The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia

Study Overview
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Brief Summary
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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.

Official Title
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The Effect of Exercise-induced Hyperlacticacidemia on Counterregulatory Responses, Symptoms, Cognitive Function and Brain Lactate Accumulation During Hypoglycemia in (Hypoglycemic Unaware)Type I Diabetes Patients and Normal Controls

Conditions
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Type 1 Diabetes Mellitus, Hypoglycemia Unawareness

Intervention / Treatment
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* Behavioral: High intensity exercise
* Behavioral: Lay down comfortably


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria for all T1DM patients: Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy complications of T1DM, including proliferative retinopathy, neuropathy or nephropathy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High intensity exercise<br>Subjects will preform a high intensity training exercise (3* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels | Behavioral: High intensity exercise<br>* 3x30 seconds 'all out' sprints<br>|
| Sham Comparator: Lay down comfortably<br>As a control conditions, subjects wil lay down comfortably and rest | Behavioral: Lay down comfortably<br>* rest<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) |  | during 60 m of hypoglycemia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma) | Levels of counter-regulatory hormones measured in arterial plasma | During 60 min hypoglycemia | 
| Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values) | Amount of glucose 20% necessary to maintain plasma glucose at steady state values | During 60 min hypoglycemia | 
| Plasma lactate levels (Lactate levels measured in arterial plasma) | Lactate levels measured in arterial plasma | During 60 min hypoglycemia | 
| Cognitive functioning, as measured by cognitive tests | Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat | During 60 min hypoglycemia | 
| Plasma levels of inflammatory markers (levels of cytokines) | levels of cytokines | During 60 min hypoglycemia | 
| Brain perfusion measured with ASL-MRI | Brain perfusion measured with ASL-MRI | During 60 min hypoglycemia | 
| Brain lactate accumulation measured with 1H-MRS | Brain lactate levels measured with 1H-MRS | During 60 min of hypoglycemia | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRS, Type 1 Diabetes Mellitus, Hypoglycemia unawareness, Lactate, high intensity interval exercise