Metabolic Adaptation to High-frequent Hypoglycaemia in Type 1 Diabetes
- Conditions
- Type1diabetes
- Interventions
- Procedure: Muscle biopsyProcedure: Adipose tissue biopsyDevice: IPRO 2 Medtronic MinimedProcedure: 7 Tesla (7T) Magnetic Resonance ImagingProcedure: Indirect Calorimetry using Jaeger Oxycon ChampionProcedure: Core temperature and thermography using Thermovision SC645Device: Freestyle Libre 2
- Registration Number
- NCT05095259
- Lead Sponsor
- Nordsjaellands Hospital
- 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.
- Detailed Description
Study rationale The risk of severe hypoglycaemia is a major daily concern for people with diabetes treated with insulin. Severe hypoglycaemia is the main barrier in achieving the recommended glycaemic targets and may indirectly be the main driver for late diabetic complications and related morbidity, mortality and health care costs. In people with diabetes, recurrent exposure to insulin-induced mild hypoglycaemia leads to significant adaptive physiologic responses. While the metabolism of the brain and hormonal responses to hypoglycaemia have been studied extensively, this study will as the first, systematically investigate the chronic adaptation of peripheral metabolism to recurrent hypoglycaemia in diabetes. Knowledge about such responses can lead to interventions that attenuate the devastating effects of acute hypoglycaemia induced by insulin in people with diabetes. Thereby, the risk of developing severe hypoglycaemia can be reduced which ultimately will improve long-term diabetes outcomes and reduce health care costs.
Hypothesis Patients with type 1 diabetes that are exposed to high-frequent recurrent hypoglycaemia will adapt their metabolism in a way, which supports the preservation of brain fuelling.
Objectives
Primary objective 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 can 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.
Secondary objectives
* To study the metabolic consequences of recurrent hypoglycaemia in the brain, liver, muscle and adipose tissues
* To study the consequences of recurrent hypoglycaemia on resting metabolic rest
* To study the consequences of recurrent hypoglycaemia on glucagon and adrenaline sensitivity
* To study the consequences of recurrent hypoglycaemia on epigenetic profiles
* To study the consequences of recurrent hypoglycaemia on oxidative stress
* To study the psychological factors associated with recurrent hypoglycaemia
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 60
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Participants with Type 1 Diabetes Mellitus Adipose tissue biopsy Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus Indirect Calorimetry using Jaeger Oxycon Champion Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus Core temperature and thermography using Thermovision SC645 Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus Freestyle Libre 2 Participants with Type 1 Diabetes Mellitus Healthy Controls Muscle biopsy Healthy Controls Healthy Controls Glucagon Healthy Controls Participants with Type 1 Diabetes Mellitus IPRO 2 Medtronic Minimed Participants with Type 1 Diabetes Mellitus Healthy Controls Adipose tissue biopsy Healthy Controls Healthy Controls Indirect Calorimetry using Jaeger Oxycon Champion Healthy Controls Participants with Type 1 Diabetes Mellitus Muscle biopsy Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus 7 Tesla (7T) Magnetic Resonance Imaging Participants with Type 1 Diabetes Mellitus Healthy Controls IPRO 2 Medtronic Minimed Healthy Controls Healthy Controls Core temperature and thermography using Thermovision SC645 Healthy Controls Healthy Controls 7 Tesla (7T) Magnetic Resonance Imaging Healthy Controls Participants with Type 1 Diabetes Mellitus insulin human Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus Epinephrin Participants with Type 1 Diabetes Mellitus Participants with Type 1 Diabetes Mellitus Glucagon Participants with Type 1 Diabetes Mellitus Healthy Controls Epinephrin Healthy Controls Healthy Controls insulin human Healthy Controls
- Primary Outcome Measures
Name Time Method Glycogen in muscle and adipose tissue 5 minutes Glycogen in muscle and adipose tissue biopsies during euglycaemia
Brain adenosine triphosphate (ATP) concentration 20 minutes Brain ATP concentration using non-invasive MR spectroscopy during euglycaemia
Glycogen concentration 40 minutes Glycogen in liver and muscle tissue using non-invasive MR spectroscopy during euglycaemia.
Metabolite- and lipid profiling 5 minutes Metabolite- and lipid profiling of blood samples using metabolomics profiling platforms during euglycaemia
Brain lactate concentration 20 minutes Brain lactate concentration using non-invasive magnetic resonance (MR) spectroscopy during euglycaemia
Non-specific proteins in muscle and adipose tissue 5 minutes Non-specific proteins in muscle and adipose tissue biopsies during euglycaemia
- Secondary Outcome Measures
Name Time Method Plasma β-hydroxybutyrate during glucagon injections. Every 40 minutes up to 5 hours Plasma β-hydroxybutyrate during glucagon injections.
