Recurrent Hypoglycaemia in Type 1 Diabetes

Study Overview
=================
Brief Summary
-----------------
Patients with type 1 diabetes are at risk of very low blood sugar levels (hypoglycaemia) as a severe side effect to insulin therapy, in particular subjects who have lost warning of hypoglycaemia. During hypoglycaemia a low frequent activity can be seen with electroencephalography (EEG) as cognitive function declines. The purpose of the study is to investigate the activity in the brain, the cognitive function, and the skin temperature when patients are exposed to repeated hypoglycaemia. The results will show whether the response to hypoglycaemia will change after repeated episodes. It is our hope that results can contribute to improved understanding of hypoglycaemic EEG changes.

Detailed Description
-----------------
Background: Patients with type 1 diabetes are at risk of severe hypoglycaemia as a severe side effect to insulin therapy, in particular subjects who have lost warning of hypoglycaemia (hypoglycaemia unawareness). The episodes are associated with impaired quality of life and can lead to permanent brain damage and death. During hypoglycaemia a low frequent activity can be seen with electroencephalography (EEG) as cognitive function declines. Repeated hypoglycaemic episodes result in down regulation of counter regulatory and symptomatic responses. It is not known whether a similar phenomenon is present for cerebral dysfunction as judged by EEG changes and cognitive function. The purpose is to investigate the activity in the brain, the cognitive function, and the skin temperature when patients are exposed to repeated hypoglycaemia. The results will show whether the response to hypoglycaemia will change after repeated episodes. The methods: The investigators will recruit two groups of patients: Patients with hypoglycemia awareness and patients with hypoglycaemic unawareness. The patients are exposed to hypoglycaemia on two concomitant days while the investigators record EEG and perform cognitive tests. Skin temperature is assessed by the use of thermography. If the patient has hypoglycaemic unawareness a 4 week period follows where the glycaemic control is loosened to avoid hypoglycaemia episodes and the patients is then exposed to hypoglycaemia again. The prospect: It is the investigators hope that results can contribute to improved understanding of hypoglycaemic EEG changes and skin temperature changes. This could be of potential benefit for patients with hypoglycaemic unawareness.

Official Title
-----------------
Recurrent Hypoglycaemia in Type 1 Diabetes: Effects on Cognitive Function, Cerebral Electrical Activity, and Skin Temperature

Conditions
-----------------
Hypoglycaemia

Intervention / Treatment
-----------------
* Procedure: Insulin clamp


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 1 diabetes Age > 18 years - Have had diabetes for more than 5 years Negative pregnancy test Caucasian Signed written informed consent Exclusion Criteria: Pregnant or breastfeeding Epilepsy Self-perceived impaired hearing Use of antiepileptic medicine Use of neuroleptics within the last 6 months Use of benzodiazepines within the last month Use of betablockers Previous stroke or other disease in the brain Cardiovascular disease Alcohol-, drug- or medicine abuse Previous allergic reaction to heparin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Patients with hypoglycemia awareness<br>Patients who have symptoms when the blood sugar level is low | Procedure: Insulin clamp<br>* Patients will be exposed to low bloodsugar<br>* Other names: clamp;|
| Experimental: patients with hypoglycaemic unawareness.<br>Patients who do not feel any symptoms when the blood sugar levels are low | Procedure: Insulin clamp<br>* Patients will be exposed to low bloodsugar<br>* Other names: clamp;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EEG | EEG will be analysed in order to see whether there are any differences between aware and unaware patients during hypoglycaemia. It is our hope that the result can help develop an alarm before the patient experiences severe hypoglycaemia. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTc interval | The investigators want to investigate whether the QTc complex gets wider during hypoglycaemia. This is in order to see whether long QTc could be the explanation behind sudden dearth in diabetes patients. | 2 years | 
| Skin temperature | Skin temperature will be measured by thermography. The investigators want to see whether the skin can be used as a biomarker for hypoglycaemia. | 2 years | 
| Auditory evoked potentials | The investigators what to see whether there is any difference in auditory evoked potentials (AEP) between aware and unaware diabetic patients. The subject will hear a common and a rare sound in a 4:1 ratio while the EEG is recorded. Afterwards the data is analyzed and the AEPs are addressed. | 2 years | 
| Cognitive function | The investigators want to address whether there are any differences in the cognitive function between aware and unaware patients. The cognitive function will be addressed by the use of cognitive function tests (CalCAP) and Stroops tests as well. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, Hypoglycaemia, EEG, Thermography, Hypoglycaemia-associated autonomic failure, QTc interval, Hypoglycemic alarm device, Hormone response