Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses (HCIR)

Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses in Patients With Diabetes Mellitus Type 1, Type 2 and Healthy Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Hypoglycemia; Diabetes Mellitus, Type 1; Inflammatory Response
• Intervention / Treatment: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

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 Type: Interventional
• Enrollment (Actual): 110
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Nordsjaelland
    • Hillerød, Nordsjaelland, Denmark, 3400
      • Nordsjællands University Hospital
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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: hypoglycaemic clamp
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: hypoglycaemic clamp
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: hypoglycaemic clamp
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: hypoglycaemic clamp
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: hypoglycaemic clamp
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: hypoglycaemic clamp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1.5 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation.	Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B	1.5 year
Metabolomics profile of each group	Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library	1.5 year
Epigenetic modifications	Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes	1.5 year
Cardiac function responses to hypoglycaemia using echocardiography	Cardiac function responses to hypoglycaemia using echocardiography	1.5 year
Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT)	Amount of correct answers	1.5 year
Oxidative stress responses using oxidative stress marker	Excretion of guanine nucleosides in urine (ng/mL)	1.5 year

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: 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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2019
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): March 31, 2021

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: June 3, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): May 12, 2021
• Last Update Submitted That Met QC Criteria: May 11, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypoglycemia; Physiological Effects of Drugs; Hypoglycemic Agents
• Other Study ID Numbers: HCIR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No IPD sharing plan necessary

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No