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

Type 1 Diabetes Mellitus Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02308293
• Other study ID #: End_lac_sympt
• Status: Completed
• Phase: N/A
• First received: November 14, 2014
• Last updated: November 23, 2016
• Start date: January 2015
• Est. completion date: July 2016

Study information

• Verified date: April 2016
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hypoglycemia
• Hypoglycemia Unawareness
• Type 1 Diabetes Mellitus
• Unconsciousness

Intervention

Behavioral:
• High intensity exercise
3x30 seconds 'all out' sprints
• Lay down comfortably
rest

Locations

Country	Name	City	State
Netherlands	Radboud umc	Nijmegen

Sponsors (3)

Lead Sponsor	Collaborator
Radboud University	Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes

Country where clinical trial is conducted

Netherlands, 

References & Publications (5)

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. — View 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. — View 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 ¹³C magnetic resonance spectroscopy. Diabetes. 2011 May;60(5):1467-73. doi: 10.2337/db10-1592. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Plasma glucose concentration	Plasma glucose concentration, necessary to adjust glucose infusion rate	During 60 min hypoglycemia	No
Other	Plasma insulin concentration (Insulin levels, measured in arterial plasma)	Insulin levels, measured in arterial plasma	During 60 min hypoglycemia	No
Primary	Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)		during 60 m of hypoglycemia	No
Secondary	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	During 60 min hypoglycemia	No
Secondary	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	During 60 min hypoglycemia	No
Secondary	Plasma lactate levels (Lactate levels measured in arterial plasma)	Lactate levels measured in arterial plasma	During 60 min hypoglycemia	No
Secondary	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	During 60 min hypoglycemia	No
Secondary	Plasma levels of inflammatory markers (levels of cytokines)	levels of cytokines	During 60 min hypoglycemia	No
Secondary	Brain perfusion measured with ASL-MRI	Brain perfusion measured with ASL-MRI	During 60 min hypoglycemia	No
Secondary	Brain lactate accumulation measured with 1H-MRS	Brain lactate levels measured with 1H-MRS	During 60 min of hypoglycemia	No