Targeting Glutamine Metabolism to Prevent Diabetic Cardiovascular Complications (GLUTADIAB)

Experimental data suggest that glutamine catabolism in involved in the activation of macrophages by generating TCA(Tricarboxylic acid) intermediates that promote the pro-inflammatory polarization of macrophages. The project investigates the possible link between glutaminolysis, monocytes polarization and diabetes related cardiovascular complications in humans

Study Overview

• Status: Recruiting
• Conditions: Diabetic; Cardiovascular Complications; Glutamine
• Intervention / Treatment: Biological: Bio collection

Detailed Description

The aim of the study is to investigate the role of glutamine metabolism in the pro-inflammatory activation of macrophages in diabetes and related cardiovascular complications.

The study focuses on 3 adult patients' population with different diabetic status and level of cardiovascular risk:

• Patients with uncomplicated type 1 or type 2 diabetes and low cardiovascular risk
• Patients with uncomplicated type 1 or type 2 diabetes and high cardiovascular risk
• Patients with complicated type 1 or type 2 diabetes

Participants (n=975) will be recruited at clinical sites, in the diabetes and cardiology departments (APHP, Bichat - Claude-Bernard Hospital and APHP, Lariboisière Hospital), over a 2-year period.

The study will consist in a single visit. During a scheduled hospitalization or consultation as part of the follow-up of their diabetes or as part of the follow-up of their cardiological problems, clinical data will be collected as well as additional blood and urine samples for analyses and biobanking. There will be no other intervention specific to the study.

• Study Type: Observational
• Enrollment (Estimated): 975

Contacts and Locations

• Study Contact: Name: Louis POTIER, MD; Phone Number: 01 40 25 73 01; Email: louis.potier@aphp.fr
• Study Contact Backup: Name: Aline DECHANET; Phone Number: 01 40 25 78 30; Email: aline.dechanet@aphp.fr

Study Locations

• France
  • Paris, France, 75010
    • Recruiting
    • Diabétologie - Hôpital Lariboisière
    • Contact: Jean-Francois GAUTIER; Phone Number: 01 49 95 90 20; Email: jean-francois.gautier@aphp.fr
  • Paris, France, 75018
    • Recruiting
    • Diabetologie Bichat
    • Contact: Louis POTIER; Phone Number: 01 40 25 73 01

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult Type 1 and 2 diabetic patients and non-diabetic subjects with various levels of cardiovascular risk

Description

Inclusion criteria General inclusion criteria applying to the five populations are the following:

• Age above 18 years
• BMI between 25 and 40 kg/m²

Inclusion criteria according to study group are listed below.

Group 1: Patients with uncomplicated diabetes and low cardiovascular risk, additional inclusion criteria are:

• 5 or more years of diabetes
• 6% < HbA1c < 10%
• no history of cardiovascular event, diabetic microvascular complications (kidney function normal and albuminuria/creatininuria < 30 mg/g)
• Coronary artery calcium score < 100 (assessment < 12 months)

Group 2: Patients with uncomplicated diabetes and high cardiovascular risk, additional inclusion criteria are:

• 5 or more years of diabetes
• 6% < HbA1c < 10%
• no history of cardiovascular eventand diabetic nephropathy no more than stage 2 (i.e. GFR ≥ 60 ml/min by MDRD or CKD-EPI formula and albuminuria/creatininuria ≤ 30 mg/g)
• Coronary artery calcium score > 400 (assessment < 12 months)

Group 3: Patients with complicated diabetes, additional inclusion criteria are:

• 5 or more years of diabetes
• 6% < HbA1c < 10%
• A history of cardiovascular event (myocardial infarction, stroke, peripheral vascular disease, or angioplasty) at least 3 months ago

Exclusion Criteria:

• Solid organ or bone marrow transplant patient
• Pregnant or breastfeeding woman
• Absence of free and informed consent
• Non-affiliation to a social security regimen or CMU (universal health coverage)
• Subject deprived of freedom, subject under a legal protective measure

