Clinical trial NCT05095259: Metabolic Adaptation to High-frequent Hypoglycaemia in Type 1 Diabetes
Official title: Metabolic Adaptation to High-frequent Hypoglycaemia in Type 1 Diabetes - the HypoADAPT Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Type1diabetes
Keywords: Diabetes Complications
Hypoglycemia
Metabolism
Lead sponsor: Nordsjaellands Hospital
Sponsor class: OTHER
Collaborators: name: Danish Research Centre for Magnetic Resonance
name: University of Copenhagen
name: Steno Diabetes Center Copenhagen
First posted: 2021-10-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Experimental Observational Case-Control study. Two groups: One group of type 1 diabetes and one group of healthy controls.
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: Inclusion Criteria:

1. Ability to provide written informed consent
2. Male or female aged 18-70 years
3. Must be able to speak and read Danish
4. Type 1 diabetes patients or healthy individuals (control goup)
5. A documented clinically relevant history of type 1 diabetes
6. In insulin treatment regimen
7. The subject must be willing and able to comply with trial protocol

Exclusion Criteria:

1. History of severe psychological condition
2. History of severe heart disease
3. History of epilepsy, former apoplexies and dementia
4. History of muscle diseases
5. History of liver disease
6. History of malignancy unless a disease-free period exceeding 5 years
7. Implants not compatible for MRI scans
8. History of alcohol or drug abuse
9. Pregnant or lactating woman

Primary outcomes:
measure: Metabolite- and lipid profiling
timeFrame: 5 minutes
measure: Brain lactate concentration
timeFrame: 20 minutes
measure: Brain adenosine triphosphate (ATP) concentration
timeFrame: 20 minutes
measure: Glycogen in muscle and adipose tissue
timeFrame: 5 minutes
measure: Non-specific proteins in muscle and adipose tissue
timeFrame: 5 minutes
measure: Glycogen concentration
timeFrame: 40 minutes
Secondary outcomes:
measure: Estimated glucose production during glucagon stimulation
timeFrame: Every 5 minutes up to 5 hours
measure: Estimated glucose production during epinephrine stimulation
timeFrame: Every 5 minutes up to 90 minutes
measure: Indirect calorimetry
timeFrame: 60 minutes
measure: Thermography
timeFrame: 5 minutes
measure: Plasma lactate during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma free fatty acids during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma glycerol during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma alanine during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma β-hydroxybutyrate during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma insulin during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma glucagon during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma metabolomics during glucagon injections.
timeFrame: Every 40 minutes up to 5 hours
measure: Plasma lactate during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma free fatty acids during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma glycerol during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma alanine during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma β-hydroxybutyrate during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma insulin during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma glucagon during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma epinephrine during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma norepinephrine during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Plasma metabolomics during epinephrine infusion
timeFrame: Every 20 minutes up to 90 minutes
measure: Personality traits using the psychometry questionnaire Type D Scale-14 (DS-14)
timeFrame: 30 minutes
measure: Personality traits using the psychometry questionnaire Toronto Alexithymia Scale (TAS-20)
timeFrame: 30 minutes
measure: Diabetes and hypoglycaemia status using psychometry questionnaire Hypoglycemia Fear Survey - Worry (HFS-W)
timeFrame: 30 minutes
measure: Diabetes and hypoglycaemia status using psychometry questionnaire Hypoglycemia Attitudes and Behavior Scale (HABS)
timeFrame: 30 minutes
measure: Diabetes and hypoglycaemia status using psychometry questionnaire Problem Areas in Diabetes (PAID)
timeFrame: 30 minutes
measure: Food consumption
timeFrame: 30 minutes
measure: Hypoglycemia awareness status
timeFrame: 10 minutes
Other outcomes:
Locations:
city: Gentofte
country: Denmark
facility: Steno Diabetes Center Copenhagen
city: Hillerød
country: Denmark
facility: Nordsjaellands Hospital
Study officials:
affiliation: Nordsjaellands Hospital
name: Ulrik Pedersen-Bjergaard, MD,PhD,Prof
role: PRINCIPAL_INVESTIGATOR
References: