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

Sponsor

University of Colorado, Denver (Other)

Overall Status

Recruiting

CT.gov ID

NCT05065372

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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 12-21 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 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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Diabetic Kidney Disease Cardiovascular Diseases Endothelial Dysfunction Insulin Sensitivity	Drug: Metformin Hcl 1000Mg Tab Drug: Aminohippurate Sodium 20 % Injection Drug: Iohexol 300 Mg/mL Injectable Solution Drug: Placebo	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jul 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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 additional to assessments of cardiovascular and endothelial function.	Drug: Metformin Hcl 1000Mg Tab Agent used to modify insulin sensitivity Other Names: Fortamet Glucophage Glumetza Riomet Drug: Aminohippurate Sodium 20 % Injection Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance Other Names: Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL) Para-aminohippurate Aminohippuric acid Drug: Iohexol 300 Mg/mL Injectable Solution Diagnostic aid/agent used to measure glomerular filtration rate Other Names: Omnipaque 300
Placebo Comparator: 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 additional to assessments of cardiovascular and endothelial function.	Drug: Aminohippurate Sodium 20 % Injection Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance Other Names: Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL) Para-aminohippurate Aminohippuric acid Drug: Iohexol 300 Mg/mL Injectable Solution Diagnostic aid/agent used to measure glomerular filtration rate Other Names: Omnipaque 300 Drug: Placebo Identical to Metformin Hcl 1000Mg Tab but without metabolic effects
Other: Multiple daily insulin injections plus continuous glucose monitor Participants with type 1 diabetes using multiple daily injections 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 additional to assessments of cardiovascular and endothelial function.	Drug: Aminohippurate Sodium 20 % Injection Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance Other Names: Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL) Para-aminohippurate Aminohippuric acid Drug: Iohexol 300 Mg/mL Injectable Solution Diagnostic aid/agent used to measure glomerular filtration rate Other Names: Omnipaque 300

Arm

Intervention/Treatment

Active Comparator: 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 additional to assessments of cardiovascular and endothelial function.

Drug: Metformin Hcl 1000Mg Tab

Agent used to modify insulin sensitivity

Other Names:

Fortamet

Glucophage

Glumetza

Riomet

Drug: Aminohippurate Sodium 20 % Injection

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

Other Names:

Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL)

Para-aminohippurate

Aminohippuric acid

Drug: Iohexol 300 Mg/mL Injectable Solution

Diagnostic aid/agent used to measure glomerular filtration rate

Other Names:

Omnipaque 300

Placebo Comparator: 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 additional to assessments of cardiovascular and endothelial function.

Drug: Aminohippurate Sodium 20 % Injection

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

Other Names:

Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL)

Para-aminohippurate

Aminohippuric acid

Drug: Iohexol 300 Mg/mL Injectable Solution

Diagnostic aid/agent used to measure glomerular filtration rate

Other Names:

Omnipaque 300

Drug: Placebo

Identical to Metformin Hcl 1000Mg Tab but without metabolic effects

Other: Multiple daily insulin injections plus continuous glucose monitor

Participants with type 1 diabetes using multiple daily injections 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 additional to assessments of cardiovascular and endothelial function.

Drug: Aminohippurate Sodium 20 % Injection

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

Other Names:

Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL)

Para-aminohippurate

Aminohippuric acid

Drug: Iohexol 300 Mg/mL Injectable Solution

Diagnostic aid/agent used to measure glomerular filtration rate

Other Names:

Omnipaque 300

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

Arterial stiffness [4 months]
Measured by SphygmoCor
Endothelial function [4 months]
Measured by EndoPAT
Insulin sensitivity [4 months]
Measured by hyperinsulinemic-euglycemic clamp

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Youth with pancreatic antibody positive type 1 diabetes
Age 12-21 years
Use of an automated insulin delivery system or multiple daily insulin injections plus a continuous glucose monitor for > 6 months
Pubertal
Weight > 54 kg and BMI > 5th percentile for age and sex
Hemoglobin A1c < 11%
No recent episodes of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS)

Exclusion Criteria:

Blood pressure > 140/90 mm Hg
Anemia
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