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Type 1 Diabetes MellitusNCT02308293

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

A study testing High intensity exercise and Lay down comfortably in people with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness, run by Radboud University Medical Center at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 40 yearsHealthy volunteers can take part
What is being tested?
High intensity exercise and Lay down comfortably
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
30 participants
Where
1 siteNetherlands
Study dates
Jan 2015to Jul 2016
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
Show all 9Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Radboud umc

    Nijmegen

Other trials in Netherlands

About this study

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

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.

Being tested
High intensity exercise, Lay down comfortably
Keywords
Type 1 Diabetes Mellitus, Hypoglycemia unawareness, Lactate, high intensity interval exercise, MRS
Medical subject headings
Diabetes Mellitus, Type 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • High intensity exerciseBehavioural

    3x30 seconds 'all out' sprints

  • Lay down comfortablyBehavioural

    rest

Study groups in NCT02308293
Study groupRoleWhat they receive
High intensity exerciseExperimentalSubjects will preform a high intensity training exercise (3* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels
Receives: Behavioral: High intensity exercise
Lay down comfortablySham comparatorAs a control conditions, subjects wil lay down comfortably and rest
Receives: Behavioral: Lay down comfortably

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: during 60 m of hypoglycemia

Secondary outcomes (7)

  1. 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

    Measured: During 60 min hypoglycemia

  2. 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

    Measured: During 60 min hypoglycemia

  3. Plasma lactate levels (Lactate levels measured in arterial plasma)

    Lactate levels measured in arterial plasma

    Measured: During 60 min hypoglycemia

  4. 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

    Measured: During 60 min hypoglycemia

  5. Plasma levels of inflammatory markers (levels of cytokines)

    levels of cytokines

    Measured: During 60 min hypoglycemia

  6. Brain perfusion measured with ASL-MRI

    Brain perfusion measured with ASL-MRI

    Measured: During 60 min hypoglycemia

  7. Brain lactate accumulation measured with 1H-MRS

    Brain lactate levels measured with 1H-MRS

    Measured: During 60 min of hypoglycemia

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Dec 2014 (estimated)
  2. Study startJan 2015
  3. Primary completionMay 2016
  4. Study completionJul 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02308293
Sponsor's protocol ID
End_lac_sympt
Status last verified
Apr 2016
First submitted
14 Nov 2014
Last updated
25 Nov 2016
Results posted
No
Data monitoring committee
No

Publications

  • van de Ven KC, van der Graaf M, Tack CJ, Klomp DW, Heerschap A, de Galan BE. Optimized [1-(13)C]glucose infusion protocol for 13C magnetic resonance spectroscopy at 3T of human brain glucose metabolism under euglycemic and hypoglycemic conditions. J Neurosci Methods. 2010 Jan 30;186(1):68-71. doi: 10.1016/j.jneumeth.2009.10.025. Epub 2009 Nov 11.

    PubMed 19913052

  • van de Ven KC, de Galan BE, van der Graaf M, Shestov AA, Henry PG, Tack CJ, Heerschap A. Effect of acute hypoglycemia on human cerebral glucose metabolism measured by (1)(3)C magnetic resonance spectroscopy. Diabetes. 2011 May;60(5):1467-73. doi: 10.2337/db10-1592. Epub 2011 Apr 4.

    PubMed 21464446

  • van de Ven KC, van der Graaf M, Tack CJ, Heerschap A, de Galan BE. Steady-state brain glucose concentrations during hypoglycemia in healthy humans and patients with type 1 diabetes. Diabetes. 2012 Aug;61(8):1974-7. doi: 10.2337/db11-1778. Epub 2012 Jun 11.

    PubMed 22688331

  • De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.

    PubMed 23715622

  • Maddock RJ, Casazza GA, Buonocore MH, Tanase C. Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): a dynamic 1H-MRS study. Neuroimage. 2011 Aug 15;57(4):1324-30. doi: 10.1016/j.neuroimage.2011.05.048. Epub 2011 May 27.

    PubMed 21640838

  • Wiegers EC, Rooijackers HM, van Asten JJA, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. Diabetologia. 2019 Jun;62(6):1065-1073. doi: 10.1007/s00125-019-4862-9. Epub 2019 Apr 19.

    PubMed 31001674

  • Wiegers EC, Rooijackers HM, Tack CJ, Groenewoud HJMM, Heerschap A, de Galan BE, van der Graaf M. Effect of Exercise-Induced Lactate Elevation on Brain Lactate Levels During Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2017 Dec;66(12):3105-3110. doi: 10.2337/db17-0794. Epub 2017 Sep 21.

    PubMed 28935628

  • Rooijackers HM, Wiegers EC, van der Graaf M, Thijssen DH, Kessels RPC, Tack CJ, de Galan BE. A Single Bout of High-Intensity Interval Training Reduces Awareness of Subsequent Hypoglycemia in Patients With Type 1 Diabetes. Diabetes. 2017 Jul;66(7):1990-1998. doi: 10.2337/db16-1535. Epub 2017 Apr 18.

    PubMed 28420673

Questions about this trial

What is this clinical trial studying?

A study testing High intensity exercise and Lay down comfortably in people with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness, run by Radboud University Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Nov 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma) (time frame: during 60 m of hypoglycemia). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02308293, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Nov 2016.

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