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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lucy Hall, MS; Phone Number: 720-777-2692; Email: Lucy.Hall@childrenscolorado.org
• Study Contact Backup: Name: Kalie Tommerdahl, MD; Phone Number: 720-777-5898; Email: Kalie.Tommerdahl@childrenscolorado.org

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Campus
      • Contact: Lucy Hall, MS; Phone Number: 720-777-2692; Email: Lucy.Hall@childrenscolorado.org
      • Contact: Kalie Tommerdahl, MD; Phone Number: 720-777-6128; Email: Kalie.Tommerdahl@childrenscolorado.org
      • Principal Investigator: Kalie Tommerdahl, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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: Glucophage; Glumetza; Fortamet; Riomet; Drug: Aminohippurate Sodium 20 % Injection; Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance; Other Names: Para-aminohippurate; Aminohippuric acid; Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL); 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: Para-aminohippurate; Aminohippuric acid; Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL); 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: Para-aminohippurate; Aminohippuric acid; Sodium 4-amino hippurate (PAH) injection 20% (2g/10 mL); Drug: Iohexol 300 Mg/mL Injectable Solution; Diagnostic aid/agent used to measure glomerular filtration rate; Other Names: Omnipaque 300

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial stiffness	Measured by SphygmoCor	4 months
Endothelial function	Measured by EndoPAT	4 months
Insulin sensitivity	Measured by hyperinsulinemic-euglycemic clamp	4 months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: September 22, 2021
• First Posted (Actual): October 4, 2021

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 21, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Type 1 diabetes; Cardiovascular function; Insulin sensitivity; Diabetic kidney disease; Youth
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Hyperinsulinism; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hypersensitivity; Cardiovascular Diseases; Diabetes Mellitus; Kidney Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 21-3483; K23HL159292 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No