Cardiovascular Diseases, Diabetes Mellitus, Type 1, Inflammation, Innate Immune System, Metabolism Disorder, Glucose
Conditions
Brief summary
Hyperglycemia is a well-known cardiovascular risk factor. It has also been shown that episodes of hyperglycemia increase the risk for cardiovascular diseases despite return to normoglycemia, a phenomenon termed 'glycemic or metabolic memory'. The molecular mechanism underlying this phenomenon remains unclear. Cardiovascular events, such as myocardial infarction and stroke are caused by atherosclerosis, which is characterized by low grade inflammation of the vascular wall, including accumulation of innate immune cells such as monocytes and macrophages. The investigators hypothesize that chronic hyperglycemia shifts intracellular metabolism of innate immune cells towards glycolysis and changes the epigenetic state of (progenitors of) innate immune cells (monocytes and macrophages), which reprograms these cells towards a more aggressive, pro-atherogenic phenotype, thereby accelerating atherosclerosis. In this study, the investigators aim to test this hypothesis. This research will reveal whether the innate immune cells of patients with chronic hyperglycemia show a durable shift in intracellular metabolism and epigenetic changes and whether this associates with vascular inflammation.
Interventions
RADIATIONPET-CT (positron emission tomography - computer tomography)
PET-CT to determine vascular inflammation
DIAGNOSTIC_TESTBlood drawn
Blood drawn
Sponsors
European Foundation for the Study of Diabetes
Radboud University Medical Center
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Group 1 and 2 (patients with type 1 diabetes): * Diagnosis based on clinical criteria * Duration of diabetes ≥10 years * Age ≥20 years, ≤ 60 years * Group 1: HbA1c \>64 mmol/mol * Group 2: HbA1c ≤64 mmol/mol * Written informed consent Group 3 (healthy controls): * Absence of disease, no use of medication * Matched for age, gender and BMI * HbA1c \<42 mmol/mol * Written informed consent
Exclusion criteria
* Inability to provide informed consent * Smoking * Specific Medication use: * Use of immunosuppressive drugs * Use of statins \< 2 weeks before performing PET-CT (Those that use statins will be asked to discontinue for two weeks. This can be safely done in the context of primary prevention.) * Use of acetylsalicylic acid * Previous cardiovascular events (ischemic stroke/TIA (transient ischemic attack), myocardial infarction, peripheral arterial disease) * Auto-inflammatory or auto-immune diseases * Current or recent infection (\< 3 months) * Previous vaccination (\< 3 months) * Renal failure (MDRD \<45) * BMI\>30 kg/m2 * Pregnancy * Claustrophobia * Severe hypoglycaemia \< 1 week before PET-CT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arterial wall inflammation, measured by 18F-FDG-PET/CT | through study completion, within 1 year | Compare arterial wall inflammation (expressed as target-to-background-ratio (TBR) measured in large arterial vessels) between well- and poorly-controlled patients. The TBR is the ratio of FDG uptake in large arterial and large venous bloodvessels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FDG (fluorodeoxyglucose) uptake in spleen and bone marrow, measured by 18F-FDG-PET/CT. | through study completion, within 1 year | Measurement of FDG uptake in bone marrow and spleen. |
| Inflammatory phenotype | Most measurements within 1 week after inclusion. Cytokine measurements after completion of the inclusion of all patients. | Blood will be collected for all subjects. LPS induced TNF production |
| Intracellular metabolism, measured by Seahorse respirometer | within 1 day after inclusion | Measurement of mitochondrial stress test = oxygen consumption rate (OCR) |
| Epigenetic changes | Within 2 months after inclusion | Measurement of epigenetic changes by ChIP-seq (chromatin immunoprecipitation) |
| Arterial wall inflammation, measured by 18F-FDG-PET/CT | through study completion, within 1 year | Compare arterial wall inflammation between diabetes patients and healthy subjects. Comparison by using TBR (see description Outcome 1). |
Countries
Netherlands
Outcome results
None listed