Comparison of Hematopoietic Stem Cell Activity in Adipose Tissue From Type 2 Diabetic Patients and Healthy Volunteers
NCT ID: NCT03260452
Last Updated: 2019-04-02
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
NA
Total Enrollment
20 participants
Study Classification
INTERVENTIONAL
Study Start Date
2018-06-28
Study Completion Date
2019-01-24
Brief Summary
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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.
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Detailed Description
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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.
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.
Conditions
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Type2 Diabetes
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
20 male volunteers: 10 overweight/obese subjects with T2D and 10 healthy volunteers, age-matched.
All volunteers will be treated in the same way.
All volunteers will be treated in the same way.
Primary Study Purpose
BASIC_SCIENCE
Blinding Strategy
NONE
All laboratory analyses will be performed blindly.
Study Groups
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Patients
'Abdominal subcutaneous biopsies and Blood test'
Group Type
EXPERIMENTAL
Abdominal subcutaneous biopsies and Blood test
Intervention Type
PROCEDURE
Abdominal subcutaneous biopsies and blood test for each volunteer.
Interventions
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Abdominal subcutaneous biopsies and Blood test
Abdominal subcutaneous biopsies and blood test for each volunteer.
Intervention Type
PROCEDURE
Eligibility Criteria
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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%).
* 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).
* 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).
Minimum Eligible Age
37 Years
Maximum Eligible Age
63 Years
Eligible Sex
MALE
Accepts Healthy Volunteers
Yes
Sponsors
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University Hospital, Toulouse
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Pierre GOURDY
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Toulouse
Locations
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CHU de Toulouse - Rangueil
Toulouse, , France
Site Status
Countries
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France
References
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Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003 Dec;112(12):1821-30. doi: 10.1172/JCI19451.
Reference Type
BACKGROUND
Ito R, Takahashi T, Katano I, Ito M. Current advances in humanized mouse models. Cell Mol Immunol. 2012 May;9(3):208-14. doi: 10.1038/cmi.2012.2. Epub 2012 Feb 13.
Reference Type
BACKGROUND
Casteilla L, Planat-Benard V, Laharrague P, Cousin B. Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J Stem Cells. 2011 Apr 26;3(4):25-33. doi: 10.4252/wjsc.v3.i4.25.
Reference Type
BACKGROUND
Bour S, Caspar-Bauguil S, Iffiu-Soltesz Z, Nibbelink M, Cousin B, Miiluniemi M, Salmi M, Stolen C, Jalkanen S, Casteilla L, Penicaud L, Valet P, Carpene C. Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 deficiency reduces leukocyte infiltration into adipose tissue and favors fat deposition. Am J Pathol. 2009 Mar;174(3):1075-83. doi: 10.2353/ajpath.2009.080612. Epub 2009 Feb 13.
Reference Type
BACKGROUND
Brooks-Worrell B, Narla R, Palmer JP. Biomarkers and immune-modulating therapies for type 2 diabetes. Trends Immunol. 2012 Nov;33(11):546-53. doi: 10.1016/j.it.2012.07.002. Epub 2012 Aug 14.
Reference Type
BACKGROUND
Cancello R, Clement K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG. 2006 Oct;113(10):1141-7. doi: 10.1111/j.1471-0528.2006.01004.x. Epub 2006 Aug 10.
Reference Type
BACKGROUND
Caspar-Bauguil S, Cousin B, Bour S, Casteilla L, Penicaud L, Carpene C. Adipose tissue lymphocytes: types and roles. J Physiol Biochem. 2009 Dec;65(4):423-36. doi: 10.1007/BF03185938.
Reference Type
BACKGROUND
Cousin B, Andre M, Arnaud E, Penicaud L, Casteilla L. Reconstitution of lethally irradiated mice by cells isolated from adipose tissue. Biochem Biophys Res Commun. 2003 Feb 21;301(4):1016-22. doi: 10.1016/s0006-291x(03)00061-5.
Reference Type
BACKGROUND
Dalmas E, Tordjman J, Guerre-Millo M, Clement K. [Adipose tissue, a new playground for immune cells]. Med Sci (Paris). 2011 Nov;27(11):993-9. doi: 10.1051/medsci/20112711016. Epub 2011 Nov 30. French.
Reference Type
BACKGROUND
Han J, Koh YJ, Moon HR, Ryoo HG, Cho CH, Kim I, Koh GY. Adipose tissue is an extramedullary reservoir for functional hematopoietic stem and progenitor cells. Blood. 2010 Feb 4;115(5):957-64. doi: 10.1182/blood-2009-05-219923. Epub 2009 Nov 6.
Reference Type
BACKGROUND
Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013 May 7;17(5):695-708. doi: 10.1016/j.cmet.2013.04.001.
Reference Type
BACKGROUND
Nikolajczyk BS, Jagannathan-Bogdan M, Denis GV. The outliers become a stampede as immunometabolism reaches a tipping point. Immunol Rev. 2012 Sep;249(1):253-75. doi: 10.1111/j.1600-065X.2012.01142.x.
Reference Type
BACKGROUND
Poglio S, De Toni-Costes F, Arnaud E, Laharrague P, Espinosa E, Casteilla L, Cousin B. Adipose tissue as a dedicated reservoir of functional mast cell progenitors. Stem Cells. 2010 Nov;28(11):2065-72. doi: 10.1002/stem.523.
Reference Type
BACKGROUND
Poglio S, De Toni F, Lewandowski D, Minot A, Arnaud E, Barroca V, Laharrague P, Casteilla L, Cousin B. In situ production of innate immune cells in murine white adipose tissue. Blood. 2012 Dec 13;120(25):4952-62. doi: 10.1182/blood-2012-01-406959. Epub 2012 Oct 15.
Reference Type
BACKGROUND
Prunet-Marcassus B, Cousin B, Caton D, Andre M, Penicaud L, Casteilla L. From heterogeneity to plasticity in adipose tissues: site-specific differences. Exp Cell Res. 2006 Apr 1;312(6):727-36. doi: 10.1016/j.yexcr.2005.11.021. Epub 2005 Dec 28.
Reference Type
BACKGROUND
Richardson VR, Smith KA, Carter AM. Adipose tissue inflammation: feeding the development of type 2 diabetes mellitus. Immunobiology. 2013 Dec;218(12):1497-504. doi: 10.1016/j.imbio.2013.05.002. Epub 2013 May 16.
Reference Type
BACKGROUND
Shapiro H, Lutaty A, Ariel A. Macrophages, meta-inflammation, and immuno-metabolism. ScientificWorldJournal. 2011;11:2509-29. doi: 10.1100/2011/397971. Epub 2011 Dec 28.
Reference Type
BACKGROUND
Spinetti G, Cordella D, Fortunato O, Sangalli E, Losa S, Gotti A, Carnelli F, Rosa F, Riboldi S, Sessa F, Avolio E, Beltrami AP, Emanueli C, Madeddu P. Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res. 2013 Feb 1;112(3):510-22. doi: 10.1161/CIRCRESAHA.112.300598. Epub 2012 Dec 18.
Reference Type
BACKGROUND
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 Dec;112(12):1796-808. doi: 10.1172/JCI19246.
Reference Type
BACKGROUND
Other Identifiers
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2017-A01697-46
Identifier Type: OTHER
Identifier Source: secondary_id
RC31/15/7739
Identifier Type: -
Identifier Source: org_study_id
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