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

Phase 1

Recruiting

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

• Registration Number: NCT05065372
• Lead Sponsor: University of Colorado, Denver

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 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-09-13
• Study First Submitted QC: 2021-09-22
• Study First Posted: 2021-10-04
• Study Start: 2022-07-01
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-12
• Last Update Posted: 2024-06-13
• Primary Completion: 2026-01-01
• Study Completion: 2026-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Youth with pancreatic antibody positive type 1 diabetes
• 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
• 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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo plus automated insulin delivery system	Placebo	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.
Multiple daily insulin injections plus continuous glucose monitor	Aminohippurate Sodium 20 % Injection	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.
Metformin plus automated insulin delivery system	Metformin Hcl 1000Mg Tab	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.
Placebo plus automated insulin delivery system	Iohexol 300 Mg/mL Injectable Solution	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.
Multiple daily insulin injections plus continuous glucose monitor	Iohexol 300 Mg/mL Injectable Solution	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.
Metformin plus automated insulin delivery system	Aminohippurate Sodium 20 % Injection	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.
Metformin plus automated insulin delivery system	Iohexol 300 Mg/mL Injectable Solution	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.
Placebo plus automated insulin delivery system	Aminohippurate Sodium 20 % Injection	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Arterial stiffness	4 months	Measured by SphygmoCor
Endothelial function	4 months	Measured by EndoPAT
Insulin sensitivity	4 months	Measured by hyperinsulinemic-euglycemic clamp

Trial Locations

Locations (1)

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States