Targeting Glutamine Metabolism to Prevent Diabetic Cardiovascular Complications

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Targeting Glutamine Metabolism to Prevent Diabetic Cardiovascular Complications

Conditions
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Glutamine, Diabetic, Cardiovascular Complications

Intervention / Treatment
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* Biological: Bio collection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>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<br>* venous blood sampling and collection of urine<br>|
| Group 2<br>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<br>* venous blood sampling and collection of urine<br>|
| Group 3<br>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<br>* venous blood sampling and collection of urine<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Cardiovascular complications, Glutamine metabolism