Metabolic Adaptation to High-frequent Hypoglycaemia in Type 1 Diabetes
HypoADAPT
2 other identifiers
interventional
60
1 country
2
Brief Summary
An experimental mechanistic study. The overall objective is to gain new knowledge about mechanisms involved in adaptation to recurrent hypoglycaemia in diabetes by investigating patients with type 1 diabetes and healthy controls. The knowledge to be obtained may feed into experimental hypoglycaemic clamp studies to further elucidate the effect of the adaptations during acute hypoglycaemia. Ultimately, it may lead to intervention studies aiming at the maintenance of functional capability during hypoglycaemia in patients with type 1 diabetes to reduce their risk of severe hypoglycaemia.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for not_applicable
Started Dec 2019
Longer than P75 for not_applicable
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
December 16, 2019
CompletedFirst Submitted
Initial submission to the registry
October 1, 2021
CompletedFirst Posted
Study publicly available on registry
October 27, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
December 1, 2023
CompletedMay 3, 2023
February 1, 2023
4 years
October 1, 2021
May 1, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (6)
Metabolite- and lipid profiling
Metabolite- and lipid profiling of blood samples using metabolomics profiling platforms during euglycaemia
5 minutes
Brain lactate concentration
Brain lactate concentration using non-invasive magnetic resonance (MR) spectroscopy during euglycaemia
20 minutes
Brain adenosine triphosphate (ATP) concentration
Brain ATP concentration using non-invasive MR spectroscopy during euglycaemia
20 minutes
Glycogen in muscle and adipose tissue
Glycogen in muscle and adipose tissue biopsies during euglycaemia
5 minutes
Non-specific proteins in muscle and adipose tissue
Non-specific proteins in muscle and adipose tissue biopsies during euglycaemia
5 minutes
Glycogen concentration
Glycogen in liver and muscle tissue using non-invasive MR spectroscopy during euglycaemia.
40 minutes
Secondary Outcomes (29)
Estimated glucose production during glucagon stimulation
Every 5 minutes up to 5 hours
Estimated glucose production during epinephrine stimulation
Every 5 minutes up to 90 minutes
Indirect calorimetry
60 minutes
Thermography
5 minutes
Plasma lactate during glucagon injections.
Every 40 minutes up to 5 hours
- +24 more secondary outcomes
Study Arms (2)
Participants with Type 1 Diabetes Mellitus
EXPERIMENTALParticipants with Type 1 Diabetes Mellitus
Healthy Controls
ACTIVE COMPARATORHealthy Controls
Interventions
Hyperinsulinemic glucose clamp studies require that insulin is administered at a steady continuous rate to achieve stable levels of hyperinsulinemia. To reach this, insulin needs to be infused intravenously using a standard intravenous pump system. The insulin dose will be adjusted according to the body surface area, aiming for insulin levels of \~170 mIU/l, which is within the physiological range. Thus, for a subject with a bodyweight of 70 kg, body length of 180 cm and - consequently - a body surface area of 1.936 m2, the required insulin infusion can be calculated as: 1.936 x 60 x 60 ÷ 1000 = 7.0 units per hour
Epinephrine are prepared in 100 ml isotone saline solution according to weight and infused in 3 different infusion rates: 10 ng∙kg-1∙min-1, 25 ng∙kg-1∙min-1 and 50 ng∙kg-1∙min-1, for 20 minutes each. After each adrenaline infusion, substrate response will be measured by blood samples of glucose, lactate, free fatty acids, alanine, β-hydroxybutyrate, glycerol and insulin. Furthermore, cardiovascular measurements such as pulse and blood pressure are monitored as well.
With the study subject resting in the supine position, the skin is disinfected on the lateral side of the thigh around 15 cm above the knee, with chlorhexidine alcohol. Then 3-4 mL of local anaesthetic (lidocaine 20 mg/mL) is injected into the skin, subcutaneous tissue and in the upper part of the muscle with a very thin needle. When the anaesthetic effect has set in after a couple of minutes an insertion is made in the skin and the subcutaneous tissue through which the biopsy cannula is inserted into the muscle. A small piece (around 150 mg) of the muscle is collected, which may be experienced as somewhat unpleasant, but will last for a very short while ( \~1-2 seconds). The needle is removed, a sterile Band-Aid is applied, and the study subject can leave the site after termination of the trial. The biopsy may cause some muscular tenderness for 2-3 days corresponding to minor muscular trauma.
