Comparison of Hematopoietic Stem Cell Activity in Adipose Tissue From Type 2 Diabetic Patients and Healthy Volunteers

Comparison of Hematopoietic Stem Cell Activity in Adipose Tissue From Type 2 Diabetic Patients and Healthy Volunteers: Proof of Concept Study. White Adipose Tissue and Type 2 Diabetes Onset: WAT2DO

Based on solid preclinical results in mice and preliminary data in humans, this study aims to provide the proof of concept of the crucial role of the hematopoietic process occurring in human adipose tissue in the initiation of the inflammatory process at the origin of insulin resistance and type 2 diabetes (T2D). The main objective is to compare the number of pro-inflammatory macrophages derived from human adipose tissue hematopoietic stem cells (HSC) according to their origin, type 2 diabetes subjects or healthy volunteers.

In mice, increasing data demonstrate a causal relationship between the inflammatory process in adipose tissue and the development of insulin resistance, resulting in type 2 diabetes occurrence. However, the mechanisms mediating inflammation and its metabolic consequences are still unclear. In humans, recent publications have suggested an important interaction between the metabolic status and medullar hematopoietic activity. A preliminary study performed by the STROMAlab's research team has identified functional hematopoietic stem cells in human adipose tissue samples, indicating that adipose tissue-hematopoiesis is an active mechanism.

To determine whether an alteration in adipose tissue-hematopoiesis could be a hallmark of type 2 diabetes in human, biopsies of subcutaneous adipose tissue will be performed in 2 groups of 10 volunteers: overweight/obese type 2 diabetes subjects versus healthy volunteers, matched on age.

Then, hematopoietic stem cells extracted from human biopsies will be grafted into immunodeficient mice and after 12 weeks, flow cytometry using antibodies specific for human cell surface markers will be performed to quantify proinflammatory macrophages derived from human adipose tissue-hematopoietic stem cells.

Inclusion Criteria:

• No major weight variation for at least 3 months
• Biological assessment without clinically significant anomaly from the point of view of the investigator.
• Acceptance of constraints related to participation in the study
• Acceptance of participation in the constitution of a cell bank, a tissue bank and a serum library.
• Affiliation to a social security scheme.

Type 2 diabetic subjects:

• Type 2 diabetes (discovered after the age of 35 years, without inaugural ketosis and absence of insulin therapy during the first year).
• 40 to 60 year-old.
• BMI between 27 and 35 kg / m² (included).
• Treated by modification of lifestyle alone or associated to oral anti-diabetic therapy only.
• With stable oral anti-diabetic treatment for at least 3 months.
• HbA1c ≤ 8.5%.

Healthy Volunteers:

• BMI between 23 and 27 kg / m² (included).
• 37 to 63 year-old, age-matched to a type 2 diabetes subject ± 5 years.
• Fasting blood glucose < 1,10 g / L.
• HbA1c within normal limits (4 to 6%).

Exclusion Criteria:

• Excessive chronic alcohol consumption (> 30 g / day or 210 g / week).
• Tobacco consumption> 10 cigarettes / day that cannot be stopped for 24 hours.
• Anti-diabetic treatments that require sub-cutaneous injections
• History of chronic or acute hematological pathology.
• Systemic or acute inflammatory pathology.
• Treatment with antiplatelet agents, non-steroidal anti-inflammatory drugs, glucocorticoids (excluding eye drops and sprays), or other immunosuppressive drugs.
• History of cancer (except basal cell carcinoma).
• Allergy to xylocaine or one of its derivatives.
• Any significant pathology at the discretion of the investigator.
• Any biological anomaly at the discretion of the investigator.
• Positive human immunodeficiency virus serology.
• Positive hepatitis B serology.
• Positive hepatitis C serology.
• Glomerular filtration rate less than 60 ml / min
• Aspartate aminotransferase or alanine aminotransferase higher than 2.5-fold the upper normal value.
• Hypertriglyceridemia > 2.5 g / l
• Person under the protection of justice, guardianship or curators.
• Subject involved in another research protocol or in an exclusion period from another research protocol.
• Cognitive disorder or mental pathology (at the discretion of the investigator).