The Gut Microbiome in Type 1 Diabetes and Mechanism of Metformin Action

Study Overview
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Brief Summary
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Obesity prevalence in persons with T1D has increased, which further complicates management and risk for complications. The proposed study is relevant to public health because it helps us understand the role of the gut microbiome in disease pathophysiology in T1D youth with obesity as well as potential mechanisms to modify disease.

Official Title
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The Gut Microbiome in Lean and Overweight Youth With Type 1 Diabetes and Novel Mechanism of Action of Metformin

Conditions
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Obesity, Type 1 Diabetes

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obese youth 11-18 years of age with T1D at time of enrollment. Lean youth 11-18 years of age with T1D at time of enrollment. Exclusion Criteria: Known monogenic forms of diabetes or Type 2 diabetes (confirmed clinically and by genetic/antibody testing). History of ongoing infection or antibiotic treatment within the past month; History of immune-compromise, recurrent infections, steroid intake (inhaled or oral forms) or other immunosuppressant use in the past 6 months. History of chronic gastrointestinal disease, possible or confirmed celiac disease; Participation in any research intervention trials within the past 3 months. History of treatment or use of metformin, a type 2 diabetes medication.

Ages Eligible for Study
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Minimum Age: 11 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The investigators will examine the differences in the gut microbiome between lean and obese youth with type 1 diabetes and then enroll the obese youth with type 1 diabetes into the clinical trial to receive metformin as an intervention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Comparison of microbiome by BMI Category<br>The gut microbiome and metabolites of 42 lean and 42 obese youth with type 1 diabetes will be evaluated cross-sectionally. | |
| Experimental: Metformin<br>This is a group of 30 youth with type 1 diabetes and obesity who will receive metformin for 6 months. | Drug: Metformin<br>* Metformin is an oral medication that improves insulin sensitivity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in the gut microbiome in lean and obese youth with type 1 diabetes | cross sectional comparison of stool microbiome using metagenomic sequencing data | 2 years | 
| Differences in the gut microbial metabolites in lean and obese youth with type 1 diabetes | The investigators will measure and compare the stool and serum short chain fatty acids using mass spectrometry | 2 years | 
| Differences in the gut microbial metabolites in lean and obese youth with type 1 diabetes | The investigators will measure and compare the stool and serum secondary bile acids using mass spectrometry | 2 years | 
| Changes in the gut microbiome in obese youth with type 1 diabetes in response to metformin | longitudinal comparison before and after taking metformin for 6 months, stool samples will be collected at baseline, 3 months and 6 months and sequenced for microbiome profile using metagenomic sequencing | 3 years | 
| Changes in the gut microbial metabolites in obese youth with type 1 in response to metformin | The investigators will measure and compare the stool and serum metabolites (short chain fatty acids and secondary bile acids) before, during and after 6 months of daily metformin therapy using mass spectrometry | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in measures of C-peptide as a measure of beta cell health in lean and obese T1D youth | The investigators will measure serum C-peptide to calculate a ratio of proinsulin to C-peptide as a marker of beta cell health. These measures will then be compared between the lean and obese T1D youth. | 2 years | 
| Differences in measures Proinsulin as a measure of beta cell health in lean and obese T1D youth | The investigators will measure serum proinsulin and calculate a ratio of proinsulin to C-peptide as a marker of beta cell health. These measures will then be compared between the lean and obese T1D youth. | 2 years | 
| Differences in measures of insulin sensitivity in lean and obese T1D youth | Insulin sensitivity will be assessed in individuals using the estimated insulin sensitivity score (eIS), which is based on waist circumference (cm), HbA1c (%) and triglycerides (mg/dl) | 2 years | 
| Changes in measures of C-peptide as a measure of beta cell health in obese T1D youth in response to metformin | Serum C-peptide will be used to calculate proinsulin to C-peptide ratio as a measure of beta cell health before and after metformin therapy | 3 years | 
| Changes in measures of proinsulin as a measure of beta cell health in obese T1D youth in response to metformin | Serum proinsulin will be used to calculate proinsulin to C-peptide ratio as a measure of beta cell health before and after metformin therapy | 3 years | 
| Changes in measures of insulin sensitivity in obese T1D youth in response to metformin | Estimated insulin sensitivity score will be used to assess response metformin therapy | 3 years | 
| Changes in measures of beta cell function using a timed mixed meal tolerance test | Participants in the metformin trial will undergo a standard 2-hour mixed meal tolerance test at baseline and after 6 months of oral metformin therapy | 3 years |