Plasma metabolomics during glucagon injections. Every 40 minutes up to 5 hours Plasma metabolomics during glucagon injections.
Plasma alanine during epinephrine infusion Every 20 minutes up to 90 minutes Plasma alanine during epinephrine infusion
Plasma β-hydroxybutyrate during epinephrine infusion Every 20 minutes up to 90 minutes Plasma β-hydroxybutyrate during epinephrine infusion
Plasma insulin during epinephrine infusion Every 20 minutes up to 90 minutes Plasma insulin during epinephrine infusion
Plasma norepinephrine during epinephrine infusion Every 20 minutes up to 90 minutes Plasma catecholamines during epinephrine infusion
Plasma metabolomics during epinephrine infusion Every 20 minutes up to 90 minutes Plasma metabolomics during epinephrine infusion
Personality traits using the psychometry questionnaire Toronto Alexithymia Scale (TAS-20) 30 minutes Personality traits using the psychometry questionnaire TAS-20, score 20-100, the higher score the more likely they are alexithymia
Diabetes and hypoglycaemia status using psychometry questionnaire Hypoglycemia Fear Survey - Worry (HFS-W) 30 minutes Diabetes and hypoglycaemia status using psychometry questionnaire HFS-W, score 0-72, the higher score the higher fear for hypoglycemia
Estimated glucose production during glucagon stimulation Every 5 minutes up to 5 hours Area under the curve (AUC) for plasma glucose during glucagon injections. Plasma glucose measurement
Plasma lactate during epinephrine infusion Every 20 minutes up to 90 minutes Plasma lactate during epinephrine infusion
Plasma epinephrine during epinephrine infusion Every 20 minutes up to 90 minutes Plasma catecholamines during epinephrine infusion
Personality traits using the psychometry questionnaire Type D Scale-14 (DS-14) 30 minutes Personality traits using the psychometry questionnaire DS-14, score between 0-28, the higher, the more likely they have type D personality
Diabetes and hypoglycaemia status using psychometry questionnaire Problem Areas in Diabetes (PAID) 30 minutes Diabetes and hypoglycaemia status using psychometry questionnaire PAID, 0-80, the higher score, the more problems with diabetes
Food consumption 30 minutes Using Food Frequency Questionnaire to analyze food consumption
Hypoglycemia awareness status 10 minutes Using hypoglycemia awareness status questionnaire
, 0-7, higher score indicate hypoglycemia unawarenessIndirect calorimetry 60 minutes Estimating resting metabolic rate, before and during hyperinsulinemic-hypoglycemic clamp
Plasma lactate during glucagon injections. Every 40 minutes up to 5 hours Plasma lactate during glucagon injections.
Plasma free fatty acids during glucagon injections. Every 40 minutes up to 5 hours Plasma free fatty acids during glucagon injections.
Plasma glycerol during glucagon injections. Every 40 minutes up to 5 hours Plasma glycerol during glucagon injections.
Plasma alanine during glucagon injections. Every 40 minutes up to 5 hours Plasma alanine during glucagon injections.
Plasma insulin during glucagon injections. Every 40 minutes up to 5 hours Plasma insulin during glucagon injections.
Plasma glycerol during epinephrine infusion Every 20 minutes up to 90 minutes Plasma glycerol during epinephrine infusion
Plasma glucagon during epinephrine infusion Every 20 minutes up to 90 minutes Plasma glucagon during epinephrine infusion
Estimated glucose production during epinephrine stimulation Every 5 minutes up to 90 minutes Area under the curve (AUC) for plasma glucose during epinephrine infusion. Plasma glucose measurement
Thermography 5 minutes Estimating skin temperature, before and during hyperinsulinemic-hypoglycemic clamp
Diabetes and hypoglycaemia status using psychometry questionnaire Hypoglycemia Attitudes and Behavior Scale (HABS) 30 minutes Diabetes and hypoglycaemia status using psychometry questionnaire HABS, score from 14-45, higher score more fear of hypoglycemia
Plasma glucagon during glucagon injections. Every 40 minutes up to 5 hours Plasma glucagon during glucagon injections.
Plasma free fatty acids during epinephrine infusion Every 20 minutes up to 90 minutes Plasma free fatty acids during epinephrine infusion
Trial Locations
- Locations (2)
Nordsjaellands Hospital
🇩🇰Hillerød, Denmark
Steno Diabetes Center Copenhagen
🇩🇰Gentofte, Denmark