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1; Patients with uncomplicated diabetes and low cardiovascular risk During a scheduled hospitalization or consultation as part of the follow-up of their diabetes additions of biological samples, which include: A unique venous blood sampling of 9 tubes: 4 x 7 mL EDTA (Éthylènediaminetétraacétique) tubes + 3 x 5 mL EDTA tubes + 2 x 4 mL no additive tubes (total: 51 mL) at a single time during the study and collection of 2 monovettes of 1.6 ml urine (total: 3.2 mL).	Biological: Bio collection; venous blood sampling and collection of urine
Group 2; Patients with uncomplicated diabetes and high cardiovascular risk During a scheduled hospitalization or consultation as part of the follow-up of their diabetes additions of biological samples, which include: A unique venous blood sampling of 9 tubes: 4 x 7 mL EDTA tubes + 3 x 5 mL EDTA tubes + 2 x 4 mL no additive tubes (total: 51 mL) at a single time during the study and collection of 2 monovettes of 1.6 ml urine (total: 3.2 mL).	Biological: Bio collection; venous blood sampling and collection of urine
Group 3; Patients with complicated diabetes During a scheduled hospitalization or consultation as part of the follow-up of their diabetes additions of biological samples, which include: A unique venous blood sampling of 9 tubes: 4 x 7 mL EDTA tubes + 3 x 5 mL EDTA tubes + 2 x 4 mL no additive tubes (total: 51 mL) at a single time during the study and collection of 2 monovettes of 1.6 ml urine (total: 3.2 mL).	Biological: Bio collection; venous blood sampling and collection of urine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare the plasma concentrations of glutamine in patients with various levels of cardiovascular (CV) risk.	plasma concentration of glutamine in each subject.	DAY 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study glutamine metabolism in patients with various levels of CV risk	plasma concentration of glutamate in each treatment group	DAY 1
Study glutamine metabolism in patients with various levels of CV risk	plasma concentration of a-ketoglutarate, fumarate, and succinate in each treatment group	DAY1
Study glutamine metabolism in patients with various levels of CV risk	monocyte cytoplasmic concentration of a-ketoglutarate, fumarate and succinate in each treatment group	DAY 1
study the inflammatory status in patients with various levels of CV risk	plasma concentration of VEGF (Vascular endothelial growth factor) in each treatment group	DAY 1
study the inflammatory status in patients with various levels of CV risk	plasma concentration of the proinflammatory cytokines IL-1, IL-6, IL-8 (interleukin) and TNF-a (Tumor Necrosis Factor alpha)	DAY 1
study the inflammatory status in patients with various levels of CV risk	blood concentration of circulating PBMCs (peripheral blood mononuclear cell)	DAY 1
study the monocyte activation status in patients with various levels of CV risk	frequency of monocyte subsets (CD14++CD16+, CD14++CD16++, CD14+CD16++)	DAY 1
characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B (Lysine Demethylase 6B) and TET2 (Ten-eleven-translocation 2) activity in blood monocytes from patients with various levels of CV risk	Number of transcript for each gene	DAY 1
characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B and TET2 activity in blood monocytes from patients with various levels of CV risk	Number of methylated gene loci and their proportion of methylation	DAY 1
characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B and TET2 activity in blood monocytes from patients with various levels of CV risk	Frequency and level of histone H3K27me (Methylation of lysine 27 on histone H3) methylation	DAY 1

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: National Research Agency, France

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2020
• Primary Completion (Estimated): January 16, 2024
• Study Completion (Estimated): January 16, 2024

Study Registration Dates

• First Submitted: April 16, 2020
• First Submitted That Met QC Criteria: April 16, 2020
• First Posted (Actual): April 21, 2020

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Cardiovascular complications; Glutamine metabolism
• Other Study ID Numbers: GLUTADIAB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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