Activation Innate Immune System in Type 1 Diabetes

Completed

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

Interventions: Radiation: PET-CT (positron emission tomography - computer tomography)
Diagnostic Test: Blood drawn

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.

Recruitment & Eligibility

Inclusion Criteria

Group 3 (healthy controls):

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

Arm && Interventions

Group	Intervention	Description
Patients with type 1 diabetes, poor glycemic control	PET-CT (positron emission tomography - computer tomography)	* Diagnosis based on clinical criteria * Duration of diabetes ≥10 years * Age ≥20 years, ≤ 60 years * HbA1c \>64 mmol/mol
Patients with type 1 diabetes, poor glycemic control	Blood drawn	* Diagnosis based on clinical criteria * Duration of diabetes ≥10 years * Age ≥20 years, ≤ 60 years * HbA1c \>64 mmol/mol
Patients with type 1 diabetes, good glycemic control	Blood drawn	* Diagnosis based on clinical criteria * Duration of diabetes ≥10 years * Age ≥20 years, ≤ 60 years * HbA1c \<64 mmol/mol
Healthy subjects	Blood drawn	* Absence of disease, no use of medication * Matched for age, gender and BMI * HbA1c \<42 mmol/mol
Patients with type 1 diabetes, good glycemic control	PET-CT (positron emission tomography - computer tomography)	* Diagnosis based on clinical criteria * Duration of diabetes ≥10 years * Age ≥20 years, ≤ 60 years * HbA1c \<64 mmol/mol
Healthy subjects	PET-CT (positron emission tomography - computer tomography)	* Absence of disease, no use of medication * Matched for age, gender and BMI * HbA1c \<42 mmol/mol

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).

Locations (1): Radboud University Nijmegen Medical Centre, Department of Internal Medicine
🇳🇱
Nijmegen, Netherlands