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Completed

NCT Number: NCT02308293

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

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.

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Key information

Age range

18 year–40 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Radboud umc

Nijmegen, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

High intensity exercise

Behavioral

3x30 seconds 'all out' sprints

Lay down comfortably

Behavioral

rest

Primary outcomes

  1. Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)

    Time frame: during 60 m of hypoglycemia

Secondary outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Collaborators

  • Dutch Diabetes Research Foundation
  • European Foundation for the Study of Diabetes

Registry information

Official study 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

Important dates

Study start
2015
Primary completion
2016
Study completion
2016
First posted
Dec 4, 2014
Registry last updated
Nov 25, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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