Back to results

Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses (HCIR)

Primary Purpose

Hypoglycemia, Inflammatory Response, Diabetes Mellitus, Type 1

Status

Completed

Phase

Not Applicable

Locations

International

Study Type

Interventional

Intervention

hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

About this trial

This is an interventional diagnostic trial for Hypoglycemia

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Nordsjællands University Hospital
Radboudumc

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Arm Label

T1DM poor glycaemic control

T1DM impaired awareness

T1DM Normal awareness

T2DM + Insulin

Healthy control T2DM

Healthy control T1DM

Arm Description

patients with type 1 diabetes and poor glycaemic control (HbA1c >8% / >64 mmol/mol will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

patients with type 1 diabetes and impaired awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

patients with type 1 diabetes and normal awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

patients with type 2 diabetes with insulin treatment for at least 1 year will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

healthy controls without diabetes and age, gender and BMI matched with diabetes type 2 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Healthy controls without diabetes and age, gender and BMI matched with diabetes type 1 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Outcomes

Primary Outcome Measures

Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA

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.

Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B

Metabolomics profile of each group

Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library

Epigenetic modifications

Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes

Cardiac function responses to hypoglycaemia using echocardiography

Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT)

Amount of correct answers

Oxidative stress responses using oxidative stress marker

Excretion of guanine nucleosides in urine (ng/mL)

Full Information

NCT ID

NCT03976271

First Posted

November 8, 2018

Last Updated

May 11, 2021

Sponsor

Radboud University Medical Center

Collaborators

Rigshospitalet, Denmark

1. Study Identification

Unique Protocol Identification Number

NCT03976271

Brief Title

Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses

Acronym

HCIR

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

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

August 12, 2019 (Actual)

Primary Completion Date

March 31, 2021 (Actual)

Study Completion Date

March 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

Collaborators

Rigshospitalet, Denmark

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypoglycemia, Inflammatory Response, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Masking Description

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.

Allocation

Non-Randomized

Enrollment

110 (Actual)

8. Arms, Groups, and Interventions

Arm Title

T1DM poor glycaemic control

Arm Type

Active Comparator

Arm Description

patients with type 1 diabetes and poor glycaemic control (HbA1c >8% / >64 mmol/mol will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Arm Title

T1DM impaired awareness

Arm Type

Active Comparator

Arm Description

patients with type 1 diabetes and impaired awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Arm Title

T1DM Normal awareness

Arm Type

Active Comparator

Arm Description

patients with type 1 diabetes and normal awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Arm Title

T2DM + Insulin

Arm Type

Active Comparator

Arm Description

patients with type 2 diabetes with insulin treatment for at least 1 year will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Arm Title

Healthy control T2DM

Arm Type

Active Comparator

Arm Description

healthy controls without diabetes and age, gender and BMI matched with diabetes type 2 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Arm Title

Healthy control T1DM

Arm Type

Active Comparator

Arm Description

Healthy controls without diabetes and age, gender and BMI matched with diabetes type 1 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Intervention Type

Procedure

Intervention Name(s)

hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

Other Intervention Name(s)

hypoglycaemic clamp

Intervention Description

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.

Primary Outcome Measure Information:

Title

Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA

Description

Cytokine production (TNF-alfa, IL-6, IL-10 and IL-1β) of isolated and stimulated monocytes

Time Frame

1.5 year

Secondary Outcome Measure Information:

Title

Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation.

Description

Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B

Time Frame

1.5 year

Title

Metabolomics profile of each group

Description

Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library

Time Frame

1.5 year

Title

Epigenetic modifications

Description

Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes

Time Frame

1.5 year

Title

Cardiac function responses to hypoglycaemia using echocardiography

Description

Cardiac function responses to hypoglycaemia using echocardiography

Time Frame

1.5 year

Title

Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT)

Description

Amount of correct answers

Time Frame

1.5 year

Title

Oxidative stress responses using oxidative stress marker

Description

Excretion of guanine nucleosides in urine (ng/mL)

Time Frame

1.5 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bastiaan E de Galan, MD, PhD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Ulrik Pedersen-Bjergaard, MD, PhD

Organizational Affiliation

Nordsjællands University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Nordsjællands University Hospital

City

Hillerød

State/Province

Nordsjaelland

ZIP/Postal Code

3400

Country

Denmark

Facility Name

Radboudumc

City

Nijmegen

State/Province

Gelderland

ZIP/Postal Code

6525 GA

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

No IPD sharing plan necessary

Citations:

PubMed Identifier

35876660

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.

Results Reference

derived

Learn more about this trial

Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses

We'll reach out to this number within 24 hrs