Metabolic Adaptation to High-frequent Hypoglycaemia in Type 1 Diabetes

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.

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