Activation Innate Immune System in Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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Activation of the Innate Immune System and Vascular Inflammation in Patients With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1, Cardiovascular Diseases, Innate Immune System, Inflammation, Metabolism Disorder, Glucose

Intervention / Treatment
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* Radiation: PET-CT (positron emission tomography - computer tomography)
* Diagnostic Test: Blood drawn


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with type 1 diabetes, poor glycemic control<br>Diagnosis based on clinical criteria Duration of diabetes ≥10 years Age ≥20 years, ≤ 60 years HbA1c >64 mmol/mol | Radiation: PET-CT (positron emission tomography - computer tomography)<br>* PET-CT to determine vascular inflammation<br>Diagnostic Test: Blood drawn<br>* Blood drawn<br>|
| Patients with type 1 diabetes, good glycemic control<br>Diagnosis based on clinical criteria Duration of diabetes ≥10 years Age ≥20 years, ≤ 60 years HbA1c <64 mmol/mol | Radiation: PET-CT (positron emission tomography - computer tomography)<br>* PET-CT to determine vascular inflammation<br>Diagnostic Test: Blood drawn<br>* Blood drawn<br>|
| Healthy subjects<br>Absence of disease, no use of medication Matched for age, gender and BMI HbA1c <42 mmol/mol | Radiation: PET-CT (positron emission tomography - computer tomography)<br>* PET-CT to determine vascular inflammation<br>Diagnostic Test: Blood drawn<br>* Blood drawn<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial wall inflammation, measured by 18F-FDG-PET/CT | 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. | through study completion, within 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FDG (fluorodeoxyglucose) uptake in spleen and bone marrow, measured by 18F-FDG-PET/CT. | Measurement of FDG uptake in bone marrow and spleen. | through study completion, within 1 year | 
| Inflammatory phenotype | Blood will be collected for all subjects. LPS induced TNF production | Most measurements within 1 week after inclusion. Cytokine measurements after completion of the inclusion of all patients. | 
| Intracellular metabolism, measured by Seahorse respirometer | Measurement of mitochondrial stress test = oxygen consumption rate (OCR) | within 1 day after inclusion | 
| Epigenetic changes | Measurement of epigenetic changes by ChIP-seq (chromatin immunoprecipitation) | Within 2 months after inclusion | 
| Arterial wall inflammation, measured by 18F-FDG-PET/CT | Compare arterial wall inflammation between diabetes patients and healthy subjects. Comparison by using TBR (see description Outcome 1). | through study completion, within 1 year |