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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

Tracking Information
First Submitted Date  ICMJE November 14, 2014
First Posted Date  ICMJE December 4, 2014
Last Update Posted Date November 25, 2016
Study Start Date  ICMJE January 2015
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 3, 2014)
Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) [ Time Frame: during 60 m of hypoglycemia ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02308293 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2014)
  • 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
  • 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
  • Plasma lactate levels (Lactate levels measured in arterial plasma) [ Time Frame: During 60 min hypoglycemia ]
    Lactate levels measured in arterial plasma
  • 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
  • Plasma levels of inflammatory markers (levels of cytokines) [ Time Frame: During 60 min hypoglycemia ]
    levels of cytokines
  • Brain perfusion measured with ASL-MRI [ Time Frame: During 60 min hypoglycemia ]
    Brain perfusion measured with ASL-MRI
  • Brain lactate accumulation measured with 1H-MRS [ Time Frame: During 60 min of hypoglycemia ]
    Brain lactate levels measured with 1H-MRS
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 3, 2014)
  • Plasma glucose concentration [ Time Frame: During 60 min hypoglycemia ]
    Plasma glucose concentration, necessary to adjust glucose infusion rate
  • Plasma insulin concentration (Insulin levels, measured in arterial plasma) [ Time Frame: During 60 min hypoglycemia ]
    Insulin levels, measured in arterial plasma
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Type 1 Diabetes Mellitus
  • Hypoglycemia Unawareness
Intervention  ICMJE
  • Behavioral: High intensity exercise
    3x30 seconds 'all out' sprints
  • Behavioral: Lay down comfortably
    rest
Study Arms  ICMJE
  • 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
    Intervention: Behavioral: High intensity exercise
  • Sham Comparator: Lay down comfortably
    As a control conditions, subjects wil lay down comfortably and rest
    Intervention: Behavioral: Lay down comfortably
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 3, 2014)
30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2016
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02308293
Other Study ID Numbers  ICMJE End_lac_sympt
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE
  • Dutch Diabetes Research Foundation
  • European Foundation for the Study of Diabetes
Investigators  ICMJE
Principal Investigator: Bastiaan de Galan, Dr. Radboud umc
PRS Account Radboud University
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP