Activation Innate Immune System in Type 1 Diabetes

Activation of the Innate Immune System and Vascular Inflammation in Patients With 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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Inflammation; Diabetes Mellitus, Type 1; Metabolism Disorder, Glucose; Innate Immune System
• Intervention / Treatment: Radiation: PET-CT (positron emission tomography - computer tomography); Diagnostic test: Blood drawn

• Study Type: Observational
• Enrollment (Actual): 66

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, PO BOX 9101, 6500 HB
    • Radboud University Nijmegen Medical Centre, Department of Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with type 1 diabetes, poor glycemic control; 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); PET-CT to determine vascular inflammation; Diagnostic test: Blood drawn; Blood drawn
Patients with type 1 diabetes, good glycemic control; 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); PET-CT to determine vascular inflammation; Diagnostic test: Blood drawn; Blood drawn
Healthy subjects; 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); PET-CT to determine vascular inflammation; Diagnostic test: Blood drawn; Blood drawn

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: European Foundation for the Study of Diabetes

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2018
• Primary Completion (Actual): January 21, 2019
• Study Completion (Actual): January 21, 2019

Study Registration Dates

• First Submitted: January 22, 2018
• First Submitted That Met QC Criteria: February 15, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): April 2, 2019
• Last Update Submitted That Met QC Criteria: March 29, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Inflammation; Metabolic Diseases; Glucose Metabolism Disorders
• Other Study ID Numbers: NL62200.091.17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No