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

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT02308293

Collaborator

Dutch Diabetes Research Foundation (Other), European Foundation for the Study of Diabetes (Other)

Enrollment

Location

Arms

Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

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	N/A

Study Design

Study Type:

Interventional

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 :

Jan 1, 2015

Actual Primary Completion Date :

May 1, 2016

Actual Study Completion Date :

Jul 1, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) [during 60 m of hypoglycemia]

Secondary Outcome Measures

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
Plasma levels of inflammatory markers (levels of cytokines) [During 60 min hypoglycemia]
levels of cytokines
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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts 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 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