Hypoglycemia Unawareness, Type 1 Diabetes Mellitus
Conditions
Keywords
Type 1 Diabetes Mellitus, Hypoglycemia unawareness, Lactate, high intensity interval exercise, MRS
Brief summary
Iatrogenic hypoglycemia is the most frequent acute complication of insulin therapy in people with type 1 diabetes (T1DM). Recurrent hypoglycemic events initiate a process of habituation, characterized by suppression of hypoglycemic symptoms, eventually leading to hypoglycemia unawareness, which creates a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for (brain) lactate in the pathogenesis of hypoglycemia unawareness. Indeed, exogenous lactate administration may preserve brain function and attenuate counterregulatory responses to and symptomatic awareness of hypoglycemia. It is unknown whether endogenous elevation of plasma lactate produces the same effects and whether such effects differ between patients with T1DM with and without hypoglycemia unawareness and healthy controls. Objective: To investigate the effect of elevated levels of endogenous lactate on brain lactate accumulation and on counterregulatory responses to, symptomatic awareness of and cognitive function during hypoglycemia in patients with T1DM with and without hypoglycemia unawareness and normal controls. Hypothesis: The investigators hypothesize first that endogenous lactate, when raised through high intensity exercise, preserves neuronal metabolism during subsequent hypoglycemia, which in turn will attenuate counterregulatory hormone responses, appearance of symptoms and deterioration of cognitive function. Second, the investigators posit that these effects will be augmented in patients with hypoglycemia unawareness compared to healthy subjects and T1DM patients with normal awareness as a consequence of greater transport capacity of lactate into the brain.
Interventions
BEHAVIORALHigh intensity exercise
3x30 seconds 'all out' sprints
BEHAVIORALLay down comfortably
rest
Sponsors
Dutch Diabetes Research Foundation
European Foundation for the Study of Diabetes
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
for healthy subjects * Age: 18-40 years * Body-Mass Index: 18-30 kg/m2 * Blood pressure: \<160/90 mmHg * Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week. Inclusion criteria T1DM patients with normal hypoglycemic awareness * Diabetes duration ≥ 1 year * Age: 18-40 years * Body-Mass Index: 18-30 kg/m2 * HbA1c: 42-75 mmol/mol (6-9%) * Outcome Clarke questionnaire: 0-1 * Blood pressure: \<160/90 mmHg * Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week Inclusion criteria T1DM patients with hypoglycemia unawareness * Diabetes duration ≥ 1 year * Age: 18-40 years * Body-Mass Index: 18-30 kg/m2 * HbA1c: 42-75 mmol/mol (6-9%) * Outcome Clarke questionnaire: =\>3 * Blood pressure: \<160/90 mmHg * Recreationally active
Exclusion criteria
* Inability to provide informed consent * Presence of any medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event or anxiety disorders * Use of any medication, except for oral contraceptives * MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body) * Orthopedic and/or neurological diseases that impair exercise * Cardiopulmonary disease as stated in the 2001 American heart association and 2002 American college of cardiology/American heart association guidelines Additional
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) | during 60 m of hypoglycemia |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma) | During 60 min hypoglycemia | Levels of counter-regulatory hormones measured in arterial plasma |
| Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values) | During 60 min hypoglycemia | Amount of glucose 20% necessary to maintain plasma glucose at steady state values |
| Plasma lactate levels (Lactate levels measured in arterial plasma) | During 60 min hypoglycemia | Lactate levels measured in arterial plasma |
| Cognitive functioning, as measured by cognitive tests | During 60 min hypoglycemia | Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat |
| Brain perfusion measured with ASL-MRI | During 60 min hypoglycemia | Brain perfusion measured with ASL-MRI |
| Brain lactate accumulation measured with 1H-MRS | During 60 min of hypoglycemia | Brain lactate levels measured with 1H-MRS |
| Plasma levels of inflammatory markers (levels of cytokines) | During 60 min hypoglycemia | levels of cytokines |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma glucose concentration | During 60 min hypoglycemia | Plasma glucose concentration, necessary to adjust glucose infusion rate |
| Plasma insulin concentration (Insulin levels, measured in arterial plasma) | During 60 min hypoglycemia | Insulin levels, measured in arterial plasma |
Countries
Netherlands
Outcome results
None listed