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

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

Ovwerweight and 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 overweight and obesity as well as potential mechanisms to modify disease.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Type 1 Diabetes
• Intervention / Treatment: Drug: Metformin

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Heba M Ismail; Phone Number: 317-274-2114; Email: heismail@iu.edu
• Study Contact Backup: Name: HI Team; Phone Number: 317-274-2114; Email: hiteam@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University School of Medicine
      • Contact: Heba Ismail; Phone Number: 317-278-7856; Email: heismail@iu.edu
      • Contact: HI Team; Phone Number: 317-278-7042; Email: hiteam@iu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Overweight/obese youth 11-18 years of age with T1D at time of enrollment.
2. Lean youth 11-18 years of age with T1D at time of enrollment.

Exclusion Criteria:

1. Known monogenic forms of diabetes or Type 2 diabetes (confirmed clinically and by genetic/antibody testing).
2. History of ongoing infection or antibiotic treatment within the past month;
3. History of immune-compromise, recurrent infections, steroid intake (inhaled or oral forms) or other immunosuppressant use in the past 6 months.
4. History of chronic gastrointestinal disease and active within the past 6 months, possible or confirmed celiac disease.
5. Participation in any research intervention trials within the past 3 months.
6. History of treatment or use of metformin, a type 2 diabetes medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in the gut microbiome in lean and overweight/obese youth with type 1 diabetes	cross sectional comparison of stool microbiome using metagenomic sequencing data	Baseline
Differences in the gut microbial metabolites in lean and overweight/obese youth with type 1 diabetes	The investigators will measure and compare the stool and serum short chain fatty acids using mass spectrometry	Baseline
Differences in the gut microbial metabolites in lean and overweight/obese youth with type 1 diabetes	The investigators will measure and compare the stool and serum secondary bile acids using mass spectrometry	Baseline
Changes in the gut microbiome in overweight/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	Baseline, Month 3, and Month 6
Changes in the gut microbial metabolites in overweight/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	Baseline, Month 3, and Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline and Month 6
Differences in measures of C-peptide as a measure of beta cell health in lean and overweight/obeseT1D 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.	Baseline
Differences in measures Proinsulin as a measure of beta cell health in lean and overweight/obeseT1D 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.	Baseline
Differences in measures of insulin sensitivity in lean and overweight/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)	Baseline
Changes in measures of C-peptide as a measure of beta cell health in overweight/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	Baseline, Month 3, and Month 6
Changes in measures of proinsulin as a measure of beta cell health in overweight/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	Baseline, Month 3, and Month 6
Changes in measures of insulin sensitivity in overweight/obese T1D youth in response to metformin	Estimated insulin sensitivity score will be used to assess response metformin therapy	Baseline, Month 3, and Month 6

Collaborators and Investigators

• Sponsor: Heba M. Ismail
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2022
• Primary Completion (Estimated): November 2, 2026
• Study Completion (Estimated): November 2, 2026

Study Registration Dates

• First Submitted: May 31, 2022
• First Submitted That Met QC Criteria: June 8, 2022
• First Posted (Actual): June 10, 2022

Study Record Updates

• Last Update Posted (Actual): July 25, 2025
• Last Update Submitted That Met QC Criteria: July 22, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: 15498; 1K23DK129799 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No