HCIR: Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: T1DM poor glycaemic control patients with type 1 diabetes and poor glycaemic control (HbA1c >8% / >64 mmol/mol will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
| Active Comparator: T1DM impaired awareness patients with type 1 diabetes and impaired awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
| Active Comparator: T1DM Normal awareness patients with type 1 diabetes and normal awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
| Active Comparator: T2DM + Insulin patients with type 2 diabetes with insulin treatment for at least 1 year will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
| Active Comparator: Healthy control T2DM healthy controls without diabetes and age, gender and BMI matched with diabetes type 2 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
| Active Comparator: Healthy control T1DM Healthy controls without diabetes and age, gender and BMI matched with diabetes type 1 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp |
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA [1.5 year]
Cytokine production (TNF-alfa, IL-6, IL-10 and IL-1β) of isolated and stimulated monocytes
Secondary Outcome Measures
- Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation. [1.5 year]
Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B
- Metabolomics profile of each group [1.5 year]
Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library
- Epigenetic modifications [1.5 year]
Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes
- Cardiac function responses to hypoglycaemia using echocardiography [1.5 year]
Cardiac function responses to hypoglycaemia using echocardiography
- Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT) [1.5 year]
Amount of correct answers
- Oxidative stress responses using oxidative stress marker [1.5 year]
Excretion of guanine nucleosides in urine (ng/mL)
Eligibility Criteria
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)
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Body-Mass Index: 19-40 kg/m2
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Age ≥18 years, ≤ 80 years
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Blood pressure: <140/90 mmHg
-
Duration of diabetes > 1 year (except for group 5)
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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.
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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.
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Group 4: Insulin treatment for at least 1 year
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Group 5/6: HbA1c <42 mmol/mol
Exclusion Criteria:
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- 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
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Use of immune-modifying drugs or antibiotics
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Treatment with glucose-modifying (other than insulin, SGLT-2 inhibitors and metformin) agents (e.g. prednisolon)
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Use of anti-depressive drugs
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Pregnancy or breastfeeding or unwillingness to undertake measures for birth control
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Use of statins (e.g. stop statins >2 weeks before performing blood sampling. This can be safely done in the context of primary prevention)
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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
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Any infection in past three months
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Previous vaccination in the past three months
-
Laser coagulation for proliferative retinopathy in the past six months
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Proliferative retinopathy
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nordsjællands University Hospital | Hillerød | Nordsjaelland | Denmark | 3400 |
| 2 | Radboudumc | Nijmegen | Gelderland | Netherlands | 6525 GA |
Sponsors and Collaborators
- Radboud University Medical Center
- Rigshospitalet, Denmark
Investigators
- Principal Investigator: Bastiaan E de Galan, MD, PhD, Radboud University Medical Center
- Principal Investigator: Ulrik Pedersen-Bjergaard, MD, PhD, Nordsjællands University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HCIR