Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses

NCT03976271 | Completed DMC

• 1 other identifier: HCIR
• Study Type: interventional
• Target: 110
• Locations: 2 countries
• Sites: 2

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

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

  1.5 year

• Metabolomics profile of each group

  1.5 year

• Epigenetic modifications

  1.5 year

• Cardiac function responses to hypoglycaemia using echocardiography

  1.5 year

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

  1.5 year

Study Arms (6)

T1DM poor glycaemic control

ACTIVE COMPARATOR

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

T1DM impaired awareness

ACTIVE COMPARATOR

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

Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

T1DM Normal awareness

ACTIVE COMPARATOR

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

Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

T2DM + Insulin

ACTIVE COMPARATOR

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

Healthy control T2DM

ACTIVE COMPARATOR

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

Healthy control T1DM

ACTIVE COMPARATOR

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

Interventions

hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp PROCEDURE

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.

Also known as: hypoglycaemic clamp

Healthy control T1DM; Healthy control T2DM; T1DM Normal awareness; T1DM impaired awareness; T1DM poor glycaemic control; T2DM + Insulin

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• \- 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Rigshospitalet, Denmark: collaborator

Study Sites (2)

Nordsjællands University Hospital

Hillerød, Nordsjaelland, 3400, Denmark

Location

Radboudumc

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Related Publications (3)

• Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra R, Teerenstra S, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE; Hypo-RESOLVE consortium. The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode. Cardiovasc Diabetol. 2024 Feb 8;23(1):55. doi: 10.1186/s12933-023-02095-w.

  PMID: 38331900 DERIVED

• Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra R, Teerenstra S, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE; Hypo-RESOLVE consortium. Hypoglycaemia induces a sustained pro-inflammatory response in people with type 1 diabetes and healthy controls. Diabetes Obes Metab. 2023 Nov;25(11):3114-3124. doi: 10.1111/dom.15205. Epub 2023 Jul 24.

  PMID: 37485887 DERIVED

• 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.

  PMID: 35876660 DERIVED

MeSH Terms

Conditions

Hypoglycemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Bastiaan E de Galan, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

• Ulrik Pedersen-Bjergaard, MD, PhD

  Nordsjællands University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2018
• First Posted: June 6, 2019
• Study Start: August 12, 2019
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: May 12, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1); NL (1)