With the study subject resting in the supine position, the skin is disinfected on one side of the abdomen around 5-10 cm lateral from the umbilicus to the knee, with chlorhexidine alcohol. Then 3-4 mL of local anaesthetic (lidocaine 20 mg/mL) is injected into the skin, subcutaneous tissue and in the upper part of the adipose tissue with a very thin needle. When the anaesthetic effect has set in after a couple of minutes an insertion is made in the skin and the subcutaneous tissue through which the biopsy cannula is inserted into the adipose tissue. A small piece (around 1 gram) of the adipose tissue is collected, which may be experienced as somewhat unpleasant, but will last for a very short while ( \~1-2 seconds). The needle is removed, a sterile Band-Aid is applied, and the study subject can leave the site after termination of the trial. The biopsy may cause some tenderness for 2-3 days corresponding to minor trauma.
Glucagon is prepared in doses of 10 µg, 25 µg, and 50 µg and intravenously injected with intervals of 2 hours. After each glucagon injection, blood samples will be drawn to measure plasma glucose, glucagon, lactate, free fatty acids, alanine, amino-acids, β-hydroxybutyrate, glycerol and insulin. Furthermore, cardiovascular measurements such as pulse and blood pressure are monitored as well.
All potential subjects will receive a blinded continuous glucose sensor at Visit 1. At the following visits, the continuous glucose monitor (CGM) will be reviewed for hypoglycaemia episodes and replaced at the same time. At Visit 2 a final screening of the inclusion criteria will take place, which involves the CGM data of the first week. A blinded CGM will be installed a week before every visit.
Subjects will undergo a hyperinsulinemic euglycaemic glucose clamp, as mentioned above, in the MRI scanning room. After 30 minutes of stable normoglycaemia, subjects are taken into the MRI scanner (Philips Achieva 7.0 T) where brain, liver, thigh and calf muscle are scanned. After every anatomically different area, the subjects must be taken out of the scanner, while scanning coils are replaced. All subjects are advised to lie still and press the alarm button if necessary.
Resting metabolic rate will be estimated, after reaching stable plasma glucose level, via a hyperinsulinemic euglycaemic clamp, as mentioned above. This will be done by indirect calorimetry, using a ventilated hood system (Jaeger Oxycon Champion, software version 4.3, Jaeger, Mijnhardt). Subjects are instructed to lie down and rest for a period of 30 minutes. Subjects are also instructed not to move, talk or sleep unless necessary during the period of measurement. The recorded measurement after 5 minutes to 30 minutes will be used for analysis.
Thermography (Thermovision SC645, FLIR Systems, Wilsonville, OR, USA) is used to determine cutaneous vascular perfusion. Data is analogue-digital converted and sampled at 100 Hz (Powerlab, ADInstruments, Colorado Springs, CO, USA).
All potential subjects will receive a continuous glucose sensor at Visit 1. At the following visits, the CGM will be reviewed for hypoglycaemia episodes and replaced at the same time. At Visit 2 a final screening of the inclusion criteria will take place, which involves the CGM data of the first week. A CGM will be installed a week before every visit.
Eligibility Criteria
You may qualify if:
- Ability to provide written informed consent
- Male or female aged 18-70 years
- Must be able to speak and read Danish
- Type 1 diabetes patients or healthy individuals (control goup)
- A documented clinically relevant history of type 1 diabetes
- In insulin treatment regimen
- The subject must be willing and able to comply with trial protocol
You may not qualify if:
- History of severe psychological condition
- History of severe heart disease
- History of epilepsy, former apoplexies and dementia
- History of muscle diseases
- History of liver disease
- History of malignancy unless a disease-free period exceeding 5 years
- Implants not compatible for MRI scans
- History of alcohol or drug abuse
- Pregnant or lactating woman
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Nordsjaellands Hospitallead
- Danish Research Centre for Magnetic Resonancecollaborator
- University of Copenhagencollaborator
- Steno Diabetes Center Copenhagencollaborator
Study Sites (2)
Steno Diabetes Center Copenhagen
Gentofte Municipality, 2820, Denmark
Nordsjaellands Hospital
Hillerød, 3400, Denmark
Related Publications (1)
She R, Suvitaival T, Andersen HU, Hommel E, Norgaard K, Wojtaszewski JFP, Legido-Quigley C, Pedersen-Bjergaard U. Metabolic effect of adrenaline infusion in people with type 1 diabetes and healthy individuals. Diabetologia. 2024 Jun;67(6):1095-1106. doi: 10.1007/s00125-024-06116-5. Epub 2024 Mar 1.
PMID: 38427076DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Ulrik Pedersen-Bjergaard, MD,PhD,Prof
Nordsjaellands Hospital
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- BASIC SCIENCE
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 1, 2021
First Posted
October 27, 2021
Study Start
December 16, 2019
Primary Completion
December 1, 2023
Study Completion
December 1, 2023
Last Updated
May 3, 2023
Record last verified: 2023-02