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NCT Number: NCT03441919

Activation Innate Immune System in Type 1 Diabetes

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.

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Key information

Conditions

Diabetes Mellitus, Type 1 Autoimmune Diseases Cardiovascular Diseases Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Immune System Diseases Inflammation Innate Immune System Metabolic Diseases Metabolism Disorder, Glucose Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

20 year–60 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Radboud University Nijmegen Medical Centre, Department of Internal Medicine

Nijmegen, PO BOX 9101, 6500 HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

PET-CT (positron emission tomography - computer tomography)

Radiation

PET-CT to determine vascular inflammation

Blood drawn

Diagnostic Test

Blood drawn

Primary outcomes

  1. Arterial wall inflammation, measured by 18F-FDG-PET/CT

    Time frame: 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 outcomes

  1. FDG (fluorodeoxyglucose) uptake in spleen and bone marrow, measured by 18F-FDG-PET/CT.

    Time frame: through study completion, within 1 year

    Measurement of FDG uptake in bone marrow and spleen.

  2. Inflammatory phenotype

    Time frame: 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

  3. Intracellular metabolism, measured by Seahorse respirometer

    Time frame: within 1 day after inclusion

    Measurement of mitochondrial stress test = oxygen consumption rate (OCR)

  4. Epigenetic changes

    Time frame: Within 2 months after inclusion

    Measurement of epigenetic changes by ChIP-seq (chromatin immunoprecipitation)

  5. Arterial wall inflammation, measured by 18F-FDG-PET/CT

    Time frame: through study completion, within 1 year

    Compare arterial wall inflammation between diabetes patients and healthy subjects. Comparison by using TBR (see description Outcome 1).

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Collaborators

  • European Foundation for the Study of Diabetes

Registry information

Official study title

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

Important dates

Study start
2018
Primary completion
2019
Study completion
2019
First posted
Feb 22, 2018
Registry last updated
Apr 2, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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