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

Study Overview
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Brief Summary
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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.

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

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

Intervention / Treatment
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* Drug: Metformin Hcl 1000Mg Tab
* Drug: Aminohippurate Sodium 20 % Injection
* Drug: Iohexol 300 Mg/mL Injectable Solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin plus automated insulin delivery system<br>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<br>* Agent used to modify insulin sensitivity<br>* Other names: Riomet;Drug: Aminohippurate Sodium 20 % Injection<br>* Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance<br>* Other names: Aminohippuric acid;Drug: Iohexol 300 Mg/mL Injectable Solution<br>* Diagnostic aid/agent used to measure glomerular filtration rate<br>* Other names: Omnipaque 300;|
| Placebo Comparator: Placebo plus automated insulin delivery system<br>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<br>* Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance<br>* Other names: Aminohippuric acid;Drug: Iohexol 300 Mg/mL Injectable Solution<br>* Diagnostic aid/agent used to measure glomerular filtration rate<br>* Other names: Omnipaque 300;Drug: Placebo<br>* Identical to Metformin Hcl 1000Mg Tab but without metabolic effects<br>|
| Other: Multiple daily insulin injections plus continuous glucose monitor<br>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<br>* Diagnostic aid/agent used to measure renal plasma flow and calculate renal vascular resistance<br>* Other names: Aminohippuric acid;Drug: Iohexol 300 Mg/mL Injectable Solution<br>* Diagnostic aid/agent used to measure glomerular filtration rate<br>* Other names: Omnipaque 300;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Youth, Insulin sensitivity, Cardiovascular function, Diabetic kidney disease