Clinical trial NCT03441919: Activation Innate Immune System in Type 1 Diabetes
Official title: Activation of the Innate Immune System and Vascular Inflammation in Patients With Type 1 Diabetes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Type 1
Cardiovascular Diseases
Innate Immune System
Inflammation
Metabolism Disorder, Glucose
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: European Foundation for the Study of Diabetes
First posted: 2018-02-22
Enrollment: 66
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Type 1 diabetes patients, without macrovascular complications. Minimum diabetes duration 10 years.

Patients are recruited at university hospital.

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.


Eligibility criteria: 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

Primary outcomes:
measure: Arterial wall inflammation, measured by 18F-FDG-PET/CT
timeFrame: through study completion, within 1 year
Secondary outcomes:
measure: FDG (fluorodeoxyglucose) uptake in spleen and bone marrow, measured by 18F-FDG-PET/CT.
timeFrame: through study completion, within 1 year
measure: Inflammatory phenotype
timeFrame: Most measurements within 1 week after inclusion. Cytokine measurements after completion of the inclusion of all patients.
measure: Intracellular metabolism, measured by Seahorse respirometer
timeFrame: within 1 day after inclusion
measure: Epigenetic changes
timeFrame: Within 2 months after inclusion
measure: Arterial wall inflammation, measured by 18F-FDG-PET/CT
timeFrame: through study completion, within 1 year
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre, Department of Internal Medicine
Study officials:
References:
citation: Thiem K, van Dierendonck XAMH, Janssen AWM, Boogaard JP, Riksen NP, Tack CJ, Stienstra R. A High Glycemic Burden Relates to Functional and Metabolic Alterations of Human Monocytes in Patients With Type 1 Diabetes. Diabetes. 2020 Dec;69(12):2735-2746. doi: 10.2337/db20-0568. Epub 2020 Sep 25.