Clinical trial NCT03976271: Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses
Official title: Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses in Patients With Diabetes Mellitus Type 1, Type 2 and Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypoglycemia
Inflammatory Response
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
First posted: 2019-06-06
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: People with Type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy volunteers will undergo a hypoglycaemic clamp to to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses.

Detailed description: Objectives: The overall aim of the present study is to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses, molecular mechanisms and epigenetic profiles in various groups of people with diabetes type 1, type 2 and healthy volunteers.

Study design: Intervention study

Intervention: All subjects will undergo a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L), during and after which blood and urine will be sampled for further examination for up to one week.

Eligibility criteria: 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, ≤ 80 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: impaired awareness of hypoglycaemia (IAH) as assessed by a score of ≥3 on the modified Clarke questionnaire, ≥4 on the Gold questionnaire and a positive score on the Pedersen-Bjergaard questionnaire.
* Group 3: normal awareness of hypoglycaemia (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
* Group 5/6: HbA1c \<42 mmol/mol

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 metformin) 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

Primary outcomes:
measure: Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA
timeFrame: 1.5 year
Secondary outcomes:
measure: Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation.
timeFrame: 1.5 year
measure: Metabolomics profile of each group
timeFrame: 1.5 year
measure: Epigenetic modifications
timeFrame: 1.5 year
measure: Cardiac function responses to hypoglycaemia using echocardiography
timeFrame: 1.5 year
measure: Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT)
timeFrame: 1.5 year
measure: Oxidative stress responses using oxidative stress marker
timeFrame: 1.5 year
Other outcomes:
Locations:
city: Hillerød
country: Denmark
facility: Nordsjællands University Hospital
state: Nordsjaelland
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Bastiaan E de Galan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nordsjællands University Hospital
name: Ulrik Pedersen-Bjergaard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Verhulst CEM, Fabricius TW, Nefs G, Kessels RPC, Pouwer F, Teerenstra S, Tack CJ, Broadley MM, Kristensen PL, McCrimmon RJ, Heller S, Evans ML, Pedersen-Bjergaard U, de Galan BE. Consistent Effects of Hypoglycemia on Cognitive Function in People With or Without Diabetes. Diabetes Care. 2022 Sep 1;45(9):2103-2110. doi: 10.2337/dc21-2502.