Age: 12 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kalie Tommerdahl: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• University of Colorado, Denver: collaborator

Study Sites (2)

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

Aurora, Colorado, 80045, United States

ACTIVE NOT RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98102, United States

RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetic Nephropathies; Cardiovascular Diseases; Insulin Resistance

Interventions

Metformin; p-Aminohippuric Acid; Injections; Iohexol

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Aminohippuric Acids; Hippurates; Benzamides; Amides; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Keto Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Drug Administration Routes; Drug Therapy; Therapeutics; Triiodobenzoic Acids; Iodobenzoates

Central Study Contacts

Kalie Tommerdahl, MD

CONTACT

(206) 616-9015; ktomme@uw.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatric Endocrinology

Study Record Dates

• First Submitted: September 13, 2021
• First Posted: October 4, 2021
• Study Start: July 1, 2022
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): July 31, 2027
• Last Updated: June 13, 2025

Record last verified: 2025-06

Locations

US (2)