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

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ClinicalTrials.gov Identifier: NCT02308293
Recruitment Status : Completed
First Posted : December 4, 2014
Last Update Posted : November 25, 2016
Sponsor:
Collaborators:
Dutch Diabetes Research Foundation
European Foundation for the Study of Diabetes
Information provided by (Responsible Party):
Radboud University

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.


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Hypoglycemia Unawareness Behavioral: High intensity exercise Behavioral: Lay down comfortably Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: 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
Study Start Date : January 2015
Actual Primary Completion Date : May 2016
Actual Study Completion Date : July 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: High intensity exercise
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
3x30 seconds 'all out' sprints

Sham Comparator: Lay down comfortably
As a control conditions, subjects wil lay down comfortably and rest
Behavioral: Lay down comfortably
rest




Primary Outcome Measures :
  1. Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) [ Time Frame: during 60 m of hypoglycemia ]

Secondary Outcome Measures :
  1. Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma) [ Time Frame: During 60 min hypoglycemia ]
    Levels of counter-regulatory hormones measured in arterial plasma

  2. Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values) [ Time Frame: During 60 min hypoglycemia ]
    Amount of glucose 20% necessary to maintain plasma glucose at steady state values

  3. Plasma lactate levels (Lactate levels measured in arterial plasma) [ Time Frame: During 60 min hypoglycemia ]
    Lactate levels measured in arterial plasma

  4. Cognitive functioning, as measured by cognitive tests [ Time Frame: 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

  5. Plasma levels of inflammatory markers (levels of cytokines) [ Time Frame: During 60 min hypoglycemia ]
    levels of cytokines

  6. Brain perfusion measured with ASL-MRI [ Time Frame: During 60 min hypoglycemia ]
    Brain perfusion measured with ASL-MRI

  7. Brain lactate accumulation measured with 1H-MRS [ Time Frame: During 60 min of hypoglycemia ]
    Brain lactate levels measured with 1H-MRS


Other Outcome Measures:
  1. Plasma glucose concentration [ Time Frame: During 60 min hypoglycemia ]
    Plasma glucose concentration, necessary to adjust glucose infusion rate

  2. Plasma insulin concentration (Insulin levels, measured in arterial plasma) [ Time Frame: During 60 min hypoglycemia ]
    Insulin levels, measured in arterial plasma



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02308293


Locations
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Netherlands
Radboud umc
Nijmegen, Netherlands
Sponsors and Collaborators
Radboud University
Dutch Diabetes Research Foundation
European Foundation for the Study of Diabetes
Investigators
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Principal Investigator: Bastiaan de Galan, Dr. Radboud umc

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02308293     History of Changes
Other Study ID Numbers: End_lac_sympt
First Posted: December 4, 2014    Key Record Dates
Last Update Posted: November 25, 2016
Last Verified: April 2016
Keywords provided by Radboud University:
Type 1 Diabetes Mellitus
Hypoglycemia unawareness
Lactate
high intensity interval exercise
MRS
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Hypoglycemia
Unconsciousness
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms