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The Effect of Hypoglycaemia on Brain Lactate Accumulation and Cerebral Blood Flow

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ClinicalTrials.gov Identifier: NCT02146404
Recruitment Status : Completed
First Posted : May 23, 2014
Last Update Posted : November 10, 2015
Sponsor:
Collaborators:
Dutch Diabetes Research Foundation
European Foundation for the Study of Diabetes
Information provided by (Responsible Party):
Radboud University

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 and lead to hypoglycemia unawareness, which in itself defines a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for increased brain lactate transport capacity in the pathogenesis of hypoglycemia unawareness. However, there is uncertainty about the magnitude of this effect and whether such excess brain lactate is oxidizes as a glucose-sparing alternative energy source or acts as a metabolic regulator controlling brain glucose metabolism, oxygen consumption and cerebral blood flow.

Objective: The primary objective of this study is to investigate the effect of hypoglycemia on brain lactate accumulation and regional cerebral blood perfusion in humans. The secondary objective is to assess whether this effect is a related to hypoglycemia unawareness or a consequence of T1DM per se.

Hypothesis: The investigators hypothesize that hypoglycemia stimulates lactate transport over the blood-brain barrier leading to cerebral lactate accumulation and that this lactate accumulation is a function of prior hypoglycemic exposure frequency contributing to clinical hypoglycemia unawareness. Furthermore, the investigators expect that this effect of hypoglycemia on brain lactate accumulation is related to changes in cerebral blood flow (CBF).


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Hypoglycemia Unawareness Other: hypoglycemia Other: euglycemia Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of Insulin-induced Hypoglycemia on Brain Lactate Accumulation and Regional Cerebral Blood Flow in Patients With Type 1 Diabetes Mellitus With and Without Hypoglycemia Unawareness and Non-diabetic Controls
Study Start Date : August 2014
Actual Primary Completion Date : October 2015
Actual Study Completion Date : October 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Euglycemia
Plasma glucose levels will be clamped at a constant value of ~5.0 mmol/l
Other: euglycemia
Blood glucose levels will be kept at ~5.0 mmol/l
Other Name: Normal blood glucose levels

Experimental: Hypoglycemia
Plasma glucose levels will be clamped at a stable value of ~3.0 mmol/l
Other: hypoglycemia
Blood glucose levels will be kept at ~3.0 mmol/l
Other Name: Low blood glucose levels




Primary Outcome Measures :
  1. Brain lactate concentration [ Time Frame: during stable euglycemia and hypoglyemia ]
    Concentration brain lactate measured with 1H-MRS


Secondary Outcome Measures :
  1. Plasma lactate levels [ Time Frame: during stable euglycemia and hypoglyemia ]
    Concentration arterial plasma lactate

  2. Hormone response [ Time Frame: during stable euglycemia and hypoglyemia ]


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria for healthy subjects

  • Age: 18-50 years
  • Body-Mass Index: 18-30 kg/m2
  • Blood pressure: <160/90 mmHg

Inclusion criteria T1DM patients with normal hypoglycemic awareness

  • Diabetes duration ≥ 1 year
  • Age: 18-50 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

Inclusion criteria T1DM patients with hypoglycemia unawareness

  • Diabetes duration ≥ 1 year
  • Age: 18-50 years
  • Body-Mass Index: 18-30 kg/m2
  • HbA1c: 42-75 mmol/mol (6-9%)
  • Outcome Clarke questionnaire: >3
  • Blood pressure: <160/90 mmHg

Exclusion criteria for healthy subjects

  • 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)

Exclusion criteria for all T1DM patients

  • Inability to provide informed consent
  • Presence of any other medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event, anxiety disorders, or complications of T1DM (including neuropathy and retinopathy)
  • Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy
  • MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02146404


Locations
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Netherlands
Radboud umc
Nijmegen, Netherlands
Sponsors and Collaborators
Radboud University
Dutch Diabetes Research Foundation
European Foundation for the Study of Diabetes
Investigators
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Principal Investigator: Bastiaan de Galan, Dr. Radboud UMC
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02146404    
Other Study ID Numbers: 1H_lac_acc
First Posted: May 23, 2014    Key Record Dates
Last Update Posted: November 10, 2015
Last Verified: November 2015
Keywords provided by Radboud University:
Type 1 Diabetes Mellitus
Hypoglycemia unawareness
1H MRS
Lactate
Additional relevant MeSH terms:
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Unconsciousness
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases