Activation Innate Immune System in Type 1 Diabetes

Cardiovascular Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03441919
• Other study ID #: NL62200.091.17
• Status: Completed
• Start date: January 18, 2018
• Est. completion date: January 21, 2019

Study information

• Verified date: March 2019
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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 information / eligibility

• Status: Completed
• Enrollment: 66
• Est. completion date: January 21, 2019
• Est. primary completion date: January 21, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Glucose Metabolism Disorders
• Inflammation
• Innate Immune System
• Metabolic Diseases
• Metabolism Disorder, Glucose

Intervention

Radiation:
• PET-CT (positron emission tomography - computer tomography)
PET-CT to determine vascular inflammation

Diagnostic Test:
• Blood drawn
Blood drawn

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Centre, Department of Internal Medicine	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	European Foundation for the Study of Diabetes

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.
Secondary	Intracellular metabolism, measured by Seahorse respirometer	Measurement of mitochondrial stress test = oxygen consumption rate (OCR)	within 1 day after inclusion
Secondary	Epigenetic changes	Measurement of epigenetic changes by ChIP-seq (chromatin immunoprecipitation)	Within 2 months after inclusion
Secondary	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