Incretin Hormones in Type 1 Diabetes Mellitus;Effect of Metformin Treatment (INCREDIBLE-M)

Gut-derived Incretin Hormones in the Pathophysiology of Type 1 Diabetes Mellitus; Effect of Metformin Treatment

Investigators aim is to conduct an RCT to study the effect of adjunct metformin treatment to insulin monotherapy in patients with type 1 diabetes, targeting the intestinal incretin secretion. The patients will be randomly allocated to metformin or placebo treatment for 4 months

Study Overview

• Status: Unknown
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

Compared to the large armamentarium of antidiabetic agents for Type 2 Diabetes Mellitus (T2DM), the insulinocentric therapeutic approach in Type 1 Diabetes Mellitus (T1DM) has distracted the scientific perspective from the rise of novel therapies. Insulin monotherapy has long overshadowed the overall hormonal dysregulation that demarcates T1DM . In specific, the significance of the gut-derived incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide), which are implicated with glucose metabolism via the gut-pancreatic axis, has been merely addressed.

Investigators' goal in the current protocol is to delineate the glucoregulatory role of incretin hormones in T1DM and the therapeutic advantages of adjunct metformin treatment over insulin monotherapy. In the absence of such knowledge, the development of effective strategies to improve metabolic homeostasis and ameliorate complications in T1DM patients will remain problematic. The central hypothesis of the study is that metformin, as an incretin-secretagogue, will enhance postprandial incretin secretion in T1DM patients, which will be reflected in reduced glucagon secretion and improvement in glycemic volatility. Mechanistic insight will be provided through changes in specific amino acids and metabolites patterns, chronic inflammation and the microbiome composition.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Evangelos J Giamarellos-Bourboulis, MD, PhD; Phone Number: +306945521800; Email: egiamarel@med.uoa.gr
• Study Contact Backup: Name: Antigoni J Kotsaki, MD,PhD; Phone Number: +306946637164; Email: antigonebut@yahoo.com

Study Locations

• Greece
  • Thessaloniki
    • Thessaloníki, Thessaloniki, Greece, 54636
      • Recruiting
      • Diabetes Center, 1st Internal Medicine Department, AHEPA University General Hospital of Thessaloniki
      • Contact: Kalliopi Kotsa, MD,PhD; Phone Number: +306932045201; Email: kalli@med.auth.gr
      • Contact: Antigoni Z Lalia, MD,MSc; Phone Number: +306980661463; Email: alalia@auth.gr
      • Principal Investigator: Kalliopi Kotsa, MD,PhD
      • Sub-Investigator: Antigoni Lalia, MD,MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years
• T1DM (Diagnosis of diabetes before the age of 35 years and insulin use within 1 year of diagnosis)
• Treatment with multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII)

Exclusion Criteria:

• Any cardiovascular disease within the last 3 months
• NYHA stage 3 or 4 heart failure
• Uncontrolled angina
• Liver failure [AST>135 IU/L or ALT>129IU/L (3 x the upper normal limit)] • Kidney failure or GFR<60 ml/min/1.73m2
• Gastrointestinal disease or gastroparesis
• Prior diagnosis of cancer within 2 years
• Other medication that affect glucose metabolism within the last 3 months (metformin, SGLT2, GLP-1 analogues, amylin analogues, systemic glucocorticosteroids)
• Untreated or uncontrolled thyroid disease
• Pregnancy or breastfeeding
• Alcohol consumption > 2-drinks per day or other substance abuse

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; Patients will continue with their standard insulin therapy and will additionally receive orally metformin 2gr/day.	Drug: Metformin; Participants will be randomized to metformin 2000 mg
Placebo Comparator: Placebo; Patients will continue with their standard insulin therapy and will additionally receive placebo	Drug: Placebo; Participants will be randomized to placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in GLP-1 (glucagon like peptide) and GIP (gastric inhibitory peptide) postprandial secretion	The primary endpoint of the study is the change in postprandial GLP-1(ng/ml) and GIP (ng/ml) secretion with metformin treatment compared to placebo.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in glycemic variability pre- and post- treatment	A continuous glucose-monitoring device will be attached to each participant and record daily glucose measurements (mg/dl) for 6 consecutive days on two separate time points: a) within a week prior to randomization and b) as a follow up, within a week prior to Inpatient Visit 2.	4 months
Metabolomic profile of each treatment group	Untargeted metabolomics analysis and identification of candidate metabolites using mass spectrometry. Quantitative targeted metabolomics will then be applied on candidate metabolites to compare differences pre and post treatment between metformin and placebo treatment arm	4 months
Change in inflammatory state	Corrrelation of CRP levels (mg/dl) and treatment arm, as marker of inflammation. CRP will be measured from plasma blood samples collected during Inpatient Visits 1 and 2.	4 months
Change in endothelial dysfunction	Correlation of Serpin E1/PAI-1 levels (ng/ml), VEGF levels (pg/ml), ICAM1 levels (ng/ml) SYndecan-1 levels (ng/ml) and placebo/metformin administration, as markers of endothelial dysfunction. Concentration of adhesion molecules will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.	4 months
Change in cytokine production	Correlation of TNFα levels (pg/ml) ,IL-6 levels (pg/ml),IL-1β levels (pg/ml),IL-10 levels ,(pg/ml) and placebo/metformin administration, as markers of inflammation. Concentration of cytokines will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.	4 months
Change in matrix metalloproteinase-9 (MMP-9) levels	Correlation of MMP-9 levels (ng/ml) levels and placebo/metformin administration, as markers of inflammation. Concentration of MMP-9 will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.	4 months
Change in chemokine production	Correlation of CCL2 levels (pg/ml) ,CCL3 levels (pg/ml),CCL4 levels (pg/ml) and placebo/metformin administration, as markers of inflammation. Concentration chemokines will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.	4 months
Change in gene expression	RNA from PBMCs collected pre and post intervention will be isolated and Quantitative Real Time PCR will be used to measure the transcription of genes related to inflammation and endothelial function.	4 months
Change in gut microbiome analysis	Stool samples will be collected pre and post the intervention on Inpatient Visits 1 and 2 to identify the changes in the microbiome composition based on phylogenetic analysis of the 16S rRNA gene sequencing classification using quantitative PCR.	4 months

Collaborators and Investigators

• Sponsor: Hellenic Institute for the Study of Sepsis
• Investigators: Principal Investigator: Kotsa Kalliopi, MD,PhD, 1st Internal Medicine Department, AHEPA University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2019
• Primary Completion (Anticipated): November 29, 2022
• Study Completion (Anticipated): November 29, 2022

Study Registration Dates

• First Submitted: October 30, 2019
• First Submitted That Met QC Criteria: November 24, 2019
• First Posted (Actual): November 26, 2019

Study Record Updates

• Last Update Posted (Actual): February 18, 2020
• Last Update Submitted That Met QC Criteria: February 17, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Inflammation; Microbiome; Metformin; Incretin hormones
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: INCREDIBLE-ME

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