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

Primary Purpose

Type 1 Diabetes Mellitus, Hypoglycemia Unawareness

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
High intensity exercise
Lay down comfortably
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Type 1 Diabetes Mellitus focused on measuring Type 1 Diabetes Mellitus, Hypoglycemia unawareness, Lactate, high intensity interval exercise, MRS

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Radboud umc

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

High intensity exercise

Lay down comfortably

Arm Description

Subjects will preform a high intensity training exercise (3* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels

As a control conditions, subjects wil lay down comfortably and rest

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
Plasma lactate levels (Lactate levels measured in arterial plasma)
Lactate levels measured in arterial plasma
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
Plasma levels of inflammatory markers (levels of cytokines)
levels of cytokines
Brain perfusion measured with ASL-MRI
Brain perfusion measured with ASL-MRI
Brain lactate accumulation measured with 1H-MRS
Brain lactate levels measured with 1H-MRS

Full Information

First Posted
November 14, 2014
Last Updated
November 23, 2016
Sponsor
Radboud University Medical Center
Collaborators
Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes
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1. Study Identification

Unique Protocol Identification Number
NCT02308293
Brief Title
The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia
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 Type
Interventional

2. Study Status

Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
July 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus, Hypoglycemia Unawareness
Keywords
Type 1 Diabetes Mellitus, Hypoglycemia unawareness, Lactate, high intensity interval exercise, MRS

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
High intensity exercise
Arm Type
Experimental
Arm Description
Subjects will preform a high intensity training exercise (3* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels
Arm Title
Lay down comfortably
Arm Type
Sham Comparator
Arm Description
As a control conditions, subjects wil lay down comfortably and rest
Intervention Type
Behavioral
Intervention Name(s)
High intensity exercise
Intervention Description
3x30 seconds 'all out' sprints
Intervention Type
Behavioral
Intervention Name(s)
Lay down comfortably
Intervention Description
rest
Primary Outcome Measure Information:
Title
Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)
Time Frame
during 60 m of hypoglycemia
Secondary Outcome Measure Information:
Title
Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma)
Description
Levels of counter-regulatory hormones measured in arterial plasma
Time Frame
During 60 min hypoglycemia
Title
Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values)
Description
Amount of glucose 20% necessary to maintain plasma glucose at steady state values
Time Frame
During 60 min hypoglycemia
Title
Plasma lactate levels (Lactate levels measured in arterial plasma)
Description
Lactate levels measured in arterial plasma
Time Frame
During 60 min hypoglycemia
Title
Cognitive functioning, as measured by cognitive tests
Description
Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat
Time Frame
During 60 min hypoglycemia
Title
Plasma levels of inflammatory markers (levels of cytokines)
Description
levels of cytokines
Time Frame
During 60 min hypoglycemia
Title
Brain perfusion measured with ASL-MRI
Description
Brain perfusion measured with ASL-MRI
Time Frame
During 60 min hypoglycemia
Title
Brain lactate accumulation measured with 1H-MRS
Description
Brain lactate levels measured with 1H-MRS
Time Frame
During 60 min of hypoglycemia
Other Pre-specified Outcome Measures:
Title
Plasma glucose concentration
Description
Plasma glucose concentration, necessary to adjust glucose infusion rate
Time Frame
During 60 min hypoglycemia
Title
Plasma insulin concentration (Insulin levels, measured in arterial plasma)
Description
Insulin levels, measured in arterial plasma
Time Frame
During 60 min hypoglycemia

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bastiaan de Galan, Dr.
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Radboud umc
City
Nijmegen
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
19913052
Citation
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.
Results Reference
background
PubMed Identifier
21464446
Citation
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.
Results Reference
background
PubMed Identifier
22688331
Citation
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.
Results Reference
background
PubMed Identifier
23715622
Citation
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.
Results Reference
background
PubMed Identifier
21640838
Citation
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.
Results Reference
background
PubMed Identifier
31001674
Citation
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.
Results Reference
derived
PubMed Identifier
28935628
Citation
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.
Results Reference
derived
PubMed Identifier
28420673
Citation
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.
Results Reference
derived

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

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