The development of diabetes-associated macrovascular disease in humanized mice

The development of diabetes-associated macrovascular disease in humanized mice - Humanized mice for studying diabetes-associated cardiovascular disease

Status

Active, not recruiting

Phases

Unknown

Study type

Observational

Source

NL-OMON

Registry ID

NL-OMON36433

Enrollment

128

Registered

2011-01-21

Start date

2011-07-12

Completion date

Unknown

Last updated

2024-05-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

atherosclerosis cardiovascular disease

Interventions

None listed

Eligibility

Age

18 Years to 99 Years

Inclusion criteria

Inclusion criteria: Patients eligible for participation are diagnosed with T2DM (duration 10-15 yrs) and divided into diabetic patients with CAD or without cardiovascular disease. Patients eligible for participation in the various control groups are patients without a history of T2DM but with CAD, respectively. In addition, healthy individuals who have neither a history of diabetes, cardiovascular disease, inflammatory or autoimmune disease, nor obesity nor any other chronic disease are will be included. Definition of CAD: Coronary artery disease (CAD) CAD is defined as previous myocardial infarction, resting ECG indicative of past MI, positive ECG at exercise stress test, echocardiography stress-test positive for inducible ischemia, evidence of significant coronary artery stenose on angiography with or without typical chest pain. Participants allocated to the different groups will be matched for: - gender - age - smoking - BMI - arterial hypertension - HbA1c (diabetics) - lipid profile

Exclusion criteria

Exclusion criteria: Predefined exclusion criteria for T2DM include diagnosis of T1DM and presence of any of the following (self-reported) medical conditions: - auto-immune diseases - acute or chonic infection - age >80yrs - hemodialysis - immunosuppression - any other unrelated disease. Exclusion criteria for non-diabetics include: - diagnosis of T1DM or T2DM - auto-immune diseases - acute or chonic infection - age >80yrs - hemodialysis - immunosuppression - any other unrelated disease .

Design outcomes

Primary

Measure	Time frame
From the peripheral blood obtained PBMCs will be isolated using Ficoll density gradient centrifugation. Isolated cells will then be subjected to: 1) Flowcytometric analyses: These phenotypic analyses allows quantification circulating endothelial and smooth muscle progenitor cells (EPCs and SMPCs, respectively) in the peripheral blood of diabetic and non-diabetic subjects and correlate frequencies of these specific cell subsets to the presence of cardiovascular disease. 2) Injury to the arterial wall triggers smooth muscle cell proliferation, migration and matrix secretion. The resultant intimal hyperplasia is a common histological finding in restenosis after balloon angioplasty and other arterial occlusive diseases. We will induce arterial injury in human arterial grafts which have first been transplanted into the abdominal aorta of immunodeficient mice. The results from these in vivo experiments will reveal whether the humanized model reflects the clinical situation of the individuals providing the tissues. T2DM is expected to impair endothelial and medial smooth muscle cell function in the vascular wall and this may in turn influence the response of vascular progenitor cells upon vascular damage. Therefore, mice reconstituted with cells/tissues obtained from T2DM subjects likely develop more severe restenosis than mice transplanted with cells/tissues derived from non-diabetic controls. In order to analyze whether exposure of PBMCs and arterial grafts derived from non-diabetic individuals to a T2DM environment influences their behaviour in response to vascular injury we will adapt our humanized mouse model by developing a humanized mouse model which has a diabetic background. We will transfer non-diabetic PBMCs to both non-diabetic and T2DM immunodeficient recipient mice that receives an arterial transplant. After arterial injury, the severity of restenosis will be determined. The results from these experiments will reveal whether vascula	—

Measure

Time frame

From the peripheral blood obtained PBMCs will be isolated using Ficoll density gradient centrifugation. Isolated cells will then be subjected to: 1) Flowcytometric analyses: These phenotypic analyses allows quantification circulating endothelial and smooth muscle progenitor cells (EPCs and SMPCs, respectively) in the peripheral blood of diabetic and non-diabetic subjects and correlate frequencies of these specific cell subsets to the presence of cardiovascular disease. 2) Injury to the arterial wall triggers smooth muscle cell proliferation, migration and matrix secretion. The resultant intimal hyperplasia is a common histological finding in restenosis after balloon angioplasty and other arterial occlusive diseases. We will induce arterial injury in human arterial grafts which have first been transplanted into the abdominal aorta of immunodeficient mice. The results from these in vivo experiments will reveal whether the humanized model reflects the clinical situation of the individuals providing the tissues. T2DM is expected to impair endothelial and medial smooth muscle cell function in the vascular wall and this may in turn influence the response of vascular progenitor cells upon vascular damage. Therefore, mice reconstituted with cells/tissues obtained from T2DM subjects likely develop more severe restenosis than mice transplanted with cells/tissues derived from non-diabetic controls. In order to analyze whether exposure of PBMCs and arterial grafts derived from non-diabetic individuals to a T2DM environment influences their behaviour in response to vascular injury we will adapt our humanized mouse model by developing a humanized mouse model which has a diabetic background. We will transfer non-diabetic PBMCs to both non-diabetic and T2DM immunodeficient recipient mice that receives an arterial transplant. After arterial injury, the severity of restenosis will be determined. The results from these experiments will reveal whether vascula

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Secondary

Measure	Time frame
n.a	—

Countries

Netherlands

Outcome results