Primary objective:* To investigate the consequences of (recurrent) hypoglycaemia on inflammatory responsesSecondary objectives:* To study the atherogenic consequences of (recurrent) hypoglycaemia* To study the molecular mechanisms involved in the…
ID
Source
Brief title
Condition
- Endocrine disorders congenital
- Diabetic complications
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study endpoint is the ex vivo production of pro- and anti-inflammatory
cytokines and chemokines after ex vivo stimulation of isolated monocytes.
Secondary outcome
Furthermore we will measure the following parameters in circulating monocytes
isolated from the blood:
* Monocyte foam cell formation
* Distribution of pro- and anti-inflammatory monocyte subsets using FACS
(Fluorescence-activated Cell Sorting).
* Gene expression of circulating monocytes using mRNA-sequencing assays.
* Chromatin accessibility of circulating monocytes using ATAC-seq. (Assay for
Transposase-Accessible Chromatin sequencing)
* Epigenetic signature of circulating monocytes using DNA-methylation.
* Characterization of intracellular metabolism of isolated innate immune cells
by ex vivo Sea HorseTM respirometer
* Metabolomics
* Oxidative stress measured in urine
* MicroRNA using PCR on plasma
* Examine the changes in cardiac function with echocardiography
Background summary
Hypoglycaemia is the most common complication in people with type 1 or type 2
diabetes treated with insulin. Hypoglycaemia is associated with an increased
risk of cardiovascular events and mortality. The underlying pathophysiological
mechanism explaining this association still needs to be revealed. Several
studies have shown elevated pro-atherogenic biomarkers and inflammatory
cytokines during hypoglycaemia. A more detailed characterization of changes in
composition and inflammatory status of leukocytes, underlying pathways,
upstream and downstream effects, duration of changes and epigenetic profiling
is needed to provide deeper insights. Furthermore, the explanation might be
found in oxidative stress, or by changes in the cardiac function during
hypoglycaemia. We would also like to investigate the possibility of using miRNA
as a biomarker for cardiovascular damage due to hypoglycaemia. Finally, there
are virtually no data on the durability of such pro-atherogenic effects of
acute hypoglycaemia. Therefore we want to investigate the consequences of
hypoglycaemia on epigenetic profiles and inflammatory responses in healthy
humans and in humans with diabetes type 1.
Study objective
Primary objective:
* To investigate the consequences of (recurrent) hypoglycaemia on inflammatory
responses
Secondary objectives:
* To study the atherogenic consequences of (recurrent) hypoglycaemia
* To study the molecular mechanisms involved in the inflammatory responses to
(recurrent) hypoglycaemia
* To study the consequences of (recurrent) hypoglycaemia on epigenetic profiles
* To study the consequences of (recurrent) hypoglycaemia on oxidative stress
* To study the cardiac function using the echocardiography during hypoglycaemia
* To study the consequences of (recurrent) hypoglycaemia on cognitive function
* To study the potential of the use of miRNA as a diagnostic biomarker for
future cardiovascular damage of hypoglycaemia
Study design
Intervention study
Intervention
The subjects will undergo a modified hyperinsulinemic
normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L).
Study burden and risks
The subjects will not benefit directly from participation to the study.
In order to investigate the inflammatory effects of hypoglycaemia subjects will
have to undergo a hypoglycaemic clamp. As a consequence, subjects may
experience hypoglycaemic symptoms, such as sweating, shaking, palpitations,
hunger and concentration problems. However, this condition is generally well
tolerated by subjects. Consequent to the clamp conditions, the risk of
developing more severe hypoglycaemia leading to loss of consciousness or worse
is negligible, because plasma glucose levels are frequently monitored and
glucose 20% will be infused when glucose levels tend to fall too much. The
investigators have ample experience with the use of hyperinsulinemic
hypoglycaemic normoglycaemic clamps.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Overall inclusion criteria
* Ability to provide written informed consent
* Must be able to speak and read Danish (for Hillerød-site) and Dutch (for
Nijmegen-site)
* Insulin treatment according to basal-bolus insulin regimen (injections or
insulin pump) (except for group 5)
* Body-Mass Index: 19-40 kg/m2
* Age *18 years, * 75 years
* Blood pressure: <140/90 mmHg
* Duration of diabetes > 1 year (except for group 5)
* HbA1c < 100 mmol/mol, Group specific
* Group 1: HbA1c >64 mmol/mol
* Group 2: IAH as assessed by a score of *3 on the modified Clarke
questionnaire, *4 on the Gold questionnaires and a positive score on the
Pedersen-Bjergaard questionnaire.
* Group 3: NAH as assessed by a score of <3 on the modified Clarke
questionnaire, <4 on the Gold questionnaire and a negative score on the
Pedersen-Bjergaard.
* Group 4: Insulin treatment for at least 1 year and age*18 years, * 80 years
* Group 5: HbA1c <42 mmol/mol and age*18 years, * 80 years
Recurrent hypoglycaemia study
Healthy participants
- Ability to provide written informed consent
- Body-Mass Index: 19-40 kg/m2
- Age *16 years, * 75 years
- Blood pressure: <140/90 mmHg
Exclusion criteria
- Severe medical or psychological conditions interfering with the perception of
hypoglycaemia other than IAH such as brain injuries, epilepsy, a major
cardiovascular disease event or anxiety disorders
- Use of immune-modifying drugs or antibiotics
- Treatment with glucose-modifying (other than insulin, SGLT-2 inhibitors and
methformin) agents (e.g. prednisolon)
- Use of anti-depressive drugs
- Pregnancy or breastfeeding or unwillingness to undertake measures for birth
control
- Use of statins (e.g. stop statins >2 weeks before performing blood sampling.
This can be safely done in the context of primary prevention)
- Any event of cardiovascular disease in the past 5 years (e.g. myocardial
infarction, stroke, heart failure, symptomatic peripheral arterial disease)
- Auto-inflammatory or auto-immune diseases
- Any infection in past three months
- Previous vaccination in the past three months
- Laser coagulation for proliferative retinopathy in the past six months
- Proliferative retinopathy
- Diabetic nephropathy as reflected by an albumin-creatinine ratio * 30 mg/gor
an estimated glomerular filtration rate (by MDRD) *60ml/min/1.73m2
- History of pancreatitis (acute or chronic) or pancreatic cancer
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT03976271 |
| CCMO | NL67229.091.